Fakultas Kedokteran

Universitas Hasanuddin

Cancer Stem Cells (CSCs) in Drug Resistance and their

Therapeutic Implications in Cancer Treatment

Oleh:
Robby Rajatul Aswad
C111 13 036

Pembimbing
dr. Harry Adiwinata

Supervisor
Dr. dr. Prihantono, Sp.B(K)Onk

DIBAWAKAN DALAM RANGKA KEPANITERAAN KLINIK

BAGIAN ILMU BEDAH FAKULTAS KEDOKTERAN
UNVERSITAS HASANUDDIN
2018
 LEMBAR PENGESAHAN

Yang bertanda tangan di bawah ini menyatakan bahwa:

Nama : Robby Rajatul Aswad

NIM : C111 13 036
Judul Jurnal : Cancer Stem Cells (CSCs) pada resistensi obat dan
implikasinya dalam terapi pengobatan kanker

Telah menyelesaikan tugas dalam rangka kepaniteraan klinik pada bagian

Ilmu Bedah Fakultas Kedokteran Universitas Hasanuddin.

Makassar, 28 Desember 2018

Supervisor Pembimbing Residen Pembimbing

Dr. dr. Prihantono, Sp.B(K)Onk. dr. Harry Adiwinata

Hindawi
Stem Cells International
Volume 2018, Article ID 5416923, 16 pages
https://doi.org/10.1155/2018/5416923

Review Article
Cancer Stem Cells (CSCs) in Drug Resistance and
their Therapeutic Implications in Cancer Treatment

Lan Thi Hanh Phi , Ita Novita Sari, Ying-Gui Yang, Sang-Hyun Lee, Nayoung
Jun, Kwang Seock Kim, Yun Kyung Lee , and Hyog Young Kwon
Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea

Correspondence should be addressed to Yun Kyung Lee; yunklee@sch.ac.kr and Hyog Young Kwon; hykwon@sch.ac.kr

Received 28 September 2017; Accepted 11 January 2018; Published 28 February 2018

Academic Editor: Pratima Basak

Copyright © 2018 Lan Thi Hanh Phi et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are suggested to be responsible for drug resistance and
cancer relapse due in part to their ability to self-renew themselves and differentiate into heterogeneous lineages of cancer cells.
Thus, it is important to understand the characteristics and mechanisms by which CSCs display resistance to therapeutic agents.
In this review, we highlight the key features and mechanisms that regulate CSC function in drug resistance as well as recent
breakthroughs of therapeutic approaches for targeting CSCs. This promises new insights of CSCs in drug resistance and
provides better therapeutic rationales to accompany novel anticancer therapeutics.

1. Introduction substances used in treatment, which consequently limits the

Cancer is one of the leading causes of morbidity and mortal-ity
worldwide with about 20% of all deaths in developed countries
[1]. From preclinical and clinical cancer studies, various new
diagnostic and treatment options for cancer patients provide
notable progresses in cancer treatment and prevention [2].
Cancer heterogeneity is one of the reasons contributing to the
treatment failure and disease progression. Among several
cancer treatments, the main treatments that are commonly used
to treat patients are surgery, radiother-apy, and chemotherapy.
Surgery can successfully remove cancer from the body, while
combining radiotherapy with chemotherapy can effectively
give better results for treating many types of cancer [3]. Recent
chemotherapeutic agents are successful against primary tumor
lesions and its residue after surgery or radiotherapy [4].
However, chemotherapy induces tumor heterogeneity derived
from both normal and cancer cells and the heterogeneity within
tumors, in turn, results in reducing effects of chemotherapy;
contributing to the treatment failure and disease progression [5,
6]. Chemoresistance is a major problem in the treatment of
cancer patients, as cancer cells become resistant to chemical
efficiency of chemo agents [7]. It is also often associated
with tumors turning into more aggressive form and/or
metastatic type [8–11].
Accumulating evidences suggest that cancer stem cell
(CSC) population, a subgroup of cancer cells, is responsible
for the chemoresistance and cancer relapse, as it has ability
to self-renew and to differentiate into the heterogeneous
lineages of cancer cells in response to chemotherapeutic
agents [12–14]. CSCs are also able to induce cell cycle
arrest (quiescent state) that support their ability to become
resistant to chemo- and radiotherapy [15–20]. Common
chemother-apeutic agents target the proliferating cells to
lead their apoptosis, as mentioned previously. Although
successful cancer therapy abolishes the bulk of proliferating
tumor cells, a subset of remaining CSCs can survive and
promote cancer relapse due to their ability to establish
higher inva-siveness and chemoresistance [21, 22].
Understanding the features of CSCs is important to
establish the foundation for new era in treatment of cancer.
In this review, we address the detailed mechanisms by
which CSCs display the resistance to chemo- and
radiotherapy and their impli-cation for clinical trials.
2 Stem Cells International

Self-renewal

Stem cells
Mutation,
oncogenic activation
Differentiation

Dedifferentiation

CSC Dedifferentiation
Self-renewal

Differentiation

Bulk tumor ablation

Self-renewal
inhibition

Apoptosis/
cell cycle arrest

Figure 1: The origin of CSCs and combinational therapy of CSC targeting and bulk tumor ablation. CSCs could possibly have originated from
either stem cells with mutation/oncogenic transformation, progenitors that have undergone mutation, or from differentiated cells or cancer cells
that obtained stem-like properties by dedifferentiation. Thus, because of the plasticity of CSCs, it is suggested that combinational therapy of CSC
targeting and bulk tumor ablation may have better therapeutic effects to improve the clinical outcomes of cancer patients.

A. The Origin and Surface Markers of
Cancer Stem Cells (CSCs)
Cancer stem cells (CSCs), also known as tumor-initiating cells
(TICs), have been intensively studied in the past decade,
focusing on the possible source, origin, cellular markers,
mechanism study, and development of therapeutic strategy
targeting their pathway [23, 24]. The first convincing evi-dence
of CSCs was reported by Bonnet and Dick in 1997 by the
identification of a subpopulation of leukemia cells expressing
surface marker CD34, but not CD38. CD34+/ CD38−
subpopulation was capable of initiating tumor growth in the
NOD/SCID recipient mice after transplantation [25]. In
addition to blood cancer, CSCs have been identified in several
kinds of solid tumor [21, 26]. The first evidence of
the presence of CSCs in solid cancer in vivo was found and
identified as CD44+CD24-/lowLineage− cells in immunocom-
promised mice after transplanting human breast cancer cells
in 2003 [27] even though it has been indicated in vitro in
2002 by the discovery of clonogenic (sphere-forming) cells
isolated from human brain gliomas [28]. Over time, CSC
population was also identified from several other solid can-
cers including melanoma, brain, lung, liver, pancreas,
colon, breast cancer, as well as ovarian cancer [27, 29–35].
Although CSC model explains the heterogeneity of
cancers in terms of hierarchical structure and progression
mode, the origins of CSCs are currently unclear and con-
troversial [36, 37]. Accumulating hypotheses suggest that
depending on the tumor type, CSCs might be derived from
either adult stem cells, adult progenitor cells that have
undergone mutation, or from differentiated cells/can-cer
cells that obtained stem-like properties through dedif-
ferentiation [25, 38–50]. Because of the plasticity of CSCs,
it has been suggested that the combinational ther-apy of
targeting CSC pathways and conventional chemo-
therapeutics might have better therapeutic effect, which will
be explained later in detail (Figure 1). Early studies in AML
demonstrated that normal primitive cells, but not committed
progenitor cells, are targets for leukemic transformation
[25]. Similarly, it has been indicated that deletion of Apc in
Lgr5+ (leucine-rich-repeat containing G-protein coupled
receptor 5) long-lived intestinal stem cells, rather than
short-lived transit-amplifying cells, could lead to their
transformation, showing that stem cells are the cells-of-
origin in intestinal cancer [42]. Moreover, long-term culture
can also induce telomerase-transduced adult human
mesenchymal stem cells (hMSCs) to undergo spontaneous
transformation, showing that these cells are also the origin
of CSCs [43, 44]. Interestingly, CSCs originate from the
transformation of not only their tissue-specific stem cells
but also other tissue stem cells. For instance, bone marrow-
derived cells (BMDCs) may be an essential
Stem Cells International 3

Table 1: Cancer stem cell markers in human.

Tumor type Cancer stem cell markers Reference

+ + + +
Lung cancer CD133 , CD44 , ABCG2, ALDH, CD87 , SP, CD90 [215–217]
+ + + + +
Colon cancer CD133 , CD44 , CD24 , CD166 , EpCAM , ALDH, ESA [218, 219]
+ + + + +
Liver cancer CD133 , CD44 , CD49f , CD90 , ALDH, ABCG2, CD24 , ESA [51, 219]
+ + − +
CD133 , CD44 , CD24 , EpCAM , ALDH-1
Breast cancer [51, 218]
+ + +
Gastric cancer CD133 , CD44 , CD24 [215, 220–222]
CD34 , CD38−, CD123
+ +
Leukemia (AML) [216, 218, 223]
+ +
Prostate cancer CD133 , CD44 , α2β1, ABCG2, ALDH [51, 215, 223]
+, + + +
Pancreatic cancer CD133 CD44 , CD24 , ABCG2, ALDH, EpCAM , ESA [195, 215, 218]
+ +
Melanoma ABCB5 , CD20 [51, 217]
+ + +
Head and neck cancer SSEA-1 , CD44 , CD133 [224–226]

source of many tumor types, such as gastric cancer, neural
tumors, and even teratoma [45].
CSCs also have been demonstrated to be generated by
dedifferentiation from progenitor cells or differentiated cells
which have acquired “stemness” properties as a result of the
accumulation of extra genetic or epigenetic abnor-malities
[46]. For example, BCR-ABL fusion protein is present in
hematopoietic stem cell- (HSC-) like CML cells but
granulocyte-macrophage progenitors are found to be a
candidate of the advanced-stage LSCs during blast crisis in
blast-crisis CML by activating the self-renewal process via
β-catenin pathway [47]. In addition, it has been shown that
oncogenic Hh signaling can promote medulloblas-toma
from either lineage-restricted granule cell progenitors or
stem cells [48, 49]. Besides, most differentiated cells in the
CNS, including terminally differentiated neurons and
astrocytes, can acquire defined genetic alterations to dedif-
ferentiate into NSC or progenitor state and consequently
induce and maintain malignant gliomas [50].
Of note, CSCs can be identified by specific markers of
normal stem cells which are commonly used for isolating
CSCs from solid and hematological tumors [51]. Several cell
surface markers have been verified to identify CSC-enriched
populations, such as CD133, CD24, CD44, EpCAM (epithelial
cell adhesion molecule), THY1, ABCB5 (ATP-binding cassette
B5), and CD200 [27, 32, 34, 52]. Additionally, certain
intracellular proteins also have been used as CSCs markers,
such as aldehyde dehydrogenase 1 (ALDH1) which is used to
characterize CSCs in many types of cancer such as leukemia,
breast, colon, liver, lung, pancreas, and so forth [12, 53]. The
usage of cell surface markers as CSC markers might differ
from each cancer types depending on their characteristics and
phenotypes. The surface markers that are frequently used to
isolate CSCs from each cancer types are listed in Table 1.
 The Mechanisms by Which CSCs
Contribute to the Resistance against
Chemotherapy and Cancer Relapse
Recent studies suggest that CSCs are enriched after chemo-
therapy because a small subpopulation of cells remaining in
tumor tissue, so-called CSCs, can survive and expand though
most chemotherapeutic agents kill bulk of tumors [12–14]. For
instance, preleukemic DNMT3Amut HSCs which can initiate
clonal expansion as the first step in leukemogenesis and
regenerate the entire hematopoietic hierarchy were found to
survive and expand in the bone marrow remission after
chemotherapy [54]. Similarly, exposure to therapeutic doses of
temozolomide (TMZ), the most commonly used antiglioma
chemotherapy, consistently expands the glioma stem cell
(GSC) pool over time in both patient-derived and established
glioma cell lines, which has been shown to be a result of
phenotypic and functional interconversion between
differentiated tumor cells and GSCs [55]. Moreover, the
humanized VEGF antibody bevacizumab reduces glioblas-
toma multiforme (GBM) tumor growth but followed by tumor
recurrence, possibly due to the ongoing autocrine sig-naling
through the VEGF-VEGFR2–Neuropilin-1 (NRP1) axis,
which is associated with the enrichment of active VEGFR2
GSC subset in human GBM cells [56]. The gefitinib-resistant
subline HCC827-GR-highs established by high-concentration
method also acquire both the EMT and stem cell-like features
but do not show any EGFR-mutant– specific protein
production or further increase in the number of either mutant
allele or EGFR copy [57]. Therefore, by understanding the
mechanisms and oncogenic drivers by which the CSCs escape
the radio- and chemotherapy, we can develop more effective
treatments that could improve the clinical outcomes of cancer
patients. The mechanisms by which CSCs contribute to the
chemoresistance includ-ing EMT, MDR, dormancy, tumor
environment, and so forth are mentioned below in detail and
summarized in Figure 2.
3.1. Epithelial Mesenchymal Transition (EMT). It has been
indicated that epithelial mesenchymal transition (EMT)
markers and stem cell markers are coexpressed in circulating
tumor cells from patients with metastasis [58] and EMT
induction or activation of EMT transcription factors (TFs)
confers stem-like features in cancer cells [59]. In particular,
normal and neoplastic human breast stem-like cells express
similar markers with cells that have undergone EMT, and EMT
induces the generation of relatively unlimited numbers of
cancer stem cells from more differentiated neoplastic cells
4 Stem Cells International

Tumor environment
(i) Hypoxia
(ii) Autophagy
(iii) Cancer-associated fi
broblasts (CAFs) G0 G1/S
(iv) Inflammation G2/M
Self-renewal
(v) Immune cells Quiescent CSCs
ability

Signaling pathways Epigenetic mechanisms

(i) Wntpathways (i) Histone modifications
(ii) Notch pathways (ii) DNA methylation
(iii) Hedgehog pathways CSCs

Resistant to DNA damage-

induced cell death
(i) Enhancing ROS scavenging
(ii) Promoting the DNA repair capability
(iii) Activating the anti-apoptotic signaling
pathways
Undergo EMT
EMT induction or activation of
EMT-transcription factors
Higher expression of multidrug resistance
(MDR) or detoxification proteins
(i) Drug-transporter proteins: ABCG1, ABCB1
(ii) Aldehyde dehydrogenase (ALDH)
MRP

Figure 2: Key signaling pathways and modifications of CSCs contributing to the resistance against chemotherapeutics. In order to survive
during and after therapy, CSCs display many responses including EMT, self-renewal, tumor environment, quiescence, epigenetic
modification, MDR, and so forth. The mechanisms by which CSCs contribute to resistance against therapeutics are summarized.

[60]. Meanwhile, there is an association between EMT activa-
tion and drug resistance [61]. For instance, gefitinib-induced
resistant lung cancer cells acquire EMT phenotype [62]
through activation of Notch-1 signaling [63]. Moreover,
enhanced invasive potential, tumorigenicity, and expression of
EMT markers could be used to predict the resistance of anti-
EGFR antibody cetuximab in the cells [64]. In parallel,
compared with epithelial cell lines, the mesenchymal cells
have increased expression of genes involved in metastasis and
invasion and are significantly less susceptible to EGFR
inhibition, including erlotinib, gefitinib, and cetuximab; at least
partly via integrin-linked kinase (ILK) overexpression in
mesenchymal cells [65]. Besides, EMT mediator S100A4 has
been shown to involve in maintaining the stemness properties
and tumorigenicity of CSCs in head and neck can-cer [66].
Therefore, EMT induces the cancer cells to exhibit stem cell-
like characteristics which promote cells to invade surrounding
tissues and display therapeutic resistance [67]. Interestingly,
ZEB1, a regulator of EMT, plays an important role in key
features of cancer stem cells including the regulation of
stemness and chemoresistance induction through
transcriptional regulation of O-6-Methylguanine DNA
Methyltransferase (MGMT) via miR-200c and c-MYB in
malignant glioma [68]. Apart from EMT, the high expression
of stem cell markers such as Oct4, Nanog, Sox2, Musashi, and
Lgr5 has been considered to confer chemore-sistance as well
[69–73].
3.2. High Levels of Multidrug Resistance (MDR) or
Detoxification Proteins. Side population (SP) cells, which
exhibit a cancer stem cell-like phenotype, are detected in a
variety of different solid tumors such as retinoblastoma, neu-
roblastoma, gastrointestinal cancer, breast cancer, lung can-cer,
and glioblastoma; their high expression of drug-transporter
proteins (including MDR1, ABCG2, and ABCB1) not only
acts to exclude Hoechst dye but also expels cytotoxic drugs,
leading to high resistance to chemothera-peutic agents with
better cell survival and disease relapse [74–76]. Alisi et al.
suggest that the overexpression of ABC protein is probably the
most important protective mecha-nism for CSCs in response to
chemotherapeutic agents
[77]. Interestingly, it has been demonstrated that the PI3K/ Akt
pathway specifically regulates ABCG2 activity via its
localization to the plasma membrane, and loss of PTEN pro-
motes the SP phenotype of human glioma cancer stem-like
cells [78]. Moreover, the activity of aldehyde dehydrogenase
(ALDH), a cytosolic enzyme that is responsible for the oxida-
tion of intracellular aldehydes to protect cells from the poten-
tially toxic effects of elevated levels of reactive oxygen species
(ROS) [79], is high in both normal and patients’ CD34+/
CD38− leukemic stem cells, and thus plays an important role
in resistance to chemotherapy [80]. ALDH activity is a poten-
tial selective marker for cancer stem cells in many different
types of cancer, such as breast cancer [53], bladder cancer [81],
head and neck squamous cell carcinoma [82], lung cancer [83],
and embryonal rhabdomyosarcoma [84]. Inter-estingly, cell
culture model systems and clinical sample stud-ies show that
ALDH1A1-positive cancer stem cells promote significant
resistance to both EGFR-TKI (gefitinib) and other anticancer
chemotherapy drugs (cisplatin, etoposide, and fluorouracil)
than ALDH1A1-negative cells in lung cancer
[85]. In addition, high levels of ALDH1 expression predict
Stem Cells International
a poor response or resistance to preoperative chemoradio-
therapy in resectable esophageal cancer patients [86].
3.3. Dormancy of CSCs. It has been demonstrated that besides
the intratumoral heterogeneity initiated by the evolution of
genetically diverse subclones, there are also functionally dis-
tinct clones, which were found by tracking the progeny of
single cells using lentivirus, within a genetic lineage in colo-
rectal cancers [87]; accordingly, these diversity-generating
processes within a genetic clone promote cells for higher
survival potential, especially during stress such as chemo-
therapy. For example, chemotherapy can induce the tumor
growth of previously relatively dormant or slowly proliferat-
ing lineages that still retain potent tumor propagation potential,
leading to both cancer growth and drug resistance
[87]. Similarly, in glioblastoma multiforme, there is also the
existence of a relatively quiescent subset of endogenous tumor
cells with characteristics similar to cancer stem cells
responsible for maintaining the long-term tumor growth and
therefore leading to recurrence via the production of transient
populations of highly proliferative cells [17]. Con-comitantly,
chemotherapy-induced damages recruit the qui-escent label-
retaining pool of bladder CSCs during the gap periods between
chemotherapy cycles into an unexpected cell division response
to repopulate residual tumors, similar to wound repair
mobilization of tissue resident stem cells [88].
3.4. Resistance to DNA Damage-Induced Cell Death. CSCs
can be resistant to DNA damage-induced cell death through
several ways. These include protection against oxidative DNA
damage by enhanced ROS scavenging, promotion of the DNA
repair capability through ATM and CHK1/CHK2
phosphorylation, or activation of the anti-apoptotic signaling
pathways, such as PI3K/Akt, WNT/b-catenin, and Notch sig-
naling pathways [24]. For instance, CD44, an adhesion mol-
ecule expressed in CSC, interacts with a glutamate-cystine
transporter and controls the intracellular level of reduced
glutathione (GSH); hence, the CSCs expressing a high level of
CD44 showed an enhanced capacity for GSH synthesis,
resulting in stronger defense against ROS [89]. Interestingly,
similar to normal tissue stem cells, CSCs have lower ROS
levels, which is associated with increased expression of free
radical scavenging systems, leading to higher ROS defenses
and radiotherapy resistance as well [90]. In addition,
CD44+/CD24−/low CSC subset in breast cancer is resistant to
radiation via activation of ATM signaling but does not depend
on alteration of nonhomologous end joining (NHEJ) DNA
repair activity [91]. Similarly, CD133-expressing tumor cells
isolated from both human glioma xenografts and pri-mary
patient glioblastoma specimens preferentially activate the
DNA damage checkpoint in response to radiation and repair
radiation-induced DNA damage more effectively than CD133-
negative tumor cells [92]. Notch pathway also pro-motes the
radioresistance of glioma stem cells as the Notch inhibition
with gamma-secretase inhibitors (GSIs) induces the glioma
stem cells to be more sensitive to radi-ation at clinically
relevant doses due to the reduction of radiation-induced
PI3K/Akt activation and upregulated
5
levels of truncated apoptotic isoform of Mcl-1 (Mcl-1s)
while not altering DNA damage response [93].
3.5. Tumor Environment. It has been shown that a distinct
microenvironment of various cellular composition is impor-
tant to protect and regulate normal stem cells. An
equivalent microenvironment was also found in the CSCs
in which CSCs was favorably supported within a histologic
niche, so-called CSC microenvironment [94–96],
containing con-nective stromal [97–101] and vascular
tissues [102–106]. This environment expedites CSC
divisional dynamics, allow-ing them to differentiate
progenitor daughter cells as well as self-renew and maintain
CSCs in the primitive develop-mental state. The cells
within CSC microenvironment are capable of stimulating
signaling pathways [58], such as Notch [102, 107, 108] and
Wnt [109–111] which may facilitate CSCs to metastasize,
evade anoikis, and alter divisional dynamics, achieving
repopulation by symmetric division [109, 112–114].
3.5.1. Hypoxia. Hypoxia and HIF signaling pathway have been
shown to contribute to the regulation and sustenance of CSCs
and EMT phenotype such as cell migration, inva-sion, and
angiogenesis [115], via the increased expression of VEGF, IL-
6, and CSC signature genes such as Nanog, Oct4, and EZH2,
in pancreatic cancer for example [116]. There-fore, hypoxia
and HIF signaling pathway may also play a role in CSC
resistance to therapy. In the hypoxic microenviron-ment,
hypoxia and hypoxia-inducible factor HIF1-α signal-ing
promote CML cell persistence mainly through the upregulation
of hypoxia-inducible factor 1α (HIF1-α), inde-pendent of
BCR-ABL1 kinase activity [117]. Similarly, hypoxia increases
gefitinib-resistant lung CSCs in EGFR mutation-positive
NSCLC by upregulating expression of insulin-like growth
factor 1 (IGF1) through HIF1α and acti-vating IGF1 receptor
(IGF1R) [118]. Interestingly, autophagy is upregulated in the
pancreatic cancer in the microenviron-mental condition of low
oxygen and lack of nutrition, similar with the hypoxic tumor,
and then promotes the clonogenic survival and migration of
pancreatic CSChigh cells [119].
3.5.2. Cancer-Associated Fibroblasts (CAFs). It has been
indi-cated that besides cell autonomous resistance of CSCs,
che-motherapy preferentially targets non-CSCs by the
stimulation of cancer-associated fibroblasts (CAFs) which
creates a chemoresistant niche by increased secretion of
spe-cific cytokines and chemokines, including interleukin-
17A (IL-17A), a CSC maintenance factor by promoting
self-renewal and invasion [120]. It has been shown
previously that CSCs can differentiate into CAF-like cells
(CAFLCs) and hence they are one of the key sources of
CAFs which support the tumor maintenance and survival in
the cancer niche [121]. CAFs are known to secrete many
different growth factors, cytokines, and chemokines,
including hepa-tocyte growth factor (HGF), which activates
the MET recep-tors to protect the CSCs from apoptosis in
response to the cetuximab monotherapy targeting the EGFR
in metastatic colorectal cancer [122].
6 Stem Cells International
3.5.3. Inflammation. In addition, long-term treatment of
breast cancer cells with trastuzumab specifically enriched
CSCs which exhibit EMT phenotypes with higher levels of
secreted cytokines IL-6 compared with parental cells; as a
consequence, these cells develop trastuzumab resistance
mediated by activation of an IL-6-mediated inflammatory
feedback loop to expand the CSC population [123].
Similarly, autocrine TGF-β signaling and IL-8 expression
are also enhanced after chemotherapeutic drug paclitaxel
treatment in triple-negative breast cancer, leading to CSC
population enrichment and tumor recurrence [124].
Furthermore, stroma-secreted chemokine stroma-derived
factor 1a (SDF-1a) and its cognate receptor CXCR4 play an
impor-tant role in the migration of hematopoietic cells to
the bone marrow microenvironment [125, 126], so SDF-
1A/ CXCR4 interaction mediates the resistance of leukemia
cells to chemotherapy-induced apoptosis [127], and thus
CXCR4 inhibition with inhibitors such as AMD3100 can
enhance the sensitivity of leukemic cells to chemotherapy
by disrupting stromal/leukemia cell interactions within the
bone marrow microenvironment by Akt phosphoryla-tion
inhibition and PARP cleavage induction due to borte-zomib
in the presence of bone marrow stromal cells (BMSCs) in
coculture [128]. Moreover, the CSCs from the
chemoresistant tumors have the unique ability to pro-duce a
variety of proinflammatory signals, such as IFN regulatory
factor-5 (IRF5), which acts as a transcription factor specific
for chemoresistant tumors to induce the M-CSF production,
to consequently produce the M2-like immunoregulatory
myeloid cells from CD14+ monocytes, and to promote the
myeloid cell-mediated tumorigenic and stem cell activities
of bulk tumors [129].
3.5.4. Immune Cells. It has been indicated previously that
tumor-associated macrophages (TAMs) can promote
chemoresistance in both myeloma cell lines and primary
myeloma cells from spontaneous or chemotherapeutic drug-
induced apoptosis by directly interacting with malignant
cells within the tumor microenvironment and attenuating
the activation and cleavage of caspase-dependent apoptotic
signaling [130]. Moreover, TAM also directly induces CSC
properties of pancreatic tumor cells by activating signal
transducer and activator of transcription 3 (STAT3) and thus
inhibits the antitumor CD8+ T lympho-cyte responses in the
chemotherapeutic response [131]. Besides, in pancreatic
ductal adenocarcinoma, cancer cells secrete colony-
stimulating factor 1 (CSF1) to attract and stimulate CSF1
receptor- (CSF1R-) expressing TAM to express high levels
of cytidine deaminase (CDA), an intracel-lular enzyme
which catabolizes the bioactive form of gemci-tabine and
therefore protects the cancer cells from the chemotherapy
[132].
3.6. Epigenetics. Besides, CSC-mediated drug resistance is
regulated by epigenetic mechanisms as well, including
histone modifications and DNA methylation. First, DNA
methylation was unchanged during TGF-β-mediated EMT
but other epigenetic changes such as a lysine-specific
deaminase-1- (Lsd1-) dependent global reduction
of the heterochromatin mark H3-lys9 dimethylation
(H3K9Me2), an increase of the euchromatin mark H3-lys4
trimethylation (H3K4Me3) and the transcriptional mark
H3-lys36 trimethylation (H3K36Me3) are found; especially,
H3K4Me3 might contribute to Lsd1-regulated
chemoresistance [133]. In addition, KDM1A, a flavin ade-
nine dinucleotide- (FAD-) dependent lysine-specific
demethylase specifically with monomethyl- and dimethyl-
histone H3 lysine-4 (H3K4) and lysine-9 (H3K9) sub-
strate, is an important regulator of MLL-AF9 leukemia
stem cell (LSC) oncogenic potential by blocking differenti-
ation [134]. Besides, B-cell-specific Moloney murine leuke-
mia virus integration site 1 (BMI1), one of several
epigenetic silencer proteins belonging to Polycomb group
(PcG), is required for self-renewal of both adult stem cells
and many CSCs via various key pathways, such as
anchorage-independent growth, Wnt and Notch pathway
[135]. BMI-1 has been indicated to be involved in the
protection of cancer cells from apoptosis or drug resis-tance
in various types of cancer, including nasopharyngeal
carcinoma [136], melanoma [137], pancreatic adenocarci-
noma [138], ovarian cancer [139], and hepatocellular car-
cinoma [140]. Furthermore, another PcG member EZH2, a
catalytic subunit of polycomb repressor complex 2 (PRC2)
which trimethylates histone H3 at lysine 27 (H3K27me)
and elicits gene silencing, also participates in pancreatic
cancer chemoresistance by silencing p27 tumor suppressor
gene via methylation of histone H3-lysine 27 (H3K27)
[141]. Moreover, EZH2 protects GSCs from radiation-
induced cell death and consequently promotes GSC
survival and radioresistance via upstream regulator mitotic
kinase maternal embryonic leucine-zipper kinase (MELK)
[142]. In addition, EZH2 inhibition sensitizes BRG1 and
EGFR loss-of-function mutant lung tumors to
topoisomerase II (TopoII) inhibitor etoposide with
increased S phase, anaphase bridging, and apoptosis [143].
Interest-ingly, EZH2 and BMI1 are indicated to inversely
correlate with prognosis signature and TP53 mutation in
breast cancer [144].
Second, histone acetylation is involved in the regula-
tion of transcriptional activation and chemoresistance of
CSCs too. Treatment with HDAC inhibitors (HDACi)
effectively targets the quiescent chronic myelogenous leu-
kemia (CML) stem cells which are resistant to tyrosine
kinase inhibitor imatinib mesylate (IM) [145]. Similarly,
pretreatment with HDAC inhibitors may sensitize the
prostate stem-like cells to radiation treatment through
increased DNA damage and reduced clonogenic survival
[146]. Vorinostat, a HDAC inhibitor via inducing ubiqui-
tination and lysosome degradation, downregulates the
expression and signaling of all three receptors EGFR,
ErbB2, and ErbB3 together with reversion of EMT in
EGFR TKI gefitinib-resistant cells and therefore enhances
the antitumor effect of gefitinib in squamous cell carci-noma
of head and neck [147]. Interestingly, NANOG upregulates
histone deacetylases 1 (HDAC1) via binding to the
promoter region and decreasing K14 and K27 his-tone H3
acetylation; as a result, it induces not only the stem-like
features through epigenetic repression of cell
Stem Cells International
cycle inhibitor CDKN2D and CDKN1B but also the
immune resistance and chemoresistance through MCL-1
upregulation by epigenetic silencing of E3 ubiquitin-ligase
TRIM17 and NOXA [148].
Third, many tumor suppressor genes have been shown to
be epigenetically silenced in chemoresistant cancers by DNA
methylation on CpG promoter regions. For instance, tumor
suppressor insulin-like growth factor binding protein-3
(IGFBP-3), which is involved in controlling cell growth,
transformation, and survival, is specifically downregulated
through promoter-hypermethylation and results in acquired
resistance to chemotherapy in many different types of cancer
[149]. In addition, loss of DNA mismatch repair (MMR)
gene hMLH1 via full hypermethylation of the hMLH1 pro-
moter [150] is highly correlated with the ability of arresting
cell death and cell cycle after DNA damage induced by che-
motherapy and poor survival prediction for cancer patients
[151], hence plays a role in drug resistance in ovarian [152]
and breast cancers [153].
3.7. Signaling Pathways of CSC-Driven Chemoresistance. As
mentioned, normal stem cells and CSCs have similar charac-
teristics such as self-renewal and differentiation. They also
share numbers of key signaling pathway to maintain its exis-
tence. For example, Notch signaling was highly expressed in
the hematopoietic tumors such as T-ALL and solid tumors such
as non-small-cell lung carcinoma (NSCLC), breast can-cer,
and glioblastoma [154–156]. Activation of Hedgehog sig-
naling which in normal condition plays important roles in
embryonic development and tissue regeneration also has been
found to be involved in the regulation of various cancer stem
cells, such as pancreatic cancer, leukemias, and basal cell
carcinoma (BCC) [157]. Another signaling pathway such as
WNT, TGFβ, PI3K/Akt, EGFR, and JAK/STAT, as well as
transcriptional regulators including OCT4, Nanog, YAP/ TAZ,
and Myc are also commonly activated in various cancer stem
cells to regulate their self-renewal and differentiation state [21,
158]. CSCs have been indicated to display many
characteristics of embryonic or tissue stem cells and develop-
mental signaling pathways such as Wnt, HH, and Notch that
are highly conserved embryonically and control self-renewal
of stem cells [159]. Therefore, activation of these pathways
may play an important role in the expansion of CSCs and
hence the resistance to therapy [160]. Here, several represen-
tatives are explained.
First, it has been indicated that activation of Wnt/β-catenin
signaling enhances the chemoresistance to IFN-α/5-FU
combination therapy [161]. OV6+ HCC cells, a subpopu-lation
of less differentiated progenitor-like cells in HCC cell lines and
primary HCC tissues, have been shown to be endogenously
active Wnt/β-catenin signaling and resistant to standard
chemotherapy [162]. In addition, in neuroblas-toma,
amplification and upregulation of frizzled-1 Wnt receptor
(FZD1) activate the Wnt/β-catenin pathway in che-moresistant
cancer cells by nuclear β-catenin translocation and
transactivation of Wnt target genes such as multidrug
resistance gene (MDR1), which is known to mediate the
resistance to chemotherapy [163]. Furthermore, c-Kit, a stem
cell factor (SCF) receptor, mediates chemoresistance through
7
activation of Wnt/β-catenin and ATP-binding cassette G2
(ABCG2) pathway in ovarian cancer [164].
Secondly, Hh pathway could regulate autophagy in
CML cells and then inhibition of the Hh pathway and
autophagy simultaneously could sharply reduce cell
viability and signif-icantly induce apoptosis of imatinib-
sensitive or -resistant BCR-ABL+ cells via downregulating
the kinase activity of the BCR-ABL oncoprotein [165].
Concomitantly, the expres-sion of sonic hedgehog (SHH)
and glioma-associated onco-gene homolog 1 (GLI1), the
well-known signaling pathway molecules involved in the
drug resistance, is higher in enriched CD44+/Musashi-1 +
gastric cancer stem cells and consequently enhances the
drug resistance via high drug efflux pump activity [166]. In
glioma, CD133+ CSC popula-tion, which contributes to the
chemoresistance of therapy such as temozolomide (TMZ)
treatment, overexpresses genes involved in Notch and SHH
pathways and activates these pathways [167].
Last but not least, chemotherapy such as oxaliplatin
induces Notch-1 receptor and its downstream target Hes-1
activity by increasing gamma-secretase activity in colon
can-cer cells; hence, inhibition of Notch-1 signaling by
gamma-secretase inhibitors (GSIs) sensitizes colon cancer
cells to chemotherapy [168]. Moreover, Notch signaling
pathway and Notch3 in particular play an essential role in
the regula-tion of CSC maintenance and chemoresistance to
platinum in ovarian cancer therapy [169]. Similarly, the
enrichment of CD133+ cells in lung adenocarcinoma after
cisplatin induction leads to multidrug resistance through
activation of Notch signaling as higher levels of cleaved
Notch1 (NICD1) are detected [170]. Furthermore, it has
been shown that gefitinib-acquired resistant lung
adenocarcinoma cells undergo EMT by activation of Notch-
1 signaling via Notch-1 receptor intracellular domain
(N1IC), the activated form of the Notch-1 receptor [63].
Besides, there are also some molecules which act as the
integration of various pathways involved in the control of stem
cell fate across tissues; for example, CYP26, a primary
retinoid-inactivating enzyme through retinoid and Hedge-hog
pathways, limits the retinoic acid concentration, there-fore
leading to drug resistance in the stem cell niche [171].
4. CSC-Based Therapy
Owing to the ability of CSCs to develop chemo- and radiore-
sistance which play key roles in the malignant progression,
metastasis, and cancer recurrence, it is suggested that target-
ing cancer stem cells offers an ultimate goal to overcome a
poor prognosis, leading to a better patient survival [15, 22].
Selective targeting of CSC signaling networks that are essen-
tial for self-renewal, proliferation, and differentiation to
maintain their stem cell properties provides a new challenge in
the development of cancer treatments [19, 172]. Over the last
decades, it was suggested that the combination of con-
ventional therapy and targeted therapy against CSC-specific
pathways gives rise a better consequence compared to mono-
therapy in removal of both bulk tumor and CSC population
(Figure 1) [19]. Thus, targeting essential pathways in the CSCs
such as Notch, Wnt, and Hedgehog (HH) is being
8 Stem Cells International
developed to block the self-renewal of CSCs [21]. Lately,
some classes of Notch pathway inhibitors have been
reported to enter a clinical trial, accompanied by a
substantial variety of targets, mechanism of action, and
drug classes [19, 21]. The major class of Notch inhibitor is
the γ-secretase inhibi-tors (GSIs). GSI works by inhibiting
the final proteolytic cleavage of Notch receptors, which
results in the release of the active intracellular fragment. It
was the first class of Notch pathway inhibitor that enters a
clinical trial in the can-cer field [159, 173, 174].
HH pathway is shown to be involved in several
essential developmental pathways such as tissue patterning
during embryonic development and the repair of normal
tissues and epithelial-to-mesenchymal transition [175].
Vismode-gib, a drug targeting HH pathway, was approved
by the Euro-pean Medicines Agency (EMA) in 2013 and
the US FDA in 2012 for the therapy of metastatic BCC
patients or locally advanced BCC patients that are not
candidates for surgery or radiotherapy [176, 177].
Targeting Wnt signaling has also shown promising
results related to carcinogenesis, tumor invasiveness, and
metastasis [159]. Wnt3A-neutralizing mAb was shown to
have antiproliferation and proapoptotic effects in prostate
cancer mouse model [178]. And anti-Fz10 radio-labeled
mAb is being evaluated in a phase I trial for the synovial
sarcoma therapy. Vantictumab (OMP-18R5, a mAb that
blocks five Fz receptors such as Fz1, Fz2, Fz5, Fz7, and
Fz8) [179–181] and OMP-54F28 [181] (a mAb that blocks
fusion protein decoy receptor such as truncated Fz8) are
under investigation in phase I studies in advanced-stage
solid tumors [182].
Targeting CSCs through the EMT pathways also provides a
new challenge in the cancer therapy study. This therapy is
developed in order to prevent cancer aggressiveness and
acquired drug resistance of cancer stem cells [183, 184].
Lately, the finding of therapeutic agents to EMT-based CSC
therapy indicated three general target groups [184, 185]. These
include a group involved in the regulation of EMT
extracellular inducer such as TGF-β, EGF, Axl-Gas6 path-
ways, hypoxia, and extracellular matrix components. Another
group is the transcription factors (TFs) that pro-mote EMT
transcriptome including Twist1, Snail1, Zeb1/2, T-box TF
Brachyury as well as its downstream effectors of EMT, such as
E-Cadherin, N-Cadherin, vimentin, and HoxA9. The last one is
targeting regulators of EMT-TFs and epigenetic regulator using
microRNA [184–190].
Accumulating evidence suggests that miRNA and other
groups of long noncoding RNA (lncRNA) play important roles
in the regulation of CSCs properties such as self-renewal,
asymmetric cell division, tumor initiation, drug resistance, and
disease recurrence [186, 187, 189, 191–193].The usage of
miRNA as CSC-based therapeutic agents is reported; for
example, mir-22 that targets TET2 in leukemia (AML and
MDS) and breast cancer [194], Let-7 to target RAS and
HMGA2 in breast cancer [195], mir-128 to target BMI-1 in
brain cancer [191], mir-200 to target ZEB1/ZEB2, BMI-1, and
SUZ12 in breast cancer [189, 196, 197], and some other
miRNA in the colon cancer and prostate cancer have been
reported to reduce cancer malignancy [198–202].
Finally, cancer immunotherapy may be a breakthrough for
targeting specifically CSCs in cancer patients. For cancer
immunotherapy, several effectors, including natural killer (NK)
cells and γδT cells in innate immunity, antibodies in acquired
humoral immunity, CSC-based dendritic cells, and CSC-
primed cytotoxic T lymphocytes (CTLs) in acquired cellular
immunity, which are able to recognize and kill CSCs may be
suitable candidates to improve the efficacy of cancer treatment.
A variety of immunotherapeutic strategies that specifically
target CSCs using these effector cells have been reported. In
addition, identification of specific antigens or genetic
alterations in CSCs plays an important role in finding targets
for immunotherapy. These include CSC markers (ALDH
[203], CD44 [204, 205], CD133 [206], EpCAM [207], and
HER2 [208]), CSC niche interaction (TAM [209]), tumor
microenvironment (immune cells/myeloid-derived suppressor
cells), cytokines (IL1 [210], IL6 [211], and IL8 [212]), and
immune checkpoint (CTLA-4 [213] or PD1/PDL1 [214]).
5. Conclusion
CSCs possess stem cell-like features found in cancer and have
important implications for the chemoresistance and cancer
relapse, a notion that remains somewhat controversial. With a
small subpopulation in the malignant cell pool, the contri-
bution of CSCs is remarkable in cancer therapy, as shown by
intensive studies in recent decades. These cells can be identi-
fied based on the presence of surface biomarkers, enhanced
spheroid or colony formation in vitro and augmented tumor-
initiating potential as well as tumorigenic ability in vivo. They
are resistance to chemotherapy and radiation therapy compared
to bulk tumor cells and hence play a cru-cial role in tumor
recurrence after anticancer therapy. To sur-vive following
cancer treatment, CSCs seem to be able to manifest several
responses such as EMT, induction of signal-ing pathways that
regulate self-renewal or influence tumor environments,
expression of drug transporters or detoxifica-tion proteins, and
so forth to protect them from devastating effects caused by
therapeutic agents. Thus, the development of anticancer
therapeutics that target CSCs is not only limited to the finding
of inhibitor of CSC pathways and cell surface markers but also
to the development of EMT and CSCs microenvironment-
related inhibitors. Though the molecular mechanisms
underlying the resistance of CSCs to chemo-therapy and
radiation still require further studies in order to develop
promising strategies for suppressing tumor relapse and
metastasis, recent technological advances made it easier than
before to find mechanisms contributing to drug resistance.
Also, the recent therapeutic strategy of combining molecules
specifically targeting CSCs with conventional che-
motherapeutic drugs could possibly be a better direction for
anticancer therapy and may therefore achieve better survival
rates of cancer patients (Figure 1) [19]. Besides, as some cell
surface biomarkers and signaling pathways are similar between
CSCs and normal stem cells, it is also essentially required to
develop novel therapeutic agents targeting only CSCs to avoid
off-target effects on noncancerous cells or normal stem cells.
Stem Cells International
Conflicts of Interest
The authors declare no conflict of interest.
Authors’ Contributions
Lan Thi Hanh Phi and Ita Novita Sari contributed equally to
the work.
Acknowledgments
This work was supported by the Soonchunhyang University
Research Fund and Global Research Development Center
(NRF-2016K1A4A3914725).
References
[1] R. Siegel, D. Naishadham, and A. Jemal, “Cancer statistics,
2013,” CA: a Cancer Journal for Clinicians, vol. 63, no. 1,
pp. 11–30, 2013.
[2] D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the
next generation,” Cell, vol. 144, no. 5, pp. 646–674, 2011.
[3] Y. N. You, V. T. Lakhani, and S. A. Wells Jr., “The role of
pro-phylactic surgery in cancer prevention,” World Journal
of Surgery, vol. 31, no. 3, pp. 450–464, 2007.
[4] B. M. Putzer, M. Solanki, and O. Herchenroder, “Advances in
cancer stem cell targeting: how to strike the evil at its root,”
Advanced Drug Delivery Reviews, vol. 120, pp. 89–107, 2017.
[5] Y. A. Luqmani, “Mechanisms of drug resistance in cancer
chemotherapy,” Medical Principles and Practice, vol. 14,
no. 1, pp. 35–48, 2005.
[6] P. A. Reid, P. Wilson, Y. Li, L. G. Marcu, and E. Bezak,
“Current understanding of cancer stem cells: review of their
radiobiology and role in head and neck cancers,” Head &
Neck, vol. 39, no. 9, pp. 1920–1932, 2017.
[7] O. Tredan, C. M. Galmarini, K. Patel, and I. F. Tannock,
“Drug resistance and the solid tumor microenvironment,”
Journal of the National Cancer Institute, vol. 99, no. 19,
pp. 1441–1454, 2007.
[8] D. A. Senthebane, A. Rowe, N. E. Thomford et al., “The
role of tumor microenvironment in chemoresistance: to
survive, keep your enemies closer,” International Journal of
Molecular Sciences, vol. 18, no. 7, 2017.
[9] A. Fesler, S. Guo, H. Liu, N. Wu, and J. Ju, “Overcoming
chemoresistance in cancer stem cells with the help of
microRNAs in colorectal cancer,” Epigenomics, vol. 9, no.
6, pp. 793–796, 2017.
[10] R. Di Fiore, R. Drago-Ferrante, F. Pentimalli et al., “Micro-
RNA-29b-1 impairs in vitro cell proliferation, self‑ renewal
and chemoresistance of human osteosarcoma 3AB-OS cancer
stem cells,” International Journal of Oncology, vol. 45, no. 5,
pp. 2013–2023, 2014.
[11] D. Chen, M. Wu, Y. Li et al., “Targeting BMI1+ cancer stem
cells overcomes chemoresistance and inhibits metastases in
squamous cell carcinoma,” Cell Stem Cell, vol. 20, no. 5,
pp. 621–634.e6, 2017.
[12] J. E. Visvader and G. J. Lindeman, “Cancer stem cells in solid
tumours: accumulating evidence and unresolved questions,”
Nature Reviews Cancer, vol. 8, no. 10, pp. 755–768, 2008.
9
[13] M. R. Alison, S. M. Lim, and L. J. Nicholson, “Cancer stem
cells: problems for therapy?,” The Journal of Pathology, vol.
223, no. 2, pp. 147–161, 2011.
[14] M. Dean, T. Fojo, and S. Bates, “Tumour stem cells and
drug resistance,” Nature Reviews Cancer, vol. 5, no. 4, pp.
275–284, 2005.
[15] A. Singh and J. Settleman, “EMT, cancer stem cells and
drug resistance: an emerging axis of evil in the war on
cancer,” Oncogene, vol. 29, no. 34, pp. 4741–4751, 2010.
[16] M. H. Kiyohara, C. Dillard, J. Tsui et al., “EMP2 is a novel
therapeutic target for endometrial cancer stem cells,” Onco-
gene, vol. 36, no. 42, pp. 5793–5807, 2017.
[17] J. Chen, Y. Li, T. S. Yu et al., “A restricted cell population
propagates glioblastoma growth after chemotherapy,”
Nature, vol. 488, no. 7412, pp. 522–526, 2012.
[18] D. Fang and H. Kitamura, “Cancer stem cells and epithe-
lial–mesenchymal transition in urothelial carcinoma:
possible pathways and potential therapeutic approaches,”
International Journal of Urology, vol. 25, no. 1, pp. 7– 17,
2018.
[19] M. Cojoc, K. Mäbert, M. H. Muders, and A. Dubrovska, “A
role for cancer stem cells in therapy resistance: cellular and
molecular mechanisms,” Seminars in Cancer Biology, vol.
31, pp. 16–27, 2015.
[20] L. I. Shlush, A. Mitchell, L. Heisler et al., “Tracing the
origins of relapse in acute myeloid leukaemia to stem cells,”
Nature, vol. 547, no. 7661, pp. 104–108, 2017.
[21] D. R. Pattabiraman and R. A. Weinberg, “Tackling the cancer
stem cells — what challenges do they pose?,” Nature Reviews
Drug Discovery, vol. 13, no. 7, pp. 497–512, 2014.
[22] Z. J. Yang and R. J. Wechsler-Reya, “Hit ‘em where they
live: targeting the cancer stem cell niche,” Cancer Cell, vol.
11, no. 1, pp. 3–5, 2007.
[23] P. Valent, D. Bonnet, R. de Maria et al., “Cancer stem
cell definitions and terminology: the devil is in the details,”
Nature Reviews Cancer, vol. 12, no. 11,
pp. 767–775, 2012.
[24] C. Peitzsch, I. Kurth, L. Kunz-Schughart, M. Baumann, and
A. Dubrovska, “Discovery of the cancer stem cell related
determinants of radioresistance,” Radiotherapy and Oncol-
ogy, vol. 108, no. 3, pp. 378–387, 2013.
[25] D. Bonnet and J. E. Dick, “Human acute myeloid leukemia
is organized as a hierarchy that originates from a primitive
hematopoietic cell,” Nature Medicine, vol. 3, no. 7, pp.
730– 7, 1997.
[26] S. A. Joosse and K. Pantel, “Biologic challenges in the
detec-tion of circulating tumor cells,” Cancer Research, vol.
73, no. 1, pp. 8–11, 2013.
[27] M. Al-Hajj, M. S. Wicha, A. Benito-Hernandez, S. J.
Morrison, and M. F. Clarke, “Prospective identification of
tumorigenic breast cancer cells,” Proceedings of the
National Academy of Sciences of the United States of
Amer-ica, vol. 100, no. 7, pp. 3983–3988, 2003.
[28] T. N. Ignatova, V. G. Kukekov, E. D. Laywell, O. N. Suslov, F.
D. Vrionis, and D. A. Steindler, “Human cortical glial tumors
contain neural stem-like cells expressing astroglial and
neuronal markers in vitro,” Glia, vol. 39, no. 3,
pp. 193–206, 2002.
[29] T. Schatton, G. F. Murphy, N. Y. Frank et al., “Identification
of cells initiating human melanomas,” Nature, vol. 451, no.
7176, pp. 345–349, 2008.
10
[30] S. K. Singh, I. D. Clarke, M. Terasaki et al., “Identification
of a cancer stem cell in human brain tumors,” Cancer
Research, vol. 63, no. 18, pp. 5821–5828, 2003.
[31] A. Eramo, F. Lotti, G. Sette et al., “Identification and expan-
sion of the tumorigenic lung cancer stem cell population,” Cell
Death & Differentiation, vol. 15, no. 3, pp. 504–514, 2008.
[32] Z. F. Yang, D. W. Ho, M. N. Ng et al., “Significance of
+ can be initiated by deletion of Patched in lineage-restricted
CD90 cancer stem cells in human liver cancer,” Cancer
Cell, vol. 13, no. 2, pp. 153–166, 2008.
[33] C. Li, D. G. Heidt, P. Dalerba et al., “Identification of pancre-
atic cancer stem cells,” Cancer Research, vol. 67, no. 3,
pp. 1030–1037, 2007.
[34] C. A. O’Brien, A. Pollett, S. Gallinger, and J. E. Dick, “A
human colon cancer cell capable of initiating tumour growth in
immunodeficient mice,” Nature, vol. 445, no. 7123,
pp. 106–110, 2007.
[35] S. Zhang, C. Balch, M. W. Chan et al., “Identification and
characterization of ovarian cancer-initiating cells from pri-
mary human tumors,” Cancer Research, vol. 68, no. 11,
pp. 4311–4320, 2008.
[36] T. B. Brunner, L. A. Kunz-Schughart, P. Grosse-Gehling,
and M. Baumann, “Cancer stem cells as a predictive factor
in radiotherapy,” Seminars in Radiation Oncology, vol. 22,
no. 2, pp. 151–174, 2012.
[37] P. Dalerba, R. W. Cho, and M. F. Clarke, “Cancer stem
cells: models and concepts,” Annual Review of Medicine,
vol. 58, no. 1, pp. 267–284, 2007.
[38] M. López-Lázaro, “The migration ability of stem cells can
explain the existence of cancer of unknown primary site.
Rethinking metastasis,” Oncoscience, vol. 2, no. 5, pp. 467–
475, 2015.
[39] M. Lopez-Lazaro, “Stem cell division theory of cancer,”
Cell Cycle, vol. 14, no. 16, pp. 2547-2548, 2015.
[40] Y. Wang, J. Yang, H. Zheng et al., “Expression of mutant p53
proteins implicates a lineage relationship between neural stem
cells and malignant astrocytic glioma in a murine model,”
Cancer Cell, vol. 15, no. 6, pp. 514–526, 2009.
[41] M. Nouri, J. Caradec, A. A. Lubik et al., “Therapy-induced
developmental reprogramming of prostate cancer cells and
acquired therapy resistance,” Oncotarget, vol. 8, no. 12,
pp. 18949–18967, 2017.
[42] N. Barker, R. A. Ridgway, J. H. van Es et al., “Crypt stem
cells as the cells-of-origin of intestinal cancer,” Nature, vol.
457, no. 7229, pp. 608–611, 2009.
[43] D. Rubio, J. Garcia-Castro, M. C. Martín et al.,
“Spontaneous human adult stem cell transformation,”
Cancer Research, vol. 65, no. 8, pp. 3035–3039, 2005.
[44] J. S. Burns, B. M. Abdallah, P. Guldberg, J. Rygaard, H. D.
Schrøder, and M. Kassem, “Tumorigenic heterogeneity in
cancer stem cells evolved from long-term cultures of
telomerase-immortalized human mesenchymal stem cells,”
Cancer Research, vol. 65, no. 8, pp. 3126–3135, 2005.
[45] C. Liu, Z. Chen, Z. Chen, T. Zhang, and Y. Lu, “Multiple
tumor types may originate from bone marrow–derived
cells,” Neoplasia, vol. 8, no. 9, pp. 716–724, 2006.
[46] I. Baccelli and A. Trumpp, “The evolving concept of cancer
and metastasis stem cells,” Journal of Cell Biology, vol.
198, no. 3, pp. 281–293, 2012.
[47] C. H. M. Jamieson, L. E. Ailles, S. J. Dylla et al., “Granulocyte–
macrophage progenitors as candidate leukemic stem cells in
Stem Cells International
blast-crisis CML,” The New England Journal of Medicine,
vol. 351, no. 7, pp. 657–667, 2004.
[48] U. Schüller, V. M. Heine, J. Mao et al., “Acquisition of granule
neuron precursor identity is a critical determinant of progen-
itor cell competence to form Shh-induced medulloblastoma,”
Cancer Cell, vol. 14, no. 2, pp. 123–134, 2008.
[49] Z. J. Yang, T. Ellis, S. L. Markant et al., “Medulloblastoma
progenitors or stem cells,” Cancer Cell, vol. 14, no. 2,
pp. 135–145, 2008.
[50] D. Friedmann-Morvinski, E. A. Bushong, E. Ke et al.,
“Dedif-ferentiation of neurons and astrocytes by oncogenes
can induce gliomas in mice,” Science, vol. 338, no. 6110,
pp. 1080–1084, 2012.
[51] K. Chen, Y.-h. Huang, and J.-l. Chen, “Understanding and
targeting cancer stem cells: therapeutic implications and
challenges,” Acta Pharmacologica Sinica, vol. 34, no. 6,
pp. 732–740, 2013.
[52] P. Dalerba, S. J. Dylla, I. K. Park et al., “Phenotypic character-
ization of human colorectal cancer stem cells,” Proceedings of
the National Academy of Sciences of the United States of
America, vol. 104, no. 24, pp. 10158–10163, 2007.
[53] C. Ginestier, M. H. Hur, E. Charafe-Jauffret et al., “ALDH1 is
a marker of normal and malignant human mammary stem
cells and a predictor of poor clinical outcome,” Cell Stem
Cell, vol. 1, no. 5, pp. 555–567, 2007.
[54] L. I. Shlush, S. Zandi, A. Mitchell et al., “Identification of
pre-leukaemic haematopoietic stem cells in acute
leukaemia,” Nature, vol. 506, no. 7488, pp. 328–333, 2014.
[55] B. Auffinger, A. L. Tobias, Y. Han et al., “Conversion of differ-
entiated cancer cells into cancer stem-like cells in a glioblas-
toma model after primary chemotherapy,” Cell Death &
Differentiation, vol. 21, no. 7, pp. 1119–1131, 2014.
[56] P. Hamerlik, J. D. Lathia, R. Rasmussen et al., “Autocrine
VEGF–VEGFR2–Neuropilin-1 signaling promotes glioma
stem-like cell viability and tumor growth,” Journal of Experi-
mental Medicine, vol. 209, no. 3, pp. 507–520, 2012.
[57] K. Shien, S. Toyooka, H. Yamamoto et al., “Acquired resis-
tance to EGFR inhibitors is associated with a manifestation
of stem cell–like properties in cancer cells,” Cancer
Research, vol. 73, no. 10, pp. 3051–3061, 2013.
[58] T. Oskarsson, E. Batlle, and J. Massague, “Metastatic stem
cells: sources, niches, and vital pathways,” Cell Stem Cell,
vol. 14, no. 3, pp. 306–321, 2014.
[59] A. Puisieux, T. Brabletz, and J. Caramel, “Oncogenic roles
of EMT-inducing transcription factors,” Nature Cell
Biology, vol. 16, no. 6, pp. 488–494, 2014.
[60] S. A. Mani, W. Guo, M. J. Liao et al., “The epithelial-
mesenchymal transition generates cells with properties of
stem cells,” Cell, vol. 133, no. 4, pp. 704–715, 2008.
[61] S. Meidhof, S. Brabletz, W. Lehmann et al.,
“ZEB1‑ associated drug resistance in cancer cells is
reversed by the class I HDAC inhibitor mocetinostat,”
EMBO Molecular Medicine, vol. 7, no. 6, pp. 831–847,
2015.
[62] H. Uramoto, T. Iwata, T. Onitsuka, H. Shimokawa, T.
Hanagiri, and T. Oyama, “Epithelial−mesenchymal tran-
sition in EGFR-TKI acquired resistant lung adenocarci-
noma,” Anticancer Research, vol. 30, no. 7, pp. 2513–7,
2010.
[63] M. Xie, L. Zhang, C. S. He et al., “Activation of Notch-1
enhances epithelial–mesenchymal transition in gefitinib-
Stem Cells International
acquired resistant lung cancer cells,” Journal of Cellular
Bio-chemistry, vol. 113, no. 5, pp. 1501–1513, 2012.
[64] P. C. Black, G. A. Brown, T. Inamoto et al., “Sensitivity to
epi-dermal growth factor receptor inhibitor requires E-
cadherin expression in urothelial carcinoma cells,” Clinical
Cancer Research, vol. 14, no. 5, pp. 1478–1486, 2008.
[65] B. C. Fuchs, T. Fujii, J. D. Dorfman et al., “Epithelial-to-
mesenchymal transition and integrin-linked kinase mediate
sensitivity to epidermal growth factor receptor inhibition in
human hepatoma cells,” Cancer Research, vol. 68, no. 7, pp.
2391–2399, 2008.
[66] J. F. Lo, C. C. Yu, S. H. Chiou et al., “The epithelial-
mesenchymal transition mediator S100A4 maintains
cancer-initiating cells in head and neck cancers,” Cancer
Research, vol. 71, no. 5, pp. 1912–1923, 2011.
[67] K. Polyak and R. A. Weinberg, “Transitions between epithe-lial
and mesenchymal states: acquisition of malignant and stem cell
traits,” Nature Reviews Cancer, vol. 9, no. 4,
pp. 265–273, 2009.
[68] F. A. Siebzehnrubl, D. J. Silver, B. Tugertimur et al., “The
ZEB1 pathway links glioblastoma initiation, invasion and
chemoresistance,” EMBO Molecular Medicine, vol. 5, no. 8,
pp. 1196–1212, 2013.
[69] B. S. Koo, S. H. Lee, J. M. Kim et al., “Oct4 is a critical regu-
lator of stemness in head and neck squamous carcinoma cells,”
Oncogene, vol. 34, no. 18, pp. 2317–2324, 2015.
[70] C. E. Huang, C. C. Yu, F. W. Hu, M. Y. Chou, and L. L.
Tsai, “Enhanced chemosensitivity by targeting Nanog in
head and neck squamous cell carcinomas,” International
Journal of Molecular Sciences, vol. 15, no. 9, pp. 14935–
14948, 2014.
[71] M. Y. Chou, F. W. Hu, C. H. Yu, and C. C. Yu, “Sox2
expres-sion involvement in the oncogenicity and
radiochemoresis-tance of oral cancer stem cells,” Oral
Oncology, vol. 51, no. 1, pp. 31–39, 2015.
[72] G. Y. Chiou, T. W. Yang, C. C. Huang et al., “Musashi-1
promotes a cancer stem cell lineage and chemoresistance in
colorectal cancer cells,” Scientific Reports, vol. 7, no. 1,
p. 2172, 2017.
[73] H. Z. Cao, X. F. Liu, W. T. Yang, Q. Chen, and P. S. Zheng,
“LGR5 promotes cancer stem cell traits and
chemoresistance in cervical cancer,” Cell Death & Disease,
vol. 8, no. 9, article e3039, 2017.
[74] G. M. Seigel, L. M. Campbell, M. Narayan, and F. Gonzalez-
Fernandez, “Cancer stem cell characteristics in retinoblas-
toma,” Molecular Vision, vol. 11, pp. 729–737, 2005.
[75] C. Hirschmann-Jax, A. E. Foster, G. G. Wulf et al., “A distinct
“side population” of cells with high drug efflux capacity in
human tumor cells,” Proceedings of the National Academy of
Sciences of the United States of America, vol. 101, no. 39,
pp. 14228–14233, 2004.
[76] N. Haraguchi, T. Utsunomiya, H. Inoue et al.,
“Characteriza-tion of a side population of cancer cells from
human gastro-intestinal system,” Stem Cells, vol. 24, no. 3,
pp. 506–513, 2006.
[77] A. Alisi, W. Cho, F. Locatelli, and D. Fruci, “Multidrug
resistance and cancer stem cells in neuroblastoma and
hepatoblastoma,” International Journal of Molecular Sci-
ences, vol. 14, no. 12, pp. 24706–24725, 2013.
[78] A. M. Bleau, D. Hambardzumyan, T. Ozawa et al., “PTEN/
PI3K/Akt pathway regulates the side population phenotype
11
and ABCG2 activity in glioma tumor stem-like cells,” Cell
Stem Cell, vol. 4, no. 3, pp. 226–235, 2009.
[79] D. Raha, T. R. Wilson, J. Peng et al., “The cancer stem cell
marker aldehyde dehydrogenase is required to maintain a
drug-tolerant tumor cell subpopulation,” Cancer Research,
vol. 74, no. 13, pp. 3579–3590, 2014.
[80] D. J. Pearce, D. Taussig, C. Simpson et al., “Characterization of
cells with a high aldehyde dehydrogenase activity from cord
blood and acute myeloid leukemia samples,” Stem Cells, vol.
23, no. 6, pp. 752–760, 2005.
[81] Y. Su, Q. Qiu, X. Zhang et al., “Aldehyde dehydrogenase 1
A1–positive cell population is enriched in tumor-initiating cells
and associated with progression of bladder cancer,” Can-cer
Epidemiology Biomarkers & Prevention, vol. 19, no. 2,
pp. 327–337, 2010.
[82] M. R. Clay, M. Tabor, J. H. Owen et al., “Single-marker
iden-tification of head and neck squamous cell carcinoma
cancer stem cells with aldehyde dehydrogenase,” Head &
Neck, vol. 32, no. 9, pp. 1195–1201, 2010.
[83] F. Jiang, Q. Qiu, A. Khanna et al., “Aldehyde dehydroge-
nase 1 is a tumor stem cell-associated marker in lung can-
cer,” Molecular Cancer Research, vol. 7, no. 3, pp. 330–
338, 2009.
[84] K. Nakahata, S. Uehara, S. Nishikawa et al., “Aldehyde
dehy-drogenase 1 (ALDH1) is a potential marker for cancer
stem cells in embryonal rhabdomyosarcoma,” PLoS One,
vol. 10, no. 4, article e0125454, 2015.
[85] C. P. Huang, M. F. Tsai, T. H. Chang et al., “ALDH-positive
lung cancer stem cells confer resistance to epidermal growth
factor receptor tyrosine kinase inhibitors,” Cancer Letters, vol.
328, no. 1, pp. 144–151, 2013.
[86] J. A. Ajani, X. Wang, S. Song et al., “ALDH-1 expression
levels predict response or resistance to preoperative
chemora-diation in resectable esophageal cancer patients,”
Molecular Oncology, vol. 8, no. 1, pp. 142–149, 2014.
[87] A. Kreso, C. A. O'Brien, P. van Galen et al., “Variable
clonal repopulation dynamics influence chemotherapy
response in colorectal cancer,” Science, vol. 339, no. 6119,
pp. 543–548, 2013.
[88] A. V. Kurtova, J. Xiao, Q. Mo et al., “Blocking PGE2-induced
tumour repopulation abrogates bladder cancer chemoresis-
tance,” Nature, vol. 517, no. 7533, pp. 209–213, 2015.
[89] T. Ishimoto, O. Nagano, T. Yae et al., “CD44 variant
regulates redox status in cancer cells by stabilizing the xCT
subunit of system xc− and thereby promotes tumor growth,”
Cancer Cell, vol. 19, no. 3, pp. 387–400, 2011.
[90] M. Diehn, R. W. Cho, N. A. Lobo et al., “Association of
reactive oxygen species levels and radioresistance in can-
cer stem cells,” Nature, vol. 458, no. 7239, pp. 780–783,
2009.
[91] H. Yin and J. Glass, “The phenotypic radiation resistance of
CD44 /CD24−
+ or low
breast cancer cells is mediated through
the enhanced activation of ATM signaling,” PLoS One, vol.
6, no. 9, article e24080, 2011.
[92] S. Bao, Q. Wu, R. E. McLendon et al., “Glioma stem cells
pro-mote radioresistance by preferential activation of the
DNA damage response,” Nature, vol. 444, no. 7120, pp.
756–760, 2006.
[93] J. Wang, T. P. Wakeman, J. D. Lathia et al., “Notch promotes
radioresistance of glioma stem cells,” Stem Cells, vol. 28, no. 1,
pp. 17–28, 2010.
12
[94] K. Kise, Y. Kinugasa-Katayama, and N. Takakura, “Tumor
microenvironment for cancer stem cells,” Advanced Drug
Delivery Reviews, vol. 99, Part B, pp. 197–205, 2016.
[95] E. Y.-T. Lau, N. P.-Y. Ho, and T. K.-W. Lee, “Cancer stem
cells and their microenvironment: biology and therapeutic
implications,” Stem Cells International, vol. 2017, Article
ID 3714190, 11 pages, 2017.
[96] A. Turdo, M. Todaro, and G. StassiS. Babashah, “Targeting
cancer stem cells and the tumor microenvironment,” in Can-
cer Stem Cells: Emerging Concepts and Future Perspectives
in Translational Oncology, pp. 445–476, Springer
International Publishing, Cham, 2015.
[97] H. Adisetiyo, M. Liang, C. P. Liao et al., “Dependence of
castration-resistant prostate cancer (CRPC) stem cells on
CRPC-associated fibroblasts,” Journal of Cellular
Physiology, vol. 229, no. 9, pp. 1170–1176, 2014.
[98] C. P. Liao, H. Adisetiyo, M. Liang, and P. Roy-Burman,
“Can-cer-associated fibroblasts enhance the gland-forming
capabil-ity of prostate cancer stem cells,” Cancer Research,
vol. 70, no. 18, pp. 7294–7303, 2010.
[99] W.-J. Chen, C.-C. Ho, Y.-L. Chang et al., “Cancer-associated
fibroblasts regulate the plasticity of lung cancer stemness via
paracrine signalling,” Nature Communications, vol. 5,
p. 3472, 2014.
[100] Y. Kinugasa, T. Matsui, and N. Takakura, “CD44 expressed
on cancer-associated fibroblasts is a functional molecule
sup-porting the stemness and drug resistance of malignant
cancer cells in the tumor microenvironment,” Stem Cells,
vol. 32, no. 1, pp. 145–156, 2014.
[101] F. Cammarota and M. O. Laukkanen, “Mesenchymal stem/
stromal cells in stromal evolution and cancer progression,”
Stem Cells International, vol. 2016, Article ID 4824573, 11
pages, 2016.
[102] K. E. Hovinga, F. Shimizu, R. Wang et al., “Inhibition of
notch signaling in glioblastoma targets cancer stem cells via
an endothelial cell intermediate,” Stem Cells, vol. 28, no. 6,
pp. 1019–1029, 2010.
[103] C. Calabrese, H. Poppleton, M. Kocak et al., “A perivascular
niche for brain tumor stem cells,” Cancer Cell, vol. 11, no. 1,
pp. 69–82, 2007.
[104] S. Krishnamurthy, Z. Dong, D. Vodopyanov et al.,
“Endothe-lial cell-initiated signaling promotes the survival
and self-renewal of cancer stem cells,” Cancer Research,
vol. 70, no. 23, pp. 9969–9978, 2010.
[105] S. Krishnamurthy, K. A. Warner, Z. Dong et al., “Endothelial
interleukin-6 defines the tumorigenic potential of primary
human cancer stem cells,” Stem Cells, vol. 32, no. 11,
pp. 2845–2857, 2014.
[106] Z. Zhang, Z. Dong, I. S. Lauxen, M. S. Filho, and J. E. Nor,
“Endothelial cell-secreted EGF induces epithelial to mesen-
chymal transition and endows head and neck cancer cells with
stem-like phenotype,” Cancer Research, vol. 74, no. 10,
pp. 2869–2881, 2014.
[107] T. S. Zhu, M. A. Costello, C. E. Talsma et al., “Endothelial
cells create a stem cell niche in glioblastoma by providing
NOTCH ligands that nurture self-renewal of cancer stem-
like cells,” Cancer Research, vol. 71, no. 18, pp. 6061–
6072, 2011.
[108] J. Lu, X. Ye, F. Fan et al., “Endothelial cells promote the colo-
rectal cancer stem cell phenotype through a soluble form of
Jagged-1,” Cancer Cell, vol. 23, no. 2, pp. 171–185, 2013.
Stem Cells International
[109] S. Schwitalla, A. A. Fingerle, P. Cammareri et al.,
“Intestinal tumorigenesis initiated by dedifferentiation and
acquisition of stem-cell-like properties,” Cell, vol. 152, no.
1-2, pp. 25– 38, 2013.
[110] L. Vermeulen, F. de Sousa E Melo, M. van der Heijden et al.,
“Wnt activity defines colon cancer stem cells and is regulated
by the microenvironment,” Nature Cell Biology, vol. 12, no. 5,
pp. 468–476, 2010.
[111] X. C. He, J. Zhang, W. G. Tong et al., “BMP signaling inhibits
intestinal stem cell self-renewal through suppression of Wnt–β-
catenin signaling,” Nature Genetics, vol. 36, no. 10,
pp. 1117–1121, 2004.
[112] L. A. Milner and A. Bigas, “Notch as a mediator of cell fate
determination in hematopoiesis: evidence and speculation,”
Blood, vol. 93, no. 8, pp. 2431–2448, 1999.
[113] O.-J. Kwon, J. M. Valdez, L. Zhang et al., “Increased Notch
signalling inhibits anoikis and stimulates proliferation of
prostate luminal epithelial cells,” Nature Communications,
vol. 5, p. 4416, 2014.
[114] B. R. B. Pires, Í. S. S. De Amorim, L. D. E. Souza, J. A.
Rodri-gues, and A. L. Mencalha, “Targeting cellular
signaling path-ways in breast cancer stem cells and its
implication for cancer treatment,” Anticancer Research, vol.
36, no. 11, pp. 5681– 5692, 2016.
[115] B. Bao, A. S. Azmi, S. Ali et al., “The biological kinship of
hyp-oxia with CSC and EMT and their relationship with
deregu-lated expression of miRNAs and tumor
aggressiveness,” Biochimica et Biophysica Acta (BBA) -
Reviews on Cancer, vol. 1826, no. 2, pp. 272–296, 2012.
[116] B. Bao, S. Ali, A. Ahmad et al., “Hypoxia-induced aggressive-
ness of pancreatic cancer cells is due to increased expression of
VEGF, IL-6 and miR-21, which can be attenuated by CDF
treatment,” PLoS One, vol. 7, no. 12, article e50165, 2012.
[117] K. P. Ng, A. Manjeri, K. L. Lee et al., “Physiologic hypoxia
promotes maintenance of CML stem cells despite effective
BCR-ABL1 inhibition,” Blood, vol. 123, no. 21, pp. 3316–
3326, 2014.
[118] A. Murakami, F. Takahashi, F. Nurwidya et al., “Hypoxia
increases gefitinib-resistant lung cancer stem cells through
the activation of insulin-like growth factor 1 receptor,”
PLoS One, vol. 9, no. 1, article e86459, 2014.
[119] V. Rausch, L. Liu, A. Apel et al., “Autophagy mediates sur-
vival of pancreatic tumour-initiating cells in a hypoxic micro-
environment,” The Journal of Pathology, vol. 227, no. 3,
pp. 325–335, 2012.
[120] F. Lotti, A. M. Jarrar, R. K. Pai et al., “Chemotherapy activates
cancer-associated fibroblasts to maintain colorectal cancer-
initiating cells by IL-17A,” Journal of Experimental Medicine,
vol. 210, no. 13, pp. 2851–2872, 2013.
[121] N. Nair, A. S. Calle, M. H. Zahra et al., “A cancer stem cell
model as the point of origin of cancer-associated fibroblasts
in tumor microenvironment,” Scientific Reports, vol. 7, no.
1, p. 6838, 2017.
[122] P. Luraghi, G. Reato, E. Cipriano et al., “MET signaling in
colon cancer stem-like cells blunts the therapeutic response
to EGFR inhibitors,” Cancer Research, vol. 74, no. 6,
pp. 1857–1869, 2014.
[123] H. Korkaya, G.i. Kim, A. Davis et al., “Activation of an IL6
inflammatory loop mediates trastuzumab resistance in HER2+
breast cancer by expanding the cancer stem cell pop-ulation,”
Molecular Cell, vol. 47, no. 4, pp. 570–584, 2012.
Stem Cells International
[124] N. E. Bhola, J. M. Balko, T. C. Dugger et al., “TGF-β
inhibi-tion enhances chemotherapy action against triple-
negative breast cancer,” The Journal of Clinical
Investigation, vol. 123, no. 3, pp. 1348–1358, 2013.
[125] Y. G. Yang, I. N. Sari, M. F. Zia, S. R. Lee, S. J. Song, and
H. Y. Kwon, “Tetraspanins: spanning from solid tumors to
hema-tologic malignancies,” Experimental Hematology,
vol. 44, no. 5, pp. 322–328, 2016.
[126] H. Y. Kwon, J. Bajaj, T. Ito et al., “Tetraspanin 3 is required for
the development and propagation of acute myelogenous
leukemia,” Cell Stem Cell, vol. 17, no. 2, pp. 152–164, 2015.
[127] Z. Zeng, I. J. Samudio, M. Munsell et al., “Inhibition of
CXCR4 with the novel RCP168 peptide overcomes stroma-
mediated chemoresistance in chronic and acute leukemias,”
Molecular Cancer Therapeutics, vol. 5, no. 12, pp. 3113–
3121, 2006.
[128] A. K. Azab, J. M. Runnels, C. Pitsillides et al., “CXCR4
inhib-itor AMD3100 disrupts the interaction of multiple
myeloma cells with the bone marrow microenvironment
and enhances their sensitivity to therapy,” Blood, vol. 113,
no. 18, pp. 4341– 4351, 2009.
[129] T. Yamashina, M. Baghdadi, A. Yoneda et al., “Cancer stem-
like cells derived from chemoresistant tumors have a unique
capacity to prime tumorigenic myeloid cells,” Cancer
Research, vol. 74, no. 10, pp. 2698–2709, 2014.
[130] Y. Zheng, Z. Cai, S. Wang et al., “Macrophages are an abun-
dant component of myeloma microenvironment and protect
myeloma cells from chemotherapy drug–induced
apoptosis,” Blood, vol. 114, no. 17, pp. 3625–3628, 2009.
[131] J. B. Mitchem, D. J. Brennan, B. L. Knolhoff et al.,
“Targeting tumor-infiltrating macrophages decreases tumor-
initiating cells, relieves immunosuppression, and improves
chemother-apeutic responses,” Cancer Research, vol. 73,
no. 3, pp. 1128– 1141, 2013.
[132] M. Amit and Z. Gil, “Macrophages increase the resistance
of pancreatic adenocarcinoma cells to gemcitabine by
upregu-lating cytidine deaminase,” Oncoimmunology, vol.
2, no. 12, article e27231, 2013.
[133] O. G. McDonald, H. Wu, W. Timp, A. Doi, and A. P. Fein-
berg, “Genome-scale epigenetic reprogramming during
epithelial-to-mesenchymal transition,” Nature Structural &
Molecular Biology, vol. 18, no. 8, pp. 867–874, 2011.
[134] W. J. Harris, X. Huang, J. T. Lynch et al., “The histone
demethylase KDM1A sustains the oncogenic potential of
MLL-AF9 leukemia stem cells,” Cancer Cell, vol. 21, no. 4,
pp. 473–487, 2012.
[135] F. Crea, R. Danesi, and W. L. Farrar, “Cancer stem cell epige-
netics and chemoresistance,” Epigenomics, vol. 1, no. 1,
pp. 63–79, 2009.
[136] L. Qin, X. Zhang, L. Zhang et al., “Downregulation of BMI-1
enhances 5-fluorouracil-induced apoptosis in nasopharyn-geal
carcinoma cells,” Biochemical and Biophysical Research
Communications, vol. 371, no. 3, pp. 531–535, 2008.
[137] R. Ferretti, A. Bhutkar, M. C. McNamara, and J. A. Lees,
“BMI1 induces an invasive signature in melanoma that pro-
motes metastasis and chemoresistance,” Genes & Develop-
ment, vol. 30, no. 1, pp. 18–33, 2016.
[138] E. Proctor, M. Waghray, C. J. Lee et al., “Bmi1 enhances
tumorigenicity and cancer stem cell function in pancreatic
adenocarcinoma,” PLoS One, vol. 8, no. 2, article e55820,
2013.
13
[139] E. Wang, S. Bhattacharyya, A. Szabolcs et al., “Enhancing
chemotherapy response with Bmi-1 silencing in ovarian
can-cer,” PLoS One, vol. 6, no. 3, article e17918, 2011.
[140] J. Wu, D. Hu, and R. Zhang, “Depletion of Bmi-1 enhances 5-
fluorouracil-induced apoptosis and autophagy in hepatocel-lular
carcinoma cells,” Oncology Letters, vol. 4, no. 4,
pp. 723–726, 2012.
[141] A. V. Ougolkov, V. N. Bilim, and D. D. Billadeau,
“Regulation of pancreatic tumor cell proliferation and
chemoresistance by the histone methyltransferase enhancer
of zeste homologue 2,” Clinical Cancer Research, vol. 14,
no. 21, pp. 6790–6796, 2008.
[142] S. H. Kim, K. Joshi, R. Ezhilarasan et al., “EZH2 protects gli-
oma stem cells from radiation-induced cell death in a MELK/
FOXM1-dependent manner,” Stem Cell Reports, vol. 4, no. 2,
pp. 226–238, 2015.
[143] C. M. Fillmore, C. Xu, P. T. Desai et al., “EZH2 inhibition
sensitizes BRG1 and EGFR mutant lung tumours to TopoII
inhibitors,” Nature, vol. 520, no. 7546, pp. 239–242, 2015.
[144] A. M. Pietersen, H. M. Horlings, M. Hauptmann et al.,
“EZH2 and BMI1 inversely correlate with prognosis and
TP53 mutation in breast cancer,” Breast Cancer Research,
vol. 10, no. 6, article R109, 2008.
[145] B. Zhang, A. C. Strauss, S. Chu et al., “Effective targeting of
quiescent chronic myelogenous leukemia stem cells by
histone deacetylase inhibitors in combination with ima-tinib
mesylate,” Cancer Cell, vol. 17, no. 5, pp. 427–442, 2010.
[146] F. M. Frame, D. Pellacani, A. T. Collins et al., “HDAC inhib-
itor confers radiosensitivity to prostate stem-like cells,” Brit-ish
Journal of Cancer, vol. 109, no. 12, pp. 3023–3033, 2013.
[147] F. Bruzzese, A. Leone, M. Rocco et al., “HDAC inhibitor
vor-inostat enhances the antitumor effect of gefitinib in
squa-mous cell carcinoma of head and neck by modulating
ErbB receptor expression and reverting EMT,” Journal of
Cellular Physiology, vol. 226, no. 9, pp. 2378–2390, 2011.
[148] K.-H. Song, C. H. Choi, H.-J. Lee et al., “HDAC1 upregula-
tion by NANOG promotes multidrug resistance and a stem-
like phenotype in immune edited tumor cells,” Cancer
Research, vol. 77, no. 18, 2017.
[149] I. Ibanez de Caceres, M. Cortes-Sempere, C. Moratilla et
al., “IGFBP-3 hypermethylation-derived deficiency
mediates cis-platin resistance in non-small-cell lung
cancer,” Oncogene, vol. 29, no. 11, pp. 1681–1690, 2010.
[150] G. Strathdee, M. J. MacKean, M. Illand, and R. Brown, “A
role for methylation of the hMLH1 promoter in loss of
hMLH1 expression and drug resistance in ovarian cancer,”
Oncogene, vol. 18, no. 14, pp. 2335–2341, 1999.
[151] G. Gifford, J. Paul, P. A. Vasey, S. B. Kaye, and R. Brown,
“The acquisition of hMLH1 methylation in plasma DNA
after chemotherapy predicts poor survival for ovarian
cancer patients,” Clinical Cancer Research, vol. 10, no. 13,
pp. 4420– 4426, 2004.
[152] R. Brown, G. L. Hirst, W. M. Gallagher et al., “hMLH1
expression and cellular responses of ovarian tumour cells to
treatment with cytotoxic anticancer agents,” Oncogene, vol.
15, no. 1, pp. 45–52, 1997.
[153] H. J. Mackay, D. Cameron, M. Rahilly et al., “Reduced
MLH1 expression in breast tumors after primary
chemotherapy pre-dicts disease-free survival,” Journal of
Clinical Oncology, vol. 18, no. 1, pp. 87–93, 2000.
14
[154] J. P. Sullivan, M. Spinola, M. Dodge et al., “Aldehyde dehy-
drogenase activity selects for lung adenocarcinoma stem
cells dependent on notch signaling,” Cancer Research, vol.
70, no. 23, pp. 9937–9948, 2010.
[155] G. Dontu, K. W. Jackson, E. McNicholas, M. J. Kawamura,
W. M. Abdallah, and M. S. Wicha, “Role of Notch signaling
in cell-fate determination of human mammary stem/progen-
itor cells,” Breast Cancer Research, vol. 6, no. 6, pp. R605–
R615, 2004.
[156] D. M. Park, J. Jung, J. Masjkur et al., “Hes3 regulates cell
number in cultures from glioblastoma multiforme with stem
cell characteristics,” Scientific Reports, vol. 3, no. 1, p.
1095, 2013.
[157] L. Yang, G. Xie, Q. Fan, and J. Xie, “Activation of the
hedgehog-signaling pathway in human cancer and the clini-cal
implications,” Oncogene, vol. 29, no. 4, pp. 469–481, 2010.
[158] W. F. Tam, P. S. Hahnel, A. Schuler et al., “STAT5 is crucial to
maintain leukemic stem cells in acute myelogenous leuke-mias
induced by MOZ-TIF2,” Cancer Research, vol. 73, no. 1,
pp. 373–384, 2013.
[159] N. Takebe, L. Miele, P. J. Harris et al., “Targeting Notch,
Hedgehog, and Wnt pathways in cancer stem cells: clinical
update,” Nature Reviews Clinical Oncology, vol. 12, no. 8,
pp. 445–464, 2015.
[160] I. Kurth, C. Peitzsch, M. Baumann, and A. Dubrovska, “The
role of cancer stem cells in tumor Radioresistance,” in
Cancer Stem Cells, pp. 473–491, John Wiley & Sons,
Hoboken, New Jersey, USA, 2014.
[161] T. Noda, H. Nagano, I. Takemasa et al., “Activation of Wnt/
β-catenin signalling pathway induces chemoresistance to
interferon-α/5-fluorouracil combination therapy for hepato-
cellular carcinoma,” British Journal of Cancer, vol. 100, no.
10, pp. 1647–1658, 2009.
[162] W. Yang, H. X. Yan, L. Chen et al., “Wnt/β-catenin
signaling contributes to activation of normal and
tumorigenic liver progenitor cells,” Cancer Research, vol.
68, no. 11, pp. 4287– 4295, 2008.
[163] M. Flahaut, R. Meier, A. Coulon et al., “The Wnt receptor
FZD1 mediates chemoresistance in neuroblastoma through
activation of the Wnt/β-catenin pathway,” Oncogene, vol.
28, no. 23, pp. 2245–2256, 2009.
[164] W. K. Chau, C. K. Ip, A. S. C. Mak, H. C. Lai, and A. S. T.
Wong, “c-Kit mediates chemoresistance and tumor-
initiating capacity of ovarian cancer cells through activation
of Wnt/β-catenin–ATP-binding cassette G2 signaling,”
Oncogene, vol. 32, no. 22, pp. 2767–2781, 2013.
[165] X. Zeng, H. Zhao, Y. Li et al., “Targeting Hedgehog
signaling pathway and autophagy overcomes drug
resistance of BCR-ABL-positive chronic myeloid
leukemia,” Autophagy, vol. 11, no. 2, pp. 355–372, 2015.
[166] M. Xu, A. Gong, H. Yang et al., “Sonic hedgehog-glioma
asso-ciated oncogene homolog 1 signaling enhances drug
+ +
resis-tance in CD44 /Musashi-1 gastric cancer stem cells,”
Cancer Letters, vol. 369, no. 1, pp. 124–133, 2015.
[167] I. V. Ulasov, S. Nandi, M. Dey, A. M. Sonabend, and M. S.
Lesniak, “Inhibition of Sonic hedgehog and Notch pathways
enhances sensitivity of CD133+ glioma stem cells to temozo-
lomide therapy,” Molecular Medicine, vol. 17, no. 1-2,
pp. 103–112, 2011.
[168] R. D. Meng, C. C. Shelton, Y. M. Li et al., “γ-Secretase inhib-
itors abrogate oxaliplatin-induced activation of the Notch-1
Stem Cells International
signaling pathway in colon cancer cells resulting in
enhanced chemosensitivity,” Cancer Research, vol. 69, no.
2, pp. 573– 582, 2009.
[169] S. M. McAuliffe, S. L. Morgan, G. A. Wyant et al.,
“Targeting Notch, a key pathway for ovarian cancer stem
cells, sensitizes tumors to platinum therapy,” Proceedings of
the National Academy of Sciences of the United States of
America, vol. 109, no. 43, pp. E2939–E2948, 2012.
[170] Y. P. Liu, C. J. Yang, M. S. Huang et al., “Cisplatin selects for
multidrug-resistant CD133+ cells in lung adenocarcinoma by
activating Notch signaling,” Cancer Research, vol. 73, no. 1,
pp. 406–416, 2013.
[171] S. Alonso, R. J. Jones, and G. Ghiaur, “Retinoic acid,
CYP26, and drug resistance in the stem cell niche,”
Experimental Hematology, vol. 54, pp. 17–25, 2017.
[172] M. Krause, A. Dubrovska, A. Linge, and M. Baumann, “Can-
cer stem cells: radioresistance, prediction of radiotherapy
outcome and specific targets for combined treatments,”
Advanced Drug Delivery Reviews, vol. 109, pp. 63–73, 2017.
[173] R. Olson and C. Albright, “Recent progress in the medicinal
chemistry of γ-secretase inhibitors,” Current Topics in
Medic-inal Chemistry, vol. 8, no. 1, pp. 17–33, 2008.
[174] S. Richter, P. L. Bedard, E. X. Chen et al., “A phase I study
of the oral gamma secretase inhibitor R04929097 in
combina-tion with gemcitabine in patients with advanced
solid tumors (PHL-078/CTEP 8575),” Investigational New
Drugs, vol. 32, no. 2, pp. 243–249, 2014.
[175] P. A. Beachy, S. G. Hymowitz, R. A. Lazarus, D. J. Leahy,
and C. Siebold, “Interactions between Hedgehog proteins
and their binding partners come into view,” Genes &
Develop-ment, vol. 24, no. 18, pp. 2001–2012, 2010.
[176] L. Dirix, “Discovery and exploitation of novel targets by
approved drugs,” Journal of Clinical Oncology, vol. 32, no. 8,
pp. 720-721, 2014.
[177] A. Sekulic, M. R. Migden, A. E. Oro et al., “Efficacy and
safety of vismodegib in advanced basal-cell carcinoma,”
The New England Journal of Medicine, vol. 366, no. 23, pp.
2171– 2179, 2012.
[178] X. Li, V. Placencio, J. M. Iturregui et al., “Prostate tumor pro-
gression is mediated by a paracrine TGF-β/Wnt3a signaling
axis,” Oncogene, vol. 27, no. 56, pp. 7118–7130, 2008.
[179] M. Kahn, “Can we safely target the WNT pathway?,” Nature
Reviews Drug Discovery, vol. 13, no. 7, pp. 513–532, 2014.
[180] D. C. Smith, L. S. Rosen, R. Chugh et al., “First-in-human
evaluation of the human monoclonal antibody vantictumab
(OMP-18R5; anti-Frizzled) targeting the WNT pathway in a
phase I study for patients with advanced solid tumors,” Jour-nal
of Clinical Oncology, vol. 31, 15 Supplement, p. 2540, 2013.
[181] U.S. National Library of Medicine, “ClinicalTrials.Gov,”
2014, http://clinicaltrials.gov/show/NCT01345201.
[182] A. Jimeno, M. S. Gordon, R. Chugh et al., “A first-in-human
phase 1 study of anticancer stem cell agent OMP-54F28
(FZD8-Fc), decoy receptor for WNT ligands, in patients
with advanced solid tumors,” Journal of Clinical Oncology,
vol. 32, 15 Supplement, p. 2505, 2014.
[183] D. Friedmann-Morvinski and I. M. Verma, “Dedifferentia-
tion and reprogramming: origins of cancer stem cells,”
EMBO Reports, vol. 15, no. 3, pp. 244–253, 2014.
[184] B. Du and J. Shim, “Targeting epithelial–mesenchymal
transition (EMT) to overcome drug resistance in cancer,”
Molecules, vol. 21, no. 8, 2016.
Stem Cells International
[185] R. Malek, H. Wang, K. Taparra, and P. T. Tran, “Therapeutic
targeting of epithelial plasticity programs: focus on the
epithelial-mesenchymal transition,” Cells, Tissues, Organs,
vol. 203, no. 2, pp. 114–127, 2017.
[186] S. Knoll, S. Emmrich, and B. M. Putzer, “The E2F1-miRNA
cancer progression network,” Advances in Experimental
Medicine and Biology, vol. 774, pp. 135–147, 2013.
[187] A. A. Dar, S. Majid, D. de Semir, M. Nosrati, V. Bezrookove,
and M. Kashani-Sabet, “miRNA-205 suppresses melanoma cell
proliferation and induces senescence via regulation of E2F1
protein,” Journal of Biological Chemistry, vol. 286, no. 19, pp.
16606–16614, 2011.
[188] V. Alla, B. S. Kowtharapu, D. Engelmann et al., “E2F1
confers anticancer drug resistance by targeting ABC trans-
porter family members and Bcl-2 via the p73/DNp73-miR-
205 circuitry,” Cell Cycle, vol. 11, no. 16, pp. 3067–3078,
2012.
[189] P. A. Gregory, A. G. Bert, E. L. Paterson et al., “The miR-
200 family and miR-205 regulate epithelial to mesenchymal
tran-sition by targeting ZEB1 and SIP1,” Nature Cell
Biology, vol. 10, no. 5, pp. 593–601, 2008.
[190] C. Palena and D. H. Hamilton, “Immune targeting of tumor
epithelial–mesenchymal transition via brachyury-based
vac-cines,” Advances in Cancer Research, vol. 128, pp. 69–
93, 2015.
[191] J. Godlewski, M. O. Nowicki, A. Bronisz et al., “Targeting of
the Bmi-1 oncogene/stem cell renewal factor by microRNA-
128 inhibits glioma proliferation and self-renewal,” Cancer
Research, vol. 68, no. 22, pp. 9125–9130, 2008.
[192] C. A. O'Brien, A. Kreso, P. Ryan et al., “ID1 and ID3
regulate the self-renewal capacity of human colon cancer-
initiating cells through p21,” Cancer Cell, vol. 21, no. 6, pp.
777–792, 2012.
[193] J. Deng, M. Yang, R. Jiang, N. An, X. Wang, and B. Liu, “Long
non-coding RNA HOTAIR regulates the proliferation, self-renewal
capacity, tumor formation and migration of the can-cer stem-like
cell (CSC) subpopulation enriched from breast cancer cells,” PLoS
One, vol. 12, no. 1, article e0170860, 2017.
[194] S. J. Song, L. Poliseno, M. S. Song et al., “MicroRNA-
antago-nism regulates breast cancer stemness and
metastasis via TET-family-dependent chromatin
remodeling,” Cell, vol. 154, no. 2, pp. 311–324, 2013.
[195] F. Yu, H. Yao, P. Zhu et al., “let-7 regulates self renewal and
tumorigenicity of breast cancer cells,” Cell, vol. 131, no. 6,
pp. 1109–1123, 2007.
[196] Y. Shimono, M. Zabala, R. W. Cho et al., “Downregulation
of miRNA-200c links breast cancer stem cells with normal
stem cells,” Cell, vol. 138, no. 3, pp. 592–603, 2009.
[197] D. Iliopoulos, M. Lindahl-Allen, C. Polytarchou, H. A.
Hirsch, P. N. Tsichlis, and K. Struhl, “Loss of miR-200
inhibi-tion of Suz12 leads to polycomb-mediated repression
required for the formation and maintenance of cancer stem
cells,” Molecular Cell, vol. 39, no. 5, pp. 761–772, 2010.
[198] D. Iliopoulos, A. Rotem, and K. Struhl, “Inhibition of miR-
193a expression by Max and RXRα activates K-Ras and PLAU
to mediate distinct aspects of cellular transformation,” Cancer
Research, vol. 71, no. 15, pp. 5144–5153, 2011.
[199] N. Bitarte, E. Bandres, V. Boni et al., “MicroRNA-451 is
involved in the self-renewal, tumorigenicity, and
chemoresis-tance of colorectal cancer stem cells,” Stem
Cells, vol. 29, no. 11, pp. 1661–1671, 2011.
15
[200] P. Bu, K. Y. Chen, J. H. Chen et al., “A microRNA miR-34a-
regulated bimodal switch targets Notch in colon cancer stem
cells,” Cell Stem Cell, vol. 12, no. 5, pp. 602–615, 2013.
[201] C. Liu, K. Kelnar, B. Liu et al., “The microRNA miR-34a
inhibits prostate cancer stem cells and metastasis by directly
repressing CD44,” Nature Medicine, vol. 17, no. 2, pp.
211– 215, 2011.
[202] Y. Y. Wu, Y. L. Chen, Y. C. Jao, I. S. Hsieh, K. C. Chang, and
T. M. Hong, “miR-320 regulates tumor angiogenesis driven by
vascular endothelial cells in oral cancer by silencing neuro-
pilin 1,” Angiogenesis, vol. 17, no. 1, pp. 247–260, 2014.
[203] C. Visus, Y. Wang, A. Lozano-Leon et al., “Targeting
b-right
ALDH human carcinoma–initiating cells with
+
ALDH1A1-specific CD8 T cells,” Clinical Cancer
Research, vol. 17, no. 19, pp. 6174–6184, 2011.
[204] L. Jin, K. J. Hope, Q. Zhai, F. Smadja-Joffe, and J. E. Dick,
“Targeting of CD44 eradicates human acute myeloid leuke-
mic stem cells,” Nature Medicine, vol. 12, no. 10, pp. 1167–
1174, 2006.
[205] Y. Guo, J. Ma, J. Wang et al., “Inhibition of human melanoma
growth and metastasis in vivo by anti-CD44 monoclonal anti-
body,” Cancer Research, vol. 54, no. 6, pp. 1561–1565, 1994.
[206] S. K. Swaminathan, M. R. Olin, C. L. Forster, K. S. S. Cruz,
J. Panyam, and J. R. Ohlfest, “Identification of a novel mono-
clonal antibody recognizing CD133,” Journal of Immunolog-
ical Methods, vol. 361, no. 1-2, pp. 110–115, 2010.
[207] F. Ferrari, S. Bellone, J. Black et al., “Solitomab, an
EpCAM/ CD3 bispecific antibody construct (BiTE®), is
highly active against primary uterine and ovarian
carcinosarcoma cell lines in vitro,” Journal of Experimental
& Clinical Cancer Research, vol. 34, no. 1, p. 123, 2015.
[208] M. Sen, D. M. Wankowski, N. K. Garlie et al., “Use of anti-
CD3 × anti-HER2/neu bispecific antibody for redirecting
+
cytotoxicity of activated T cells toward HER2/neu
tumors,” Journal of Hematotherapy & Stem Cell Research,
vol. 10, no. 2, pp. 247–260, 2001.
[209] F. Dammeijer, L. A. Lievense, M. E. Kaijen-Lambers et al.,
“Depletion of tumor-associated macrophages with a CSF-
1R kinase inhibitor enhances antitumor immunity and
survival induced by DC immunotherapy,” Cancer Immunol-
ogy Research, vol. 5, no. 7, pp. 535–546, 2017.
[210] D. R. Yang, X. F. Ding, J. Luo et al., “Increased chemosensitiv-
ity via targeting testicular nuclear receptor 4 (TR4)-Oct4-
interleukin 1 receptor antagonist (IL1Ra) axis in prostate
cancer CD133+ stem/progenitor cells to battle prostate cancer,”
Journal of Biological Chemistry, vol. 288, no. 23,
pp. 16476–16483, 2013.
[211] S. Y. Kim, J. W. Kang, X. Song et al., “Role of the IL-6-
JAK1-STAT3-Oct-4 pathway in the conversion of non-stem
cancer cells into cancer stem-like cells,” Cellular Signalling,
vol. 25, no. 4, pp. 961–969, 2013.
[212] C. Ginestier, S. Liu, M. E. Diebel et al., “CXCR1 blockade
selectively targets human breast cancer stem cells in vitro
and in xenografts,” The Journal of Clinical Investigation,
vol. 120, no. 2, pp. 485–497, 2010.
[213] S. L. Topalian, F. S. Hodi, J. R. Brahmer et al., “Safety, activity, and
immune correlates of anti–PD-1 antibody in cancer,” The New
England Journal of Medicine, vol. 366, no. 26,
pp. 2443–2454, 2012.
[214] S. M. Ansell, A. M. Lesokhin, I. Borrello et al., “PD-1 blockade
with nivolumab in relapsed or refractory Hodgkin's
16 Stem Cells International

lymphoma,” The New England Journal of Medicine, vol.

372, no. 4, pp. 311–319, 2015.
[215] Y. Hu and L. Fu, “Targeting cancer stem cells: a new
therapy to cure cancer patients,” American Journal of
Cancer Research, vol. 2, no. 3, pp. 340–356, 2012.
[216] S. R. Pine, B. Marshall, and L. Varticovski, “Lung cancer stem
cells,” Disease Markers, vol. 24, no. 4-5, pp. 257–266, 2008.
[217] T. Chanmee, P. Ontong, K. Kimata, and N. Itano, “Key roles of
hyaluronan and its CD44 receptor in the stemness and sur-vival
of cancer stem cells,” Frontiers in Oncology, vol. 5, 2015.
[218] Y. J. Kim, E. L. Siegler, N. Siriwon, and P. Wang, “Therapeutic
strategies for targeting cancer stem cells,” Journal of Cancer
Metastasis and Treatment, vol. 2, no. 7, pp. 233–242, 2016.
[219] D. L. Dragu, L. G. Necula, C. Bleotu, C. C. Diaconu, and
M. Chivu-Economescu, “Therapies targeting cancer stem
cells: current trends and future challenges,” World Journal
of Stem Cells, vol. 7, no. 9, pp. 1185–1201, 2015.
[220] L. Han, S. Shi, T. Gong, Z. Zhang, and X. Sun, “Cancer
stem cells: therapeutic implications and perspectives in
cancer therapy,” Acta Pharmaceutica Sinica B, vol. 3, no. 2,
pp. 65–75, 2013.
[221] C. Zhang, C. Li, F. He, Y. Cai, and H. Yang, “Identification
of CD44+CD24+ gastric cancer stem cells,” Journal of
Cancer Research and Clinical Oncology, vol. 137, no. 11,
pp. 1679–1686, 2011.
[222] S. Takaishi, T. Okumura, S. Tu et al., “Identification of
gastric cancer stem cells using the cell surface marker
CD44,” Stem Cells, vol. 27, no. 5, pp. 1006–1020, 2009.
[223] A. T. Collins, P. A. Berry, C. Hyde, M. J. Stower, and N. J.
Maitland, “Prospective identification of tumorigenic
prostate cancer stem cells,” Cancer Research, vol. 65, no.
23, pp. 10946–10951, 2005.
[224] M. J. Son, K. Woolard, D. H. Nam, J. Lee, and H. A. Fine,
“SSEA-1 is an enrichment marker for tumor-initiating cells
in human glioblastoma,” Cell Stem Cell, vol. 4, no. 5, pp.
440–452, 2009.
[225] M. E. Prince, R. Sivanandan, A. Kaczorowski et al., “Identifi-
cation of a subpopulation of cells with cancer stem cell prop-
erties in head and neck squamous cell carcinoma,” Proceedings
of the National Academy of Sciences of the United States of
America, vol. 104, no. 3, pp. 973–978, 2007.
[226] S. K. Singh, C. Hawkins, I. D. Clarke et al., “Identification
of human brain tumour initiating cells,” Nature, vol. 432,
no. 7015, pp. 396–401, 2004.
Cancer Stem Cells (CSCs) pada resistensi obat dan implikasinya dalam
terapi pengobatan kanker.

Lan Thi Hanh Phi , Ita Novita Sari, Ying-Gui Yang, Sang-
Hyun Lee, Nayoung Jun, Kwang Seock Kim, Yun Kyung Lee
, and Hyog Young Kwon

Cancer stem cell (CSC), juga dikenal sebagai sel-sel tumor-initiating cells
(TICs), disarankan untuk bertanggung jawab untuk resistensi obat dan
kekambuhan kanker karena sebagian untuk kemampuan mereka untuk
memperbaharui diri sendiri dan differentiate ke garis keturunan heterogen sel
kanker . Dengan demikian, penting untuk memahami karakteristik dan
mekanisme yang digunakan CSC untuk menunjukkan resistensi terhadap agen
terapi. Dalam ulasan ini, kami menyoroti fitur utama dan mekanisme yang
mengatur fungsi CSC dalam resistensi obat serta terobosan terbaru dari
pendekatan terapeutik untuk menargetkan CSC. Ini menjanjikan wawasan baru
CSCs dalam resistensi obat dan memberikan alasan terapi yang lebih baik
untuk menemani terapi antikanker baru.

1. Pendahuluan

Kanker adalah salah satu penyebab utama morbiditas dan mortalitas di

seluruh dunia dengan sekitar 20% dari semua kematian di negara maju [1]. Dari
studi kanker praklinis dan klinis, berbagai pilihan diagnostik dan pengobatan baru
untuk pasien kanker memberikan kemajuan penting dalam pengobatan dan
pencegahan kanker [2]. Heterogenitas kanker adalah salah satu alasan yang
berkontribusi terhadap kegagalan pengobatan dan perkembangan penyakit. Di
antara beberapa perawatan kanker, perawatan utama yang biasa digunakan untuk
merawat pasien adalah pembedahan, radioterapi, dan kemoterapi. Bedah dapat
menghilangkan kanker dari tubuh, sementara menggabungkan radioterapi dengan
kemoterapi dapat effectively memberikan hasil yang lebih baik untuk mengobati
berbagai jenis kanker [3]. Agen kemoterapi terbaru berhasil melawan lesi tumor
primer dan residunya setelah operasi atau radioterapi [4]. Namun, kemoterapi
menyebabkan heterogenitas tumor berasal dari kedua normal dan sel kanker dan
heterogenitas dalam tumor, pada gilirannya, menghasilkan mengurangi efek
kemoterapi; berkontribusi terhadap kegagalan pengobatan dan perkembangan
penyakit [5, 6]. Chemoresistance adalah masalah utama dalam pengobatan pasien
kanker, sel-sel kanker menjadi resisten terhadap zat kimia yang digunakan dalam
pengobatan, yang akibatnya membatasi efisiensi agen kemoterapi [7]. Ini juga
sering dikaitkan dengan tumor yang berubah menjadi bentuk yang lebih agresif
dan / atau tipe metastasis [8-11].
Mengumpulkan bukti-bukti menunjukkan bahwa Cancer Stem Cell (CSC)
populasi, subkelompok sel kanker, bertanggung jawab untuk chemoresistance dan
kanker kambuh, karena memiliki kemampuan untuk memperbaharui diri dan
berdiferensiasi ke dalam garis keturunan heterogen sel kanker dalam menanggapi
agen kemoterapi [12-14]. CSC juga mampu menginduksi siklus sel tahanan (state
diam) yang mendukung kemampuan mereka untuk menjadi resisten terhadap
kemoterapi dan radioterapi [15-20]. Agen chemotherapeutic yang umum
menargetkan sel-sel yang berproliferasi untuk memimpin apoptosis mereka,
seperti yang disebutkan sebelumnya. Meskipun terapi kanker yang berhasil
menghilangkan sebagian besar sel-sel tumor yang berkembang biak, sekelompok
CSC yang tersisa dapat bertahan dan meningkatkan kekambuhan kanker karena
kemampuan mereka untuk membangun invasifitas yang lebih tinggi dan
chemoresistance [21, 22]. Memahami fitur-fitur CSC penting untuk membangun
fondasi bagi era baru dalam pengobatan kanker. Dalam ulasan ini, kami
membahas mekanisme rinci dimana CSC menampilkan resistensi terhadap
kemoterapi dan radioterapi dan implikasinya untuk uji klinis.

2. Asal dan Permukaan Penanda Sel Punca Kanker (CSC)

Cancer Stem Cell (CSC), juga dikenal sebagai tumor-initiating cells (TICs),
telah dipelajari secara intensif dalam dekade terakhir, dengan fokus pada sumber
yang mungkin, asal, penanda seluler, studi mekanisme, dan pengembangan
strategi terapi menargetkan jalur mereka [23, 24]. Yang pertama meyakinkan
dasar dari CSC dilaporkan oleh Bonnet dan Dick pada tahun 1997 oleh
pengidentifikasian dari subpopulasi sel leukemia mengekspresikan permukaan
penanda CD34, tapi tidak CD38. CD34+/ CD38- subpopulasi mampu memulai
pertumbuhan tumor pada tikus penerima NOD / SCID setelah transplantasi [25].
Selain kanker darah, CSC telah diidentifikasi dalam beberapa jenis tumor padat
[21, 26]. Bukti pertama dari kehadiran CSC pada kanker padat in vivo ditemukan
dan diidentifikasi sebagai CD44+CD24- /low. Lineage- sel pada tikus
immunocompromised setelah transplantasi sel kanker payudara manusia pada
tahun 2003 [27] meskipun memiliki telah ditunjukkan secara in vitro pada tahun
2002 oleh penemuan sel-sel klonogenik (pembentuk bola) yang diisolasi dari
glioma otak manusia [28]. Seiring waktu, populasi CSC juga diidentifikasi dari
beberapa padat kaleng-perwira lainnya termasuk melanoma, otak, paru-paru, hati,
pankreas, usus besar, kanker payudara, serta kanker ovarium [27, 29-35].
Meskipun model CSC menjelaskan heterogenitas kanker dalam hal struktur
hierarkis dan perkembangan mode, asal-usul CSC saat ini tidak jelas dan
kontroversial [36, 37]. Mengumpulkan hipotesis menunjukkan bahwa tergantung
pada jenis tumor, CSC mungkin berasal dari salah satu sel induk dewasa, sel-sel
progenitor dewasa yang telah mengalami mutasi, ataudaridiffsel-selsel-sel
erentiated/ bisa-cer yang diperoleh sifat batang-seperti melalui dedif-ferentiation
[25, 38-50]. Karena plastisitas CSC, telah menyarankan bahwa kombinasional
ther-APY menargetkan jalur CSC dan konvensional kemo-terapi mungkin
memiliki lebih baik terapi effect, yang akan dijelaskan nanti secara rinci (Gambar
1).Studi awal di AML menunjukkan bahwa sel-sel primitif normal, tetapi tidak
terikat pada sel progenitor, adalah target untuk transformasi leukemia [25].
Demikian pula, telah diindikasikan bahwa penghapusan APC dalam Lgr5+ (ulangi
kaya leusin yang mengandung reseptor ditambah G-protein 5) sel-sel induk usus
berumur panjang, daripada sel-sel penguat transit yang berumur pendek, dapat
mengarah pada transformasi mereka, menunjukkan bahwa sel-sel induk adalah
sel-asal-asal pada kanker usus [42]. Selain itu, kultur jangka panjang juga dapat
menginduksi sel batang mesenkim manusia dewasa transduksi telomerase
(hMSCs) untuk menjalani transformasi spontan, menunjukkan bahwa sel-sel ini
juga merupakan asal dari CSCs [43, 44]. Menariknya, CSC berasal dari
transformasi tidak hanya mereka jaringan spesifik sel-sel stem tetapi juga sel
induk jaringan lainnya. Sebagai contoh, sel-sel yang diturunkan dari sumsum
tulang (BMDCs) mungkin merupakan Sumber dari banyak jenis tumor, seperti
kanker lambung, tumor saraf, dan bahkan teratoma [45].
CSC juga telah dibuktikan yang akan dihasilkan oleh dediffdiferensiasi dari sel
progenitor atau differentiated sel yang telah diperoleh “stemness” sifat sebagai
akibat dari akumulasi tambahan genetik atau epigenetik abnor-malities [46].
Sebagai contoh, protein fusi BCR-ABL hadir dalam sel induk hematopoietik -
(HSC-) seperti sel CML tetapi nenek moyang granulosit-makrofag ditemukan
menjadi kandidat LSC stadium lanjut selama krisis ledakan di CML ledakan-krisis
dengan mengaktifkan proses pembaharuan diri melalui βjalur-catenin [47]. Selain
itu, telah ditunjukkan bahwa pensinyalan Hh onkogenik dapat mempromosikan
medulloblas-toma baik dari nenek moyang sel granula atau sel punca [48, 49].
Selain itu, kebanyakan differentiated sel-sel di SSP, termasuk parah differentiated
neuron dan astrosit, dapat memperolehdefiperubahan genetikned untuk dedif-
ferentiate ke NSC atau negara progenitor dan akibatnya mendorong dan
memelihara glioma ganas [50].

Dari catatan, CSC dapatdiidentifikasiolehspesifikpenanda sel induk normal

yang biasa digunakan untuk mengisolasi CSC dari tumor padat dan hematologi
[51]. Beberapa penanda permukaan sel telahdiverifikasiuntuk mengidentifikasi
populasi CSC-diperkaya, seperti CD133, CD24, CD44, EpCAM (molekul adhesi
sel epitel), THY1, ABCB5 (ATP-mengikat kaset B5), dan CD200 [27, 32, 34, 52].
Selain itu, protein intraseluler tertentu juga telah digunakan sebagai penanda CSC,
seperti aldehyde dehydrogenase 1 (ALDH1) yang digunakan untuk
mengkarakterisasi CSCs dalam banyak jenis kanker seperti leukemia, payudara,
usus besar, hati, paru-paru, pankreas, dan sebagainya [ 12, 53]. Penggunaan
penanda permukaan sel sebagai CSC penanda kekuatan differ dari masing-masing
jenis kanker tergantung pada karakteristik dan fenotipe mereka. Penanda
permukaan yang sering digunakan untuk mengisolasi CSC dari masing-masing
jenis kanker tercantum pada Tabel 1.
3. Mekanisme dimana CSC Berkontribusi pada Perlawanan terhadap
Kemoterapi dan Kambuhnya Kanker

Studi terbaru menunjukkan bahwa CSC disuburkan setelah kemoterapi karena

subpopulasi kecil dari sel yang tersisa jaringan tumor, yang disebut CSC, dapat
bertahan dan berkembang meskipun sebagian besar agen kemoterapi membunuh
sebagian besar tumor [12-14]. Sebagai contoh, preleukemik DNMT3Amut HSCs
yang dapat memulai ekspansi klon sebagai langkah pertama dalam
leukemogenesis dan meregenerasi seluruh hierarki hematopoietik ditemukan
bertahan dan berkembang dalam remisi sumsum tulang setelah kemoterapi [54].
Demikian pula, paparan dosis terapi temozolomide (TMZ), kemoterapi antiglioma
yang paling umum digunakan, secara konsisten memperluas kumpulan glioma
stem sel (GSC) dari waktu ke waktu dalam garis sel glioma yang berasal dari
pasien dan yang telah terbentuk, yang telah terbukti merupakan hasil interkonversi
fenotipik dan fungsional antara sel-sel tumor yang berdiferensiasi dan GSCs [55].
Selain itu, antibodi VEGF yang dimanusiakan bevacizumab mengurangi
pertumbuhan tumor glioblasoma multiforme (GBM) tetapi diikuti oleh
kambuhnya tumor, mungkin karena penguncian autokrin yang sedang berlangsung
melalui sumbu VEGF-VEGFR2-Neuropilin-1 (NRP1), yang terkait dengan
pengayaan bagian aktif VEGFR2 GSC dalam sel GBM manusia [56]. Subline
yang tahan gefitinib, HCC827-GR-highs yang dibuat dengan metode konsentrasi
tinggi juga memperoleh fitur EMT dan fitur sel induk tetapi tidak menunjukkan
produksi protein spesifik mutan EGFR-mutan atau peningkatan lebih lanjut dalam
jumlah alel mutan atau Salinan EGFR [57]. Oleh karena itu, dengan memahami
mekanisme dan driver onkogenik di mana CSC lolos dari radio dan kemoterapi,
kita dapat mengembangkan perawatan yang lebih efektif yang dapat
meningkatkan hasil klinis pasien kanker. Mekanisme kontribusi CSC terhadap
kemoresisten termasuk EMT, MDR, dormansi, lingkungan tumor, dan sebagainya
disebutkan di bawah ini secara rinci dan dirangkum dalam Gambar 2.

3.1. Epithelial Mesenchymal Transition (EMT).

Telah diindikasikan bahwa penanda Epithelial Mesenchymal Transition

(EMT) dan penanda sel punca secara bersamaan diekspresikan dalam sirkulasi sel
tumor dari pasien dengan metastasis [58] dan induksi EMT atau aktivasi EMT
transcription factor (TF) menghasilkan fitur seperti stem cell pada sel kanker [
59]. Secara khusus, stem cell payudara manusia yang normal dan neoplastik
mengekspresikan penanda yang serupa dengan sel-sel yang telah mengalami
EMT, dan EMT menginduksi generasi sel-sel induk kanker yang relatif tidak
terbatas dari sel-sel neoplastik yang lebih terdiferensiasi [60]. Sementara itu, ada
hubungan antara aktivasi EMT dan resistensi obat [61]. Misalnya, sel-sel kanker
paru resisten yang diinduksi gefitinib mendapatkan fenotipe EMT [62] melalui
aktivasi pensinyalan Notch-1 [63]. Selain itu, potensi invasif yang ditingkatkan,
tumorigenisitas, dan ekspresi penanda EMT dapat digunakan untuk memprediksi
resistensi cetuximab antibodi anti-EGFR dalam sel [64]. Secara paralel,
dibandingkan dengan garis sel epitel, sel mesenchymal telah meningkatkan
ekspresi gen yang terlibat dalam metastasis dan invasi dan secara signifikan
kurang rentan terhadap penghambatan EGFR, termasuk erlotinib, gefitinib, dan
cetuximab; setidaknya sebagian melalui overekspresi integrin-linked kinase (ILK)
dalam sel mesenkim [65]. Selain itu, mediator EMT S100A4 telah terbukti terlibat
dalam mempertahankan sifat batang dan tumorigenicity CSCs di kepala dan leher
kanker [66]. Oleh karena itu, EMT menginduksi sel kanker untuk menunjukkan
karakteristik seperti sel punca yang mempromosikan sel untuk menyerang
jaringan di sekitarnya dan menampilkan resistensi terapeutik [67]. Menariknya,
ZEB1, regulator EMT, memainkan peran penting dalam fitur kunci sel induk
kanker termasuk regulasi batang dan induksi chemoresistance melalui regulasi
transkripsi O-6-Methylguanine DNA Methyltransferase (MGMT) via miR-200c
dan c-MYB pada glioma ganas [68]. Selain EMT, ekspresi tinggi penanda sel
induk seperti Oct4, Nanog, Sox2, Musashi, dan Lgr5 telah dipertimbangkan untuk
memberikan chemore- sistance juga [69-73].

3.2. Protein Multidrug Resistance (MDR) atau Detoksifikasi Tingkat Tinggi.

Sel-sel side population (SP), yang menunjukkan fenotip seperti sel induk
kanker, terdeteksi pada berbagai tumor padat yang berbeda seperti retinoblastoma,
neuroblastoma, kanker gastrointestinal, kanker payudara, kanker paru-paru, dan
glioblastoma; ekspresi tinggi protein pengangkut obat (termasuk MDR1, ABCG2,
dan ABCB1) tidak hanya bertindak untuk mengecualikan pewarna Hoechst tetapi
juga mengeluarkan obat sitotoksik, yang mengarah pada resistensi tinggi terhadap
agen kemoterapi dengan kelangsungan hidup sel yang lebih baik dan kekambuhan
penyakit [74-76] ] Alisi et al. menunjukkan bahwa ekspresi berlebih dari protein
ABC mungkin merupakan mekanisme perlindungan yang paling penting untuk
CSCs dalam menanggapi agen kemoterapi. Menariknya, telah dibuktikan bahwa
jalur PI3K / Akt secara spesifik mengatur aktivitas ABCG2 melalui lokalisasi ke
membran plasma, dan hilangnya PTEN mempromosikan fenotip SP sel kanker
mirip glioma manusia seperti sel induk [78]. Selain itu, aktivitas aldehyde
dehydrogenase (ALDH), enzim sitosol yang bertanggung jawab untuk oksidasi
aldehida intraseluler untuk melindungi sel dari efek toksik potensial dari
peningkatan kadar spesies oksigen reaktif (ROS) [79], adalah tinggi pada sel
induk leukemia CD34 + / CD38− normal dan pasien, dan dengan demikian
memainkan peran penting dalam resistensi terhadap kemoterapi [80]. Aktivitas
ALDH adalah penanda selektif potensial untuk sel punca kanker pada berbagai
jenis kanker, seperti kanker payudara [53], kanker kandung kemih [81], karsinoma
sel skuamosa kepala dan leher [82], kanker paru-paru [83], dan
rhabdomyosarcoma embrional [84]. Menariknya, sistem model kultur sel dan
studi sampel klinis menunjukkan bahwa sel batang kanker positif-ALDH1A1
mempromosikan resistensi yang signifikan terhadap EGFR-TKI (gefitinib) dan
obat kemoterapi antikanker lainnya (cisplatin, etoposide, dan fluorouracil)
dibandingkan ALDH1A1-negatif. sel pada kanker paru-paru [85]. Selain itu,
tingkat ekspresi ALDH1 yang tinggi memprediksi respon atau resistensi yang
buruk terhadap terapi kemoradioaktif pra operasi pada pasien kanker
kerongkongan yang dapat direseksi [86].

3.3. Dormansi CSC.

Telah dibuktikan bahwa selain heterogenitas intratumoral yang diprakarsai

oleh evolusi subklon beragam secara genetik, ada juga klon yang berbeda secara
fungsional, yang ditemukan dengan melacak keturunan sel tunggal menggunakan
lentivirus, dalam garis keturunan genetik pada kanker kolonal [ 87]; dengan
demikian, proses-proses yang menghasilkan keragaman dalam klon genetik ini
mempromosikan sel-sel untuk potensi kelangsungan hidup yang lebih tinggi,
terutama selama stres seperti kemoterapi. Sebagai contoh, kemoterapi dapat
menginduksi pertumbuhan tumor dari garis silsilah yang sebelumnya relatif tidak
aktif atau berkembang biak yang masih mempertahankan potensi perbanyakan
tumor yang kuat, yang mengarah pada pertumbuhan kanker dan resistensi obat
[87]. Demikian pula, dalam glioblastoma multiforme, ada juga keberadaan subset
sel tumor endogen yang relatif diam dengan karakteristik yang mirip dengan sel
punca kanker yang bertanggung jawab untuk mempertahankan pertumbuhan
tumor jangka panjang dan oleh karena itu menyebabkan kekambuhan melalui
produksi populasi sementara yang sangat proliferatif. sel [17]. Secara bersamaan,
kerusakan yang diinduksi kemoterapi merekrut kelompok CSC kandung kemih
yang bertahan lama selama periode celah antara siklus kemoterapi menjadi
respons pembelahan sel yang tak terduga untuk mengisi kembali tumor residual,
mirip dengan mobilisasi perbaikan luka sel-sel batang penduduk jaringan [88 ]

3.4. Ketahanan terhadap kematian sel yang disebabkan oleh kerusakan DNA.

CSC dapat resisten terhadap kematian sel yang disebabkan oleh kerusakan
DNA melalui beberapa cara. Ini termasuk perlindungan terhadap kerusakan DNA
oksidatif dengan meningkatkan pembersihan ROS, promosi kemampuan
perbaikan DNA melalui ATM dan fosforilasi CHK1 / CHK2, atau aktivasi jalur
pensinyalan anti-apoptosis, seperti PI3K / Akt, WNT / b-catenin, dan Notch jalur
pensinyalan [24]. Misalnya, CD44, molekul adhesi yang diekspresikan dalam
CSC, berinteraksi dengan transporter glutamat-sistin dan mengendalikan level
intraseluler dari glutathione tereduksi (GSH); karenanya, CSC yang
mengekspresikan CD44 tingkat tinggi menunjukkan peningkatan kapasitas untuk
sintesis GSH, menghasilkan pertahanan yang lebih kuat terhadap ROS [89].
Menariknya, mirip dengan sel-sel induk jaringan normal, CSCs memiliki tingkat
ROS yang lebih rendah, yang dikaitkan dengan peningkatan ekspresi sistem
pembilasan radikal bebas, yang mengarah ke pertahanan ROS yang lebih tinggi
dan resistensi radioterapi juga [90]. Selain itu, subset CSC CD44 + / CD24− /
rendah pada kanker payudara resisten terhadap radiasi melalui aktivasi sinyal
ATM tetapi tidak tergantung pada perubahan aktivitas perbaikan DNA
nonhomologous end join (NHEJ) [91]. Demikian pula, sel-sel tumor pengekspres
CD133 yang diisolasi dari genoma xenografts manusia dan spesimen primer
pasien glioblastoma lebih disukai mengaktifkan pos pemeriksaan kerusakan DNA
dalam menanggapi radiasi dan memperbaiki kerusakan DNA yang diinduksi
radiasi lebih efektif daripada sel-sel tumor negatif CD133 [92]. Notch pathway
juga mempromosikan radioresistensi sel punca glioma karena penghambatan
Notch dengan gamma-secretase inhibitor (GSIs) menginduksi sel punca glioma
agar lebih peka terhadap radiasi pada dosis yang relevan secara klinis karena
pengurangan PI3K yang diinduksi oleh radiasi. / Akt aktivasi dan diregulasi
tingkat isoform apoptosis terpotong dari Mcl-1 (Mcl-1) sementara tidak
mengubah respon kerusakan DNA [93].

3.5. Lingkungan Tumor.

Telah ditunjukkan bahwa lingkungan mikro yang berbeda dari berbagai

komposisi seluler adalah penting untuk melindungi dan mengatur sel-sel induk
normal. Lingkungan mikro yang setara juga ditemukan dalam CSCs di mana
CSCs didukung dengan baik dalam ceruk histologis, yang disebut lingkungan
mikro CSC [94-96], yang mengandung stroma konektif [97-101] dan jaringan
pembuluh darah [102-106]. Lingkungan ini mempercepat dinamika divisi CSC,
memungkinkan mereka untuk membedakan sel anak nenek moyang serta
memperbarui diri dan mempertahankan CSC dalam keadaan perkembangan
primitif. Sel-sel dalam lingkungan mikro CSC mampu menstimulasi jalur
pensinyalan [58], seperti Notch [102, 107, 108] dan Wnt [109-111] yang dapat
memfasilitasi CSC untuk bermetastasis, menghindari anoikis, dan mengubah
dinamika divisi, mencapai repopulasi dengan pembagian simetris [109, 112-114].

3.5.1. Hipoksia

Jalur pensinyalan Hypoxia dan HIF telah terbukti berkontribusi pada regulasi
dan keberlanjutan CSC dan fenotip EMT seperti migrasi sel, invasi, dan
angiogenesis [115], melalui peningkatan ekspresi gen tanda tangan VEGF, IL-6,
dan CSC seperti Nanog, Oct4, dan EZH2, pada kanker pankreas misalnya [116].
Oleh karena itu, jalur pensinyalan HIF juga dapat berperan dalam resistensi CSC
terhadap terapi. Dalam lingkungan mikro hipoksik, faktor hipoksia dan faktor
yang diinduksi hipoksia HIF1-α meningkatkan persistensi sel CML terutama
melalui upregulasi faktor yang diinduksi hipoksia 1α (HIF1-α), independen dari
aktivitas kinase BCR-ABL1 [117 ] Demikian pula, hipoksia meningkatkan CSC
paru yang kebal gefitinib pada NSCLC mutasi-positif EGFR dengan
meningkatkan ekspresi faktor pertumbuhan seperti insulin 1 (IGF1) melalui
HIF1α dan mengaktifkan reseptor IGF1 (IGF1R) [118]. Menariknya, autophagy
diregulasi dalam kanker pankreas dalam kondisi mikro-oksigen rendah dan
kekurangan gizi, mirip dengan tumor hipoksia, dan kemudian mempromosikan
kelangsungan hidup klonogenik dan migrasi sel CSChigh pankreas [119].

3.5.2. Cancer-Associated Fibroblasts (CAFs).

Telah diindikasikan bahwa selain resistensi otonom sel CSC, kecapi juga
menargetkan non-CSC dengan stimulasi fibroblas terkait kanker (CAFs) yang
menciptakan ceruk tahan chemoresistant oleh peningkatan sekresi sitokin dan
kemokin khusus, termasuk interleukin-17A (IL-17A), faktor pemeliharaan CSC
dengan mempromosikan pembaruan diri dan invasi [120]. Telah ditunjukkan
sebelumnya bahwa CSC dapat berdiferensiasi menjadi sel seperti CAF (CAFLC)
dan karenanya mereka adalah salah satu sumber utama CAF yang mendukung
pemeliharaan tumor dan kelangsungan hidup di ceruk kanker [121]. CAF dikenal
untuk mensekresi berbagai faktor pertumbuhan, sitokin, dan kemokin yang
berbeda, termasuk faktor pertumbuhan hepositone (HGF), yang mengaktifkan
reseptor MET untuk melindungi CSC dari apoptosis sebagai respons terhadap
monoterapi cetuximab yang menargetkan EGFR pada kanker kolorektal
metastatik [122].

3.5.3. Peradangan.

Selain itu, pengobatan jangka panjang sel-sel kanker payudara dengan

trastuzumab secara khusus memperkaya CSC yang menunjukkan fenotipe EMT
dengan tingkat sitokin IL-6 yang lebih tinggi dibandingkan dengan sel-sel
parental; sebagai akibatnya, sel-sel ini mengembangkan resistensi trastuzumab
yang dimediasi oleh aktivasi loop umpan balik inflamasi yang dimediasi IL-6
untuk memperluas populasi CSC [123]. Demikian pula, pensinyalan TGF-β
autokrin dan ekspresi IL-8 juga ditingkatkan setelah pengobatan kemlitaxel obat
kemoterapi pada kanker payudara triple-negative, yang mengarah pada pengayaan
populasi CSC dan kekambuhan tumor [124]. Lebih lanjut, kemokin stroma yang
diturunkan faktor stroma yang diturunkan 1a (SDF-1a) dan reseptor serumpunnya
CXCR4 memainkan peran penting dalam migrasi sel hematopoietik ke
lingkungan mikro sumsum tulang [125, 126], jadi SDF-1A / CXCR4 interaksi
memediasi resistensi sel leukemia terhadap apoptosis yang diinduksi kemoterapi
[127], dan dengan demikian penghambatan CXCR4 dengan inhibitor seperti
AMD3100 dapat meningkatkan sensitivitas sel leukemia terhadap kemoterapi
dengan mengganggu interaksi sel stroma / leukemia dalam lingkungan mikro
sumsum tulang oleh Akt phosphoryla- penghambatan tion dan induksi
pembelahan PARP karena bortomomib di hadapan sel stroma sumsum tulang
(BMSCs) dalam coculture [128]. Selain itu, CSC dari tumor yang tahan chemores
memiliki kemampuan unik untuk menghasilkan berbagai sinyal proinflamasi,
seperti IFN regulatory factor-5 (IRF5), yang bertindak sebagai faktor transkripsi
khusus untuk tumor yang tahan chemores untuk menginduksi produksi M-CSF ,
untuk akibatnya menghasilkan sel myeloid imunoregulasi M2-like dari CD14 +
monosit, dan untuk mempromosikan aktivitas tumorigenik dan sel punca yang
dimediasi sel myeloid dari tumor curah [129].

3.5.4. Sel Kekebalan Tubuh

Telah diindikasikan sebelumnya bahwa makrofag terkait-tumor (TAMs) dapat

mempromosikan kemoresistensi pada kedua garis sel myeloma dan sel myeloma
primer dari apoptosis yang diinduksi oleh obat kemoterapi atau obat kemoterapi
secara langsung dengan berinteraksi dengan sel-sel ganas dalam lingkungan mikro
tumor dan melemahkan aktivasi dan pembelahan dari pensinyalan apoptosis yang
tergantung caspase [130]. Selain itu, TAM juga secara langsung menginduksi sifat
CSC sel tumor pankreas dengan mengaktifkan transduser sinyal dan aktivator
transkripsi 3 (STAT3) dan dengan demikian menghambat respon limfosit T
antitumor CD8 + T dalam respon kemoterapi [131]. Selain itu, pada
adenokarsinoma duktus pankreas, sel kanker mensekresi faktor penstimulasi
koloni 1 (CSF1) untuk menarik dan menstimulasi reseptor CSF- (CSF1R-) yang
mengekspresikan TAM untuk mengekspresikan tingkat tinggi sitidin deaminase
(CDA), suatu enzim intraseluler yang mengkatalisasi enzim bentuk bioaktif dari
tabibin dan oleh karena itu melindungi sel-sel kanker dari kemoterapi [132].

3.6. Epigenetik

Selain itu, resistensi obat yang dimediasi CSC juga diatur oleh mekanisme
epigenetik, termasuk modifikasi histone dan metilasi DNA. Pertama, metilasi
DNA tidak berubah selama EMT yang dimediasi TGF-β tetapi perubahan
epigenetik lainnya seperti lisin spesifik deaminase-1- (Lsd1-) bergantung pada
reduksi global dari tanda heterokromatin H3-lys9 dimethylation (H3K9Me2),
peningkatan tanda euchromatin H3-lys4 trimetilasi (H3K4Me3) dan tanda
transkripsi H3-lys36 trimethylation (H3K36Me3) ditemukan; terutama,
H3K4Me3 mungkin berkontribusi terhadap chemoresistance yang diatur Lsd1
[133]. Selain itu, KDM1A, flavin ade-sembilan dinucleotide- (FAD-) tergantung
demethylase spesifik lisin khusus dengan monomethyl- dan dimethyl-histone H3
lysine-4 (H3K4) dan lisin-9 (H3K9) substrat, adalah penting regulator MLL-AF9
leukemia stem cell (LSC) potensi onkogenik dengan memblokir diferensiasi
[134]. Selain itu, situs integrasi virus Moloney murine leukemia spesifik sel B
(BMI1), salah satu dari beberapa protein peredam epigenetik yang termasuk
dalam kelompok Polycomb (PcG), diperlukan untuk pembaharuan diri dari kedua
sel induk dewasa dan banyak CSC melalui berbagai jalur-jalur utama, seperti
pertumbuhan bebas-jangkar, jalur Wnt dan Notch [135]. BMI-1 telah
diindikasikan terlibat dalam perlindungan sel kanker dari apoptosis atau resistensi
obat dalam berbagai jenis kanker, termasuk karsinoma nasofaring [136],
melanoma [137], adenokarsinoma pankreas [138], kanker ovarium [139], dan
karsinoma hepatoselular [140]. Lebih jauh lagi, anggota PcG lainnya EZH2,
subunit katalitik dari kompleks penekan polycomb 2 (PRC2) yang memetilasi
histon H3 pada lisin 27 (H3K27me) dan memunculkan pembungkaman gen, juga
berpartisipasi dalam kemoterapi kanker kanker pankreas dengan membungkam
gen penekan tumor p27 melalui metilasi histone H3 -lysine 27 (H3K27) [141].
Selain itu, EZH2 melindungi GSC dari kematian sel yang diinduksi radiasi dan
akibatnya mempromosikan kelangsungan hidup GSC dan radioresisten melalui
regulator hulu mitosis kinase embrionik leucine-ritsleting kinase ibu (MELK)
[142]. Selain itu, penghambatan EZH2 peka BRG1 dan EGFR hilangnya fungsi
tumor mutan untuk topoisomerase II (TopoII) inhibitor etoposide dengan
peningkatan fase S, bridging anafase, dan apoptosis [143]. Menariknya, EZH2 dan
BMI1 diindikasikan berkorelasi terbalik dengan tanda tangan prognosis dan
mutasi TP53 pada kanker payudara [144].
Kedua, asetilasi histone terlibat dalam regulasi aktivasi transkripsi dan
chemoresistance dari CSC juga. Pengobatan dengan HDAC inhibitor (HDACi)
secara efektif menargetkan sel punca myelogenous kronis (CML) diam yang
resisten terhadap inhibitor tirosin kinase imatinib mesylate (IM) [145]. Demikian
pula, pretreatment dengan inhibitor HDAC dapat membuat peka sel-sel seperti
batang prostat untuk pengobatan radiasi melalui peningkatan kerusakan DNA dan
mengurangi kelangsungan hidup klonogenik [146]. Vorinostat, inhibitor HDAC
melalui induksi di mana-mana dan degradasi lisosom, menurunkan regulasi dan
pensinyalan dari ketiga reseptor EGFR, ErbB2, dan ErbB3 bersama dengan
pengembalian EMT dalam EGFR TKI sel tahan gefitinib dan oleh karenanya
meningkatkan efek antitumib dari gefitinib in karsinoma sel skuamosa kepala dan
leher [147]. Menariknya, NANOG meningkatkan pengaturan histone deacetylases
1 (HDAC1) melalui pengikatan ke daerah promotor dan mengurangi asetilasi H3
nada K14 dan K27; sebagai hasilnya, itu menginduksi tidak hanya fitur seperti
batang melalui represi epigenetik dari penghambat siklus sel CDKN2D dan
CDKN1B tetapi juga resistensi imun dan chemoresistance melalui peningkatan
regulasi MCL-1 oleh pembungkaman epigenetik dari E3 ubiquitin-ligase TRIM17
dan NOXA [148].
Ketiga, banyak gen penekan tumor telah terbukti secara epigenetik
dibungkam pada kanker yang resisten dengan metilasi DNA pada daerah promotor
CpG. Sebagai contoh, penekan tumor seperti faktor pertumbuhan protein pengikat
protein-3 (IGFBP-3), yang terlibat dalam mengendalikan pertumbuhan sel,
transformasi, dan kelangsungan hidup, secara spesifik diturunkan melalui
promotor-hipermetilasi dan menghasilkan resistensi yang didapat terhadap
kemoterapi di banyak berbeda. jenis kanker [149]. Selain itu, hilangnya gen
perbaikan ketidakcocokan DNA (MMR) hMLH1 melalui hypermetethylation
penuh dari propeller hMLH1 [150] sangat berkorelasi dengan kemampuan
menangkap kematian sel dan siklus sel setelah kerusakan DNA yang diinduksi
oleh cheapyapy dan prediksi survival yang buruk. untuk pasien kanker [151],
maka memainkan peran dalam resistensi obat pada ovarium [152] dan kanker
payudara [153].

3.7. Jalur pensinyalan dari CSC-Driven Chemoresistance

Seperti yang disebutkan, sel-sel induk normal dan CSC memiliki karakteristik
yang sama seperti pembaruan diri dan diferensiasi. Mereka juga berbagi jumlah
jalur pensinyalan kunci untuk mempertahankan keberadaannya. Sebagai contoh,
pensinyalan Notch sangat diekspresikan dalam tumor hematopoietik seperti T-
ALL dan tumor padat seperti karsinoma paru non-sel kecil (NSCLC), kanker
payudara, dan glioblastoma [154-156]. Aktivasi Hedgehog saling- naling yang
dalam kondisi normal memainkan peran penting dalam perkembangan embrio dan
regenerasi jaringan juga telah ditemukan terlibat dalam regulasi berbagai sel induk
kanker, seperti kanker pankreas, leukemia, dan karsinoma sel basal (BCC) [ 157].
Jalur pensinyalan lain seperti WNT, TGFβ, PI3K / Akt, EGFR, dan JAK / STAT,
serta regulator transkripsi termasuk OCT4, Nanog, YAP / TAZ, dan Myc juga
biasanya diaktifkan di berbagai sel induk kanker untuk mengatur diri mereka
sendiri. keadaan pembaruan dan diferensiasi [21, 158]. CSC telah diindikasikan
untuk menampilkan banyak karakteristik sel induk embrionik atau jaringan dan
jalur pensinyalan perkembangan seperti Wnt, HH, dan Notch yang sangat
dikonservasi secara embrionik dan mengendalikan pembaharuan diri sel induk
[159]. Oleh karena itu, aktivasi jalur ini dapat memainkan peran penting dalam
perluasan CSC dan karenanya resistensi terhadap terapi [160]. Di sini, beberapa
perwakilan dijelaskan.
Pertama, telah ditunjukkan bahwa aktivasi pensinyalan Wnt / β-catenin
meningkatkan kemoresisten terhadap terapi kombinasi IFN-α / 5- FU [161]. Sel
OV6 + HCC, subpolasi sel progenitor yang kurang terdiferensiasi dalam garis sel
HCC dan jaringan HCC primer, telah terbukti sebagai pensinyalan Wnt / β-catenin
aktif endogen dan resisten terhadap kemoterapi standar [162]. Selain itu, dalam
neuroblasoma, amplifikasi dan upregulasi reseptor Wnt frizzled-1 (FZD1)
mengaktifkan jalur Wnt /--catenin dalam sel kanker yang diproteksi dengan
translokasi β-catenin nuklir dan transaktivasi gen target Wnt seperti resistansi
multidrug. gen (MDR1), yang diketahui memediasi resistensi terhadap kemoterapi
[163]. Selain itu, c-Kit, reseptor faktor sel induk (SCF), memediasi melalui
chemoresistance aktivasi jalur Wnt / β-catenin dan ATP-mengikat kaset G2
(ABCG2) pada kanker ovarium [164].
Kedua, jalur Hh dapat mengatur autophagy dalam sel-sel CML dan kemudian
penghambatan jalur Hh dan autophagy secara bersamaan dapat secara tajam
mengurangi viabilitas sel dan secara signifikan menginduksi apoptosis sel-sel
BCR-ABL + yang sensitif terhadap imatinib atau -tahan melalui penurunan
regulasi aktivitas kinase BCR -ABL oncoprotein [165]. Bersamaan dengan itu,
ekspresi sonic landak (SHH) dan homolog onco-gen yang terkait glioma (GLI1),
molekul jalur pensinyalan terkenal yang terlibat dalam resistansi obat, lebih tinggi
pada kanker lambung CD44 + / Musashi-1 + yang diperkaya. sel induk dan
akibatnya meningkatkan resistensi obat melalui aktivitas pompa efluks obat yang
tinggi [166]. Pada glioma, populasi CD133 + CSC, yang berkontribusi pada
kemoresisten terapi seperti pengobatan temozolomide (TMZ), terlalu banyak
mengekspresi gen yang terlibat dalam jalur Notch dan SHH dan mengaktifkan
jalur ini [167].
Terakhir namun tidak kalah pentingnya, kemoterapi seperti oxaliplatin
menginduksi reseptor Notch-1 dan targetnya ke hilir aktivitas Hes-1 dengan
meningkatkan aktivitas gamma-sekretase dalam sel kanker usus; karenanya,
penghambatan pensinyalan Notch-1 oleh gamma-secretase inhibitor (GSIs)
membuat sel-sel kanker usus menjadi peka terhadap kemoterapi [168]. Selain itu,
jalur pensinyalan Notch dan Notch3 secara khusus memainkan peran penting
dalam pengaturan pemeliharaan CSC dan chemoresistance terhadap platinum
dalam terapi kanker ovarium [169]. Demikian pula, pengayaan sel CD133 +
dalam adenokarsinoma paru-paru setelah induksi cisplatin mengarah pada
resistensi multi-obat melalui aktivasi pensinyalan Notch karena tingkat yang lebih
tinggi dari Notch1 terpecah (NICD1) terdeteksi [170]. Lebih lanjut, telah
ditunjukkan bahwa sel-sel adenokarsinoma paru resisten yang didapat gefitinib
menjalani EMT dengan aktivasi pensinyalan Notch-1 melalui domain intraseluler
reseptor Notch-1 (N1IC), bentuk yang diaktifkan dari reseptor Notch-1 [63].
Selain itu, ada juga beberapa molekul yang bertindak sebagai integrasi
berbagai jalur yang terlibat dalam pengendalian nasib sel induk di seluruh
jaringan; sebagai contoh, CYP26, suatu enzim pencegah-retinoid primer melalui
jalur-jalur retinoid dan Hedge-hog, membatasi konsentrasi asam retinoat, karena
itu mengarah pada resistensi obat pada ceruk sel induk [171].

4. Terapi Berbasis CSC

Karena kemampuan CSC untuk mengembangkan chemo dan radiore- sistance

yang memainkan peran kunci dalam perkembangan ganas, metastasis, dan
kambuhnya kanker, disarankan bahwa menargetkan sel-sel induk kanker
menawarkan tujuan akhir untuk mengatasi prognosis yang buruk, memimpin
untuk kelangsungan hidup pasien yang lebih baik [15, 22]. Penargetan selektif
dari jaringan pensinyalan CSC yang penting untuk pembaruan diri, proliferasi,
dan diferensiasi untuk mempertahankan sifat sel punca mereka memberikan
tantangan baru dalam pengembangan perawatan kanker [19, 172]. Selama dekade
terakhir, disarankan bahwa kombinasi terapi konvensional dan terapi bertarget
terhadap jalur spesifik CSC menimbulkan konsekuensi yang lebih baik
dibandingkan dengan monoterapi dalam pengangkatan tumor curah dan populasi
CSC (Gambar 1) [19] . Dengan demikian, penargetan jalur-jalur penting dalam
CSCs seperti Notch, Wnt, dan Hedgehog (HH) sedang dikembangkan untuk
memblokir pembaruan mandiri CSCs [21]. Akhir-akhir ini, beberapa kelas
inhibitor jalur Notch telah dilaporkan memasuki uji klinis, disertai dengan
berbagai target, mekanisme aksi, dan kelas obat [19, 21]. Kelas utama dari Notch
inhibitor adalah γ-secretase inhibitor (GSIs). GSI bekerja dengan menghambat
pembelahan proteolitik akhir dari reseptor Notch, yang menghasilkan pelepasan
fragmen intraseluler aktif. Itu adalah kelas pertama penghambat jalur Notch yang
memasuki uji klinis di bidang kanker [159, 173, 174].
Jalur HH terbukti terlibat dalam beberapa jalur perkembangan penting seperti
pola jaringan selama perkembangan embrionik dan perbaikan jaringan normal dan
transisi epitel ke mesenkimal [175]. Vismodegib, obat penargetan jalur HH, telah
disetujui oleh Badan Obat Eropa (EMA) pada 2013 dan US FDA pada 2012 untuk
terapi pasien BCC metastatik atau pasien BCC lanjut lokal yang bukan kandidat
untuk operasi atau radioterapi [176, 177].
Penargetan pensinyalan Wnt juga telah menunjukkan hasil yang menjanjikan
terkait dengan karsinogenesis, invasi tumor, dan metastasis [159]. Mnt netralisasi
Wnt3A terbukti memiliki efek antiproliferasi dan proapoptosis pada model tikus
kanker prostat [178]. Dan mAb yang berlabel radio anti-Fz10 sedang dievaluasi
dalam uji coba fase I untuk terapi sarkoma sinovial. Vantictumab (OMP-18R5,
mAb yang memblokir lima reseptor Fz seperti Fz1, Fz2, Fz5, Fz7, dan Fz8) [179-
181] dan OMP-54F28 [181] (mAb yang memblokir reseptor pemikat protein fusi
seperti terpotong) Fz8) sedang diselidiki dalam studi fase I pada tumor padat
stadium lanjut [182].
Menargetkan CSC melalui jalur EMT juga memberikan tantangan baru dalam
studi terapi kanker. Terapi ini dikembangkan untuk mencegah agresivitas kanker
dan memperoleh resistensi obat dari sel induk kanker [183, 184]. Akhir-akhir ini,
temuan agen terapeutik untuk terapi CSC berbasis EMT menunjukkan tiga
kelompok target umum [184, 185]. Ini termasuk kelompok yang terlibat dalam
regulasi penginduksi ekstraseluler EMT seperti TGF-β, EGF, jalur Axl-Gas6,
hipoksia, dan komponen matriks ekstraseluler. Kelompok lain adalah faktor
transkripsi (TF) yang mempromosikan transkriptom EMT termasuk Twist1,
Snail1, Zeb1 / 2, T-box TF Brachyury serta efektor hilir EMT, seperti E-Cadherin,
N-Cadherin, vimentin, dan HoxA9. Yang terakhir adalah menargetkan regulator
EMT-TF dan regulator epigenetik menggunakan microRNA [184-190].
Akumulasi bukti menunjukkan bahwa miRNA dan kelompok lain dari RNA
non-coding lama (lncRNA) memainkan peran penting dalam regulasi properti
CSCs seperti pembaruan diri, pembelahan sel asimetris, inisiasi tumor, resistensi
obat, dan kekambuhan penyakit [186, 187, 189, 191–193]. Penggunaan miRNA
sebagai agen terapeutik berbasis CSC dilaporkan; misalnya, mir-22 yang
menargetkan TET2 pada leukemia (AML dan MDS) dan kanker payudara [194],
Misalkan-7 untuk menargetkan RAS dan HMGA2 pada kanker payudara [195],
mir-128 menargetkan BMI-1 pada kanker otak [ 191], mir-200 untuk menargetkan
ZEB1 / ZEB2, BMI-1, dan SUZ12 pada kanker payudara [189, 196, 197], dan
beberapa miRNA lain dalam kanker usus besar dan kanker prostat telah
dilaporkan mengurangi keganasan kanker [198– 202].
Akhirnya, imunoterapi kanker dapat menjadi terobosan untuk menargetkan
secara khusus CSC pada pasien kanker. Untuk imunoterapi kanker, beberapa
efektor, termasuk sel pembunuh alami (NK) dan sel γδT dalam imunitas bawaan,
antibodi dalam imunitas humoral yang diperoleh, sel dendritik berbasis CSC, dan
limfosit T sitotoksik (CTL) prima CSC dalam imunitas seluler yang didapat, yang
terdiri dari mampu mengenali dan membunuh CSC mungkin kandidat yang cocok
untuk meningkatkan kemanjuran pengobatan kanker. Berbagai strategi
imunoterapi yang secara khusus menargetkan CSC menggunakan sel-sel efektor
ini telah dilaporkan. Selain itu, identifikasi antigen spesifik atau perubahan
genetik pada CSC memainkan peran penting dalam menemukan target
imunoterapi. Ini termasuk penanda CSC (ALDH [203], CD44 [204, 205], CD133
[206], EpCAM [207], dan HER2 [208]), interaksi ceruk CSC (TAM [209]), tumor
lingkungan mikro (sel imun / sel penekan turunan myeloid), sitokin (IL1 [210],
IL6 [211], dan IL8 [212]), dan pos pemeriksaan imun (CTLA-4 [213] atau PD1 /
PDL1 [214]).

5. Kesimpulan

CSCs memiliki fitur seperti sel induk yang ditemukan pada kanker dan
memiliki implikasi penting untuk kemoresistensi dan kekambuhan kanker, sebuah
gagasan yang tetap agak kontroversial. Dengan subpopulasi kecil di kumpulan sel
ganas, kontribusi CSC luar biasa dalam terapi kanker, seperti yang ditunjukkan
oleh penelitian intensif dalam beberapa dekade terakhir. Sel-sel ini dapat
diidentifikasi berdasarkan keberadaan biomarker permukaan, peningkatan
pembentukan spheroid atau koloni in vitro dan potensi inisiasi tumor yang
diperbesar serta kemampuan tumorigenik in vivo. Mereka resisten terhadap
kemoterapi dan terapi radiasi dibandingkan dengan sel-sel tumor curah dan
karenanya memainkan peran penting dalam kekambuhan tumor setelah terapi
antikanker. Untuk bertahan setelah perawatan kanker, CSCs tampaknya mampu
memanifestasikan beberapa respons seperti EMT, induksi jalur sinyal yang
mengatur pembaruan diri atau mempengaruhi lingkungan tumor, ekspresi
pengangkut obat atau protein detoksifikasi, dan sebagainya. untuk melindungi
mereka dari efek buruk yang disebabkan oleh agen terapi. Dengan demikian,
pengembangan terapi antikanker yang menargetkan CSC tidak hanya terbatas
pada penemuan inhibitor jalur CSC dan penanda permukaan sel, tetapi juga untuk
pengembangan EMT dan CSC, inhibitor terkait lingkungan mikro. Meskipun
mekanisme molekuler yang mendasari resistensi CSC terhadap kemoterapi dan
radiasi masih memerlukan penelitian lebih lanjut untuk mengembangkan strategi
yang menjanjikan untuk menekan kekambuhan tumor dan metastasis, kemajuan
teknologi saat ini memudahkan daripada sebelumnya untuk menemukan
mekanisme yang berkontribusi terhadap resistensi obat. Juga, strategi terapeutik
baru-baru ini dari menggabungkan molekul yang secara khusus menargetkan
CSCs dengan obat-obat terapi konvensional mungkin bisa menjadi arah yang
lebih baik untuk terapi antikanker dan karenanya dapat mencapai tingkat
kelangsungan hidup yang lebih baik dari pasien kanker (Gambar 1) [19]. Selain
itu, karena beberapa biomarker permukaan sel dan jalur pensinyalan serupa antara
CSC dan sel batang normal, pada dasarnya juga diperlukan untuk
mengembangkan agen terapi baru yang hanya menargetkan CSC untuk
menghindari efek tidak sesuai target pada sel non-kanker atau sel induk normal.

Konflik kepentingan
Penulis menyatakan tidak ada konflik kepentingan.

Kontribusi Penulis
Lan Thi Hanh Phi dan Ita Novita Sari memberikan kontribusi yang setara untuk
pekerjaan ini.

Ucapan Terima Kasih

Pekerjaan ini didukung oleh Soonchunhyang University Research Fund and
Global Research Development Center (NRF-2016K1A4A3914725).