Breast Cancer Stem Cell and Microenvironment

Inez Tasya Usup,1 Hendry Ivan Nathaniel2

Mahasiswa Fakultas Kedokteran Universitas Kristen Krida Wacana
Jalan Arjuna Utara No.06 Kebon Jeruk, Jakarta Barat

Abstact
Breast cancer is the leading cause of death in women. Breast cancer causes widespread
psychological morbidity and pressure against millions of people worldwide. These lumps have
unilateral properties and usually do not show any size variations with the menstrual cycle are also
sometimes unable to move with irregular borders. The survival rate of breast cancer patients
depends on the stage. Developing tumors recruits a wide array of cells that make up the
microenvironment, and through iterative interactions, tumor cells and their microenvironment
proliferate. New evidence suggests that mutations are confined to tumorigenic cells, and this
modifies the epigenetic program of other nontumorigenic cells in the tumor microenvironment.
human breast cancer, mesenchymal cells can be recruited from bone marrow or from normal breast
stroma. Immunohistochemical analysis has confirmed the presence of such MSC / BCSC interactions
in biopsies obtained from breast cancer patients. Expression of stem cell markers such as ALDH1 in
breast cancer. Cells have been shown to be independent predictors of adverse outcomes in women
with breast cancer.
Keywords : breast cancer, microenvironment, MSC

Abstrak
Kanker payudara adalah penyebab utama kematian pada wanita. Kanker payudara
menyebabkan morbiditas dan tekanan psikologis yang luas terhadap jutaan orang di seluruh dunia.
Benjolan ini memiliki sifat unilateral dan biasanya tidak menunjukkan variasi ukuran apapun dengan
siklus menstruasi juga terkadang tidak dapat bergerak dengan batas yang tidak beraturan. Tingkat
kelangsungan hidup penderita kanker payudara tergantung pada stadium. Mengembangkan tumor
merekrut beragam kumpulan sel yang membentuk lingkungan mikro, dan melalui interaksi literatif,
sel tumor dan lingkungan mikronya berkembang biak. Bukti baru menunjukkan bahwa mutasi
terbatas pada sel tumorigenik, dan ini memodifikasi program epigenetik sel nontumorigenik lainnya
dalam lingkungan mikro tumor. Pada kanker payudara manusia, sel mesenchymal dapat direkrut dari
sumsum tulang atau dari stroma payudara normal. Analisis imunohistokimia telah mengkonfirmasi
adanya interaksi MSC / BCSC semacam itu dalam biopsi yang diperoleh dari pasien kanker payudara.
Ekspresi penilaian sel induk seperti ALDH1 pada kanker payudara. Sel telah terbukti menjadi
prediktor independen hasil buruk pada wanita dengan kanker payudara.

Kata Kunci : Kanker Payudara, Lingkungan Mikro, MSC

Introduction
Cancers have abnormally growing cells that normally invade surrounding tissue and spread
to other organs far away even though.1 Cancer occurs due to uncontrolled cell proliferation that
occurs without limits and goals for the host.1 Although each different cancers, cancers arise through
some of the same process which in turn depend on genetic changes, crucially, are breast cancer as
an example.1 Breast cancer is the one of leading cause of cancer death in women, causing extensive
morbidity and psychological distress to millions globally.1 Encouragingly, the combination of better
screening and treatment programmes have moderately improved the chances of surviving the
disease, but there is still much to be done if the many women who are refractory to current
therapies are to have a better chance of survival.2 Over the last decade breast cancer cells with
stem-cell-like properties have been identified and characterized.2 There is now much interest around
the role that these breast cancer stem cells (CSCs) have in the disease and whether they provide the
key to unlocking new insight into the mechanisms driving breast cancer progression, drug resistance
and reoccurrence.2 CSC have been found in many solid tumors. CSC are transformed cells that can be
rare or relatively abundant, depending on the tumor type. CSC are able to preserve tumor
heterogeneity by retaining self-renewal and differentiation capacities. In addition, CSC display an
innate resistance to therapies, which in turn associates their persistence in a tissue with disease
recurrence and eventually metastatic spread.3

The contribution of the microenvironment in this situation is crucial: it is now accepted that
the “cancer” scenario is not simply composed of transformed cells working together in an isolated
and strictly autonomous machinery. Neoplastic cells, including the BCSCs, reside in specific niches
composed by stromal, immune, endothelial cells as well as connective tissue components, growth
factors and cytokines, sustaining their status and modulating their activities. The tumor
microenvironment actively collaborates with neoplastic cells at different levels: promoting
proliferation while evading growth suppression and immune-surveillance, overcoming cell death,
modulating cell metabolism, activating angiogenesis and invasion/metastasis programs.4 In addition,
the interactions between BCSCs and the microenvironment help these cells to survive common anti-
cancer therapies thus being partly responsible for disease recurrence.5

Discussion
It is important to clarify that although they share functional similarities to normal stem cells,
CSCs are not necessarily derived from stem cells. A CSC is functionally defined by the ability to (1)
form a tumor in immunocompromised mice, (2) self-renew—shown by tumor formation in
secondary mice and (3) “differentiate,” i.e., produce cells with non-stem cell characteristics.6

The stem cell characteristics of CSCs draw in to question the cell type from which they
derive. Two potential models of CSC formation are: (1) the tumor cell of origin had stem cell or
progenitor properties, or (2) the tumorigenesis process yields cells distinct from the cells of origin
that are capable of reconstituting the tumor.2 [look at Picture 1]
 Picture 1 : Tumor Formation. (27/08/2013) Sumber Ncbi.nlm.nih.gov on Tuesday 27 August 20132

The simple model of hierarchical tissue organization suggests that as cells differentiate along
a particular lineage, they lose the potential to give rise to multiple cell types and are therefore less
likely to be able to act as CSCs.2 Normal stem cells already have many of the properties associated
with CSCs.2 Moreover, the long-lived nature of stem cells allows more time for multiple genetic
lesions to be acquired. Therefore, it is possible that CSCs originate from tissue stem cells.2

The model in which the cancer cell of origin is responsible for the properties of the CSC
would be encouraging when it comes to designing therapies to tackle the disease.2 If the tumor
behaves in a rigid linear hierarchy with relatively few stem cells giving rise to the majority
“differentiated” tumor cells then therapies that can kill CSCs or drive them to differentiate would
remove the ability of the tumor to regenerate following therapy.2

However, cancer is a disease that forms over many years, so even if the original
transformation event had occurred in a stem-like cell, the tumor that presents at the clinic is likely to
be a much more evolved and heterogeneous entity than a linearly-hierarchical tissue.2 A linear
hierarchy in cancer would also not explain why recurring tumors are resistant to therapy, as
successive rounds of tumor growth may be expected to be produce similarly-sensitive progeny.2 In
this sense, it appears that tumors have also evolved mechanisms to be self-sustaining even if their
original CSC pool is destroyed, potentially via the generation CSCs cells from non-stem cells.2

Risk Factors of Breast Cancer

Factor of the biggest problems for breast cancer the disease only one or more close
relatives (sister or mother).1,7 Some of the results from genetic studies have identified major
genes, including BRCA1 on chromosome 17 and BRCA2 on chromosome 13, which
contribute to familial breast cancer.1,7 BRCA1 and BRCA2 are important in DNA repair and
work as tumor suppressors.1,7 Women who get breast cancer genes for this disease are
usually at an earlier age than women whose families have no record of the disease.1,7 Breast
cancer genes can be carried and given by both parents, seen given in an autosomal
dominant manner.1,7 Women who have a damaged BRCA1 gene have a lifetime risk of 56%
 to 85% with ovarian cancer, whereas for the damaged BRCA2 gene have the same risk of
developing breast cancer but only 10% of all women with breast cancer have a risk factor
genetic diseases.1,7 Mutations of breast cancer genes or other common cancers including
mye or p35 genes in some women are found at birth.1,7

The risk of transmission in a lifetime estrogen associated with breast cancer

formation.1,7 Women with first menstruation and advanced menopause (genetic factors),
have no or late childhood, estrogen replacement therapy for some women, breast
fibrocystic disease (epithelial hyperplasia), high-fat diet, alcohol consumption and hormone
replacement therapy (HRT) Postmenopausal women have a great chance of developing
breast cancer.1,7 Protection against breast cancer can be cultivated with a diet rich in fruits
and vegetables, regular exercise, and weight control.1,7

Clinical Features
The presence of a lump but no pain in the breast. 50% of cancers arise in the outer top
quadrant or the central 20%. These lumps have unilateral properties and usually do not
show any size variations with the menstrual cycle are also sometimes unable to move with
irregular borders; nipple retraction, nipple discharge, or wrinkles in breast tissue that may
indicate a tumor due to breast cancer; enlarged lymph nodes, both armpits and clavicles
which may indicate the presence of metastasis.1

Diagnostic Tool
Breast self-examination ( "realize") on a regular basis is important for the early detection
of tumors in which must be done by all women over the age of 20 years; mammography, x-
ray examination of the breast, examination of the detection of important conditions to
identify the cancer before the lump in the breast can be touched. Increased use of
mammography plays a role in decreasing mortality from breast cancer as a result of early
detection. Annual or biennial mammography is recommended for all women older than 40
years and for younger women whose families have a history of the disease or other risk
factors; a suspected lump biopsy will decide a diagnosis. Determination of tumor size, tumor
features, and surrounding lymph nodes allow for staging and histologic grouping of tumors.
Staging is divided into I to IV and it is important to determine a therapy and prognosis;
estrogen receptor measurements in tumor cells signify a tumor response to estrogen, which
high levels indicate that the tumor may respond well to hormone therapy in the form of a
barrier to the ability of estrogen to work on the tumor.1

Complication
Metastasis may occur. Metastasis sites include the brain, lungs, bones, liver, and
ovaries. The survival rate depends on stage: stage I (tumor <2 cm, without metastasis) 80%,
stage II (tumor 2-5 cm, metastasis to axillary lymph nodes) 65%; stage III (tumor> 5 cm,
metastasis to axillary lymph nodes and spread to skin or chest wall) 40%; stage IV (broad
metastasis) 10%.
Management of
Surgery, a mastectomy or lumpectomy (removal of a tumor plus a small amount of
surrounding tissue) by dissection of the sentinel node (primary drainage), is the first step
performed on the majority of women. If the sentinel node biopsy is positive, then other
nodes need to be removed and examined. The lymph nodes appear to indicate tumor
metastasis and require more aggressive postoperative interventions; with radiation or
chemotherapy that can improve survival rates other than surgery and reduce the possibility
of recurrence. This therapy is based on the presence or absence of metastasis; antiestrogens
or estrogens are specially made as a disruptive growth of breast tissue that has been used
for many years as a treatment of breast tumors are positive to estrogen receptor. These
same drugs, including tamoxifen, are now used to treat speculative-looking breast tumors
that are sensitive to estrogen. These medications can improve survival rates and reduce the
likelihood of recurrence; the existence of drugs made to reduce the ability of tumor growth
is also able to treat breast cancer. For example, some tumors secrete an excessive surface
receptor, called the HER2 receptor, which binds epidermal growth factors in the blood
known to stimulate the growth of cancer cells. The trastuzumab (Herceptin) drug is designed
to bind and inhibit HER2 receptors, thereby slowing or stopping the growth of this receptor.
This drug is shown to reduce the risk of breast cancer recurrence; perform breast
reconstruction to improve appearance after surgery; the importance of counseling and
support for women, spouses and families.1

Cellular Components of The Tumor Microenvironment

Developing tumors recruit a diverse collection of cells that make up the microenvironment,
and through iterative interactions both the tumor cell and its microenvironment co-evolve.8
Although early studies suggested that some of the cells in the tumor microenvironment contained
mutations,9 more recent evidence suggests that mutations are limited to the tumorigenic cells, and
that these modify the epigenetic program of other nontumorigenic cells in the tumor
microenvironment.10 The cells in the microenvironment in turn produce epigenetic changes in tumor
cells reflected in their pattern of differentiation.8,10 These reciprocal interactions are illustrated by
changes in the tumor microenvironment that occur during evolution of pre-invasive ductal
carcinoma in situ to invasive carcinoma of the breast, and involve sequential epigenetic changes in
the tumor stromal microenvironment.8,10

In human breast cancers, mesenchymal cells may be recruited from the bone marrow 11 or
from the normal breast stroma.12 As in tumor cells, ALDH1 expression identifies MSCs that are
selectively recruited to sites of growing tumor, where they interact with BCSCs through cytokine
loops involving IL-6 and CXCL7.11 The cytokine loops stimulate the self renewal of BCSCs.11
Immunohistochemical analysis has confirmed the existence of such MSC/BCSC interactions in
biopsies obtained from breast cancer patients.11 Expression of stem cell markers such as ALDH1 in
breast cancer cells has been shown to be an independent predictor of poor outcome in women with
breast cancer.13 In addition, MSCs have the ability to differentiate into adipocytes as well as tumor-
associated fibroblasts, which also interact with and influence tumor cells.14

The activation of fibroblasts and myofibroblasts was originally described in a study of wound
healing by Gabbiani and Majno, who observed morphological changes in activated myofibroblasts as
compared with quiescent tumor- and wound-associated fibroblasts.15 Based on the similarities
between the wound healing process and cancer, both of which involve infiltration of inflammatory
cells and activation of cytokine networks, it was proposed that malignant epithelial cells are
“wounds that don’t heal”.16 In an experimental mouse model, acute wounding in the mammary
gland by dermal incision accelerated breast tumor growth and metastasis.17 Although the exact
mechanisms remain unknown, paracrine signals from evolving tumors induce epigenetic changes in
the surrounding stromal fibroblasts.18 Indeed, the gene expression profile of tumor-associated
fibroblasts resembles that of wound-activated fibroblasts, and this profile is associated with poor
prognosis.19 Growth factors such as TGF-β may be involved in these epigenetic changes, which lead
to activation of fibroblasts.20 In addition, cytokines such as SDF-1 (also known as CXCL12) produced
by breast carcinoma-associated fibroblasts (but not normal fibroblasts) may promote proliferation of
tumor cells, which express the SDF-1 receptor CXCR4.21 The level of expression of SDF-1 in serum has
been associated with poor survival in breast cancer patients.22 Other growth factors such as HGF,
produced by mammary stromal cells, may also have a profound effect on developing mammary
tumors.23 HGF provides a co-stimulatory signal to the Wnt pathway during colon carcinogenesis ,24
although it remains to be determined whether similar pathways are involved in breast
carcinogenesis. Other important growth factors produced by activated fibroblasts include the FGFs.
It has recently been shown that estrogen regulates the BCSC population through a paracrine
mechanism involving FGF9.25 Additional factors produced by cells in the tumor microenvironment
regulate tumor proliferation, invasion, and metastasis; these include IGF, PDGF, Wnt, Notch ligand,
Hedgehog ligands, and MMPs.26

The immune system exerts both inhibitory and stimulatory effects on breast tumors, and the
balance of these effects may profoundly influence tumor growth. A description of tumor-mediated
immunity is beyond the scope of this piece, and the reader is referred to recent excellent reviews on
the subject.27 However, the importance of the immune system is illustrated by recent studies that
have elucidated the mechanisms by which macrophages recognize and destroy tumor cells. Recent
studies in human leukemia and lymphoma have suggested that tumor cells express the antigen
CD47, which serves as a “don’t eat me” signal to tumor-associated macrophages .28 At the same
time, these cells express calreticulin, recognized by these macrophages as an “eat me” signal.29
Administration of a blocking antibody to CD47 induced macrophage phagocytosis of tumor cells in
vitro and in mouse models.29 Importantly, these researchers showed that leukemic stem cells as well
as bulk tumor cells could be targeted by this approach. Although CD47 expression has been shown in
breast cancer cells,30 it remains to be determined whether this antigen is also expressed on BCSCs
and whether blocking this receptor would have utility in treating breast cancer.

Conclusion
Cancer is a cell that usually invades the surrounding tissue and can spread to other organs
1
far away. Cancer occurs due to uncontrolled cell proliferation that occurs indefinitely and the
purpose for host.1 For example breast cancer is the leading cause of death in women. Breast cancer
causes widespread psychological morbidity and pressure against millions of people worldwide.1
There is now much interest in the role of breast cancer such as stem cells (CSCs) .2 CSCs are
transformed cells that can be scarce or relatively abundant, depending on the type of tumor. CSC is
able to preserve tumor heterogeneity by maintaining self-renewal and differentiation capabilities. In
addition, CSC shows innate resistance to therapy, which in turn associates their persistence in tissue
with disease recurrence and eventually spreads metastatically.3 The contribution of the
microenvironment in this situation is essential. The tumor microenvironment actively cooperates
with neoplastic cells at different levels: promotes proliferation to avoid immune suppression and
suppression, overcome cell death, modulate cell metabolism, activate angiogenesis programs and
invasion / metastasis.4 Several outcomes from genetic studies have identified major genes, including
BRCA1 on chromosome 17 and BRCA2 on chromosome 13, which contribute to family breast
cancer.1,7 Women who get breast cancer genes for this disease are usually at an earlier age than
women whose families do not has a disease record.1,7 Women with damaged BRCA1 genes have a
lifetime risk of 56% to 85% with ovarian cancer, whereas for the damaged BRCA2 gene has the same
risk of breast cancer but only 10% of all women with breast cancer have genetic disease risk
factors.1,7 Mutation of breast cancer genes or other common cancers including mye or p35 genes in
some women is found at birth.1,7

In clinical features 50% of cancers appear in the outer quadrant of the upper or central
20%. These lumps have unilateral properties and usually do not show any size variations with
menstrual cycles also sometimes can not move with irregular borders. The survival rate of breast
cancer patients depends on stage: stage I (tumor <2 cm, without metastasis) 80% stage II (tumor 2-5
cm, metastasis to axillary lymph nodes) 65%; stage III (tumor> 5 cm, metastasis to axillary lymph
nodes and spread to the skin or chest wall) 40%; stage IV (metastasis area) 10%. In the majority of
women, removal of a tumor by a sentinel node surgery (primary drainage), is the first step taken. Or
with chemotherapy radiation that can increase survival rates in addition to surgery and reduce the
chances of relapse. This therapy is based on the presence or absence of metastasis.1 And
Antiestrogen or Estrogen is specifically made as an annoying growth of breast tissue that has been
used for many years due to the treatment of breast tumors positive against estrogen receptors. The
presence of drugs made to reduce the ability of tumor growth is also able to treat breast cancer. For
example, HER2 receptors, which bind to epidermal growth factors in the blood are known to
stimulate the growth of cancer cells. It is also important to conduct counseling and support for
women, spouses and families. Developing tumors recruits a wide array of cells that make up the
microenvironment, and through iterative interactions, tumor cells and microenvironment
proliferate.8 New evidence suggests that mutations are confined to tumorigenic cells, and this
modifies the epigenetic program of other nontumorigenic cells in the tumor microenvironment.10
human breast cancer, mesenchymal cells can be recruited from bone marrow11 or from normal
breast stroma.11 Immunohistochemical analysis has confirmed the presence of such MSC / BCSC
interactions in biopsies obtained from breast cancer patients.11 Expression of stem cell markers such
as ALDH1 in breast cancer. cells have been shown to be independent predictors of adverse
outcomes in women with breast cancer.13
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