CSCs

Hindawi Stem Cells International Volume
2018, Article ID 5416923, 16 halaman

https://doi.org/10.1155/2018/5416923Cell
Tinjau Artikel Stem Cancer (CSCs) dalam Resistensi

Obat dan Implikasi Terapi dalam Pengobatan Kanker
Lan Thi Hanh Phi, Ita Novita Sari, Ying-Gui Yang, Sang-Hyun Lee, Nayoung Jun, Kim
Kwang Seock, Yun Kyung Lee, dan Hyog Young Kwon
Soonchunhyang Institut Ilmu Medi-bio (SIMS), Universitas Soonchunhyang, Asan, Republik Korea.
Korespondensi harus ditujukan kepada Yun Kyung Lee; yunklee@sch.ac.kr dan Hyog Young Kwon; hykwon@sch.ac.kr
Menerima 28 September 2017; Diterima 11 Januari 2018; Diterbitkan 28

Februari 2018
Editor Akademik: Pratima Basak
Hak Cipta © 2018 Lan Thi Hanh Phi et al. Ini adalah artikel akses terbuka yang didistribusikan di bawah Lisensi Atribusi Creative
Commons, yang memungkinkan penggunaan, distribusi, dan reproduksi tanpa batas dalam media apa pun, asalkan karya aslinya
dikutip dengan benar.
Sel-sel kanker stem (CSC), juga dikenal sebagai sel-sel tumor-memulai (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.
tubuh, sementara menggabungkan radioterapi dengan
kemoterapi dapat effectively memberikan hasil yang lebih baik
untuk mengobati berbagai jenis kanker [3]. Agen kemoterapi
1. Pendahuluan terbaru berhasil melawan lesi tumor primer dan residunya
setelah operasi atau radioterapi [4]. Namun, kemoterapi
Kanker adalah salah satu penyebab utama morbiditas dan menyebabkan heterogenitas tumor berasal dari kedua normal
mortalitas di seluruh dunia dengan sekitar 20% dari semua dan sel kanker dan heterogenitas dalam tumor, pada gilirannya,
kematian di negara maju [1]. Dari studi kanker praklinis dan menghasilkan mengurangi effEctskemoterapi; berkontribusi
klinis, berbagai pilihan diagnostik dan pengobatan baru untuk terhadap kegagalan pengobatan dan perkembangan penyakit
pasien kanker memberikan kemajuan penting dalam [5, 6]. Chemoresistance adalah masalah utama dalam
pengobatan dan pencegahan kanker [2]. Heterogenitas kanker pengobatan pasien kanker, sel-sel kanker menjadi resisten
adalah salah satu alasan yang berkontribusi terhadap kegagalan terhadapkimia
pengobatan dan perkembangan penyakit. Di antara beberapa zatyang digunakan dalam pengobatan, yang akibatnya
perawatan kanker, perawatan utama yang biasa digunakan membatasi eFFIefisiensi agen kemoterapi [7]. Ini juga sering
untuk merawat pasien adalah pembedahan, radioterapi, dan dikaitkan dengan tumor yang berubah menjadi bentuk yang
kemoterapi. Bedah berhasil dapat menghapus kanker dari lebih agresif dan / atau tipe metastasis [8-11].
Mengumpulkan bukti-bukti menunjukkan bahwa stem2. Penanda Asal dan PermukaanKanker
sel kanker (CSC) populasi, subkelompok sel kanker, Sel Punca(CSC)
bertanggung jawab untuk chemoresistance dan kanker
kambuh, karena memiliki kemampuan untuk memperbaharuiSel punca kanker (CSC), juga dikenal sebagai sel pemicu
diri dan differentiate ke dalam garis keturunan heterogen seltumor (TIC), telah dipelajari secara intensif dalam dekade
kanker dalam menanggapi agen kemoterapi [12-14]. CSC jugaterakhir, dengan fokus pada sumber yang mungkin, asal,
mampu menginduksi siklus sel tahanan (state diam) yangseluler penanda, studi mekanisme, dan pengembangan strategi
mendukung kemampuan mereka untuk menjadi resistenterapi yang menargetkan jalur mereka [23, 24]. Yangpertama
terhadap kemoterapi dan radioterapi[15-20].Agen-agenmeyakinkan-bukti dence dari CSC dilaporkan oleh Bonnet dan
kemoterapi umum menargetkan sel-sel yang berproliferasiDick pada tahun 1997 olehpengidentifikasiandari
untuk memimpin apoptosis mereka, seperti yang disebutkansubpopulasi sel leukemia mengekspresikan permukaan
sebelumnya. Meskipun terapi kanker yang berhasilpenanda CD34, tapi tidak CD38. CD34+/ CD38- subpopulasi
menghapuskan sebagian besar sel-sel tumor yang berkembangmampu memulai pertumbuhan tumor pada tikus penerima
biak, sejumlah CSC yang tersisa dapat bertahan danNOD / SCID setelah transplantasi [25]. Selain kanker darah,
meningkatkan kekambuhan kanker karena kemampuan merekaCSC telahdiidentifikasidalam beberapa jenis tumor padat [21,
untuk membangun invasifitas yang lebih tinggi dan26]. pertamaBukti dari kehadiran CSC pada kanker padat in
chemoresistance [21, 22]. Memahami fitur-fitur CSC penting
vivo ditemukan dandiidentifikasisebagai CD44+CD24-
untuk membangun fondasi bagi era baru dalam pengobatan/rendah
Silsilah- sel pada tikus berjanji immunocom- setelah
kanker. Dalam ulasan ini, kami membahas mekanisme rinci di
transplantasi sel kanker payudara manusia pada tahun 2003
mana CSC menampilkan resistensi terhadap kemoterapi dan
[27] meskipun memiliki telah ditunjukkan secara in vitro pada
radioterapi dan implikasinya untuk uji klinis.
tahun 2002 oleh penemuan sel-sel klonogenik (pembentuk
bola) yang diisolasi dari glioma otak manusia [28]. Seiring
waktu, populasi CSC jugadiidentifikasidari beberapa petugas
bisa- padat 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 danperkembangan
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, atau dari differentiated sel / sel cer bisa- yang diperoleh
sifat batang-seperti melalui dedifferentiation [ 25, 38-50].
Karena plastisitas CSC, telah menyarankan bahwa APY ther-
kombinasional menargetkan jalur CSC dan terapi kemo
konvensional 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, hanyamerekajaringan-spesifiksel-selstem tetapi juga sel induk
menunjukkan bahwa sel-sel ini juga merupakan asal dari CSCs jaringan lainnya. Misalnya, sel-sel sumsum yang diturunkan
[43, 44]. Menariknya, CSC berasal dari transformasi tidak tulang (BMDCs) mungkin menjadi penting
2 Stem Sel Internasional
dedifferentiation
Mutasi, onkogenik
aktivasi
Self-
pembaharuan
Self- penghambatan
pembaharuan
erentiati Apoptosis / sel

siklus penangkapan
DCSC
edifferentiati
edifferentiati
on
on
edifferentiati
on
Diferensiasi
Massal tumor
Gambar 1: Asal usul CSC dan terapi kombinasi penargetan CSC dan ablasi tumor curah. CSC mungkin berasal dari salah satu sel dengan mutasi / onkog
yang telah mengalami mutasi, atau daridistem.ffsel erentiatedatau sel-sel kanker yang diperoleh sifat batang-seperti oleh dediffdiferensiasi Dengan demikia
disarankan bahwa terapi kombinasional penargetan CSC dan curah ablasi tumor mungkin memilikieterapi yang lebih baikffEctsuntuk meningkatkan hasil kl
Sel induk
pembaharuan diri
CSC dari masing-masing jenis kanker tercantum pada Tabel 1.
3. Mekanisme yang olehnya CSC

Berkontribusi pada Perlawanan
terhadap Kemoterapi dan Kambuhnya
Kanker
Penelitian terbaru menunjukkan bahwa CSC diperkaya setelah

kemoterapi karena sedikit subpopulasi sel yang tersisa dalam
jaringan tumor, yang disebut CSCs, dapat bertahan dan
berkembang meskipun sebagian besar agen kemoterapi
membunuh sebagian besar tumor [12-14]. Misalnya,
preleukemic DNMT3Amut HSCS yang dapat melakukan
Sumberdari banyak jenis tumor, seperti kanker lambung, ekspansi klonal sebagai pertamalangkah dalam
tumor saraf, dan bahkan teratoma [45]. leukemogenesis dan meregenerasi seluruh hirarki
CSC juga telah dibuktikan yang akan dihasilkan hematopoietik ditemukan untuk bertahan hidup dan
olehdediffdiferensiasidari sel progenitor atau differentiated sel berkembang dalam remisi sumsum tulang setelah kemoterapi
yang telah diperoleh “stemness” sifat sebagai akibat dari [54]. Demikian pula, paparan dosis terapi temozolomide
akumulasi tambahan genetik atau epigenetik malities abnor- (TMZ), kemoterapi antiglioma yang paling umum digunakan,
[46]. Sebagai contoh, protein fusi BCR-ABL hadir dalam sel secara konsisten memperluas kumpulan sel induk glioma
induk hematopoietik - (HSC-) seperti sel CML tetapi nenek (GSC) dari waktu ke waktu dalam garis sel glioma yang
moyang granulosit-makrofag ditemukan menjadi kandidat berasal dari pasien dan yang telah terbentuk, yang telah
LSC stadium lanjut selama krisis ledakan di CML ledakan- terbukti merupakan hasil interkonversi fenotipik dan
krisis dengan mengaktifkan proses pembaharuan diri melalui fungsional antara differentiated sel tumor dan GSCs [55].
βjalur-catenin [47]. Selain itu, telah ditunjukkan bahwa Selain itu, antibodi VEGF yang dimanusiakan bevacizumab
pensinyalan Hh onkogenik dapat mempromosikan mengurangi pertumbuhan tumor glioblasoma multiforme
medulloblasoma baik dari nenek moyang sel granula atau sel (GBM) tetapi diikuti oleh kekambuhan tumor, mungkin karena
punca [48, 49]. Selain itu, kebanyakan differentiated sel-sel di penguncian autokrin yang sedang berlangsung melalui sumbu
SSP, termasuk parah differentiated neuron dan astrosit, dapat VEGF-VEGFR2-Neuropilin-1 (NRP1), yang terkait dengan
memperoleh defiperubahan genetik ned untuk dedif- ferentiate pengayaan bagian aktif VEGFR2 GSC dalam sel GBM
ke NSC atau negara progenitor dan akibatnya mendorong dan manusia [56]. The gefitinib tahan subline HCC827-GR-
memelihara glioma ganas [50]. tertinggi yang ditetapkan oleh metode-konsentrasi tinggi juga
Dari catatan, CSC memperoleh baik EMT dan batang fitur seperti sel tetapi tidak
dapatdiidentifikasiolehspesifikpenanda sel induk normal yang menunjukkan EGFR-mutan- spesifikfiproduksic proteinatau
biasa digunakan untuk mengisolasi CSC dari tumor padat dan peningkatan lebih lanjut dalam jumlah baik alel mutan atau
hematologi [51]. Beberapa penanda permukaan sel salinan EGFR [57]. Oleh karena itu, dengan memahami
telahdiverifikasiuntuk mengidentifikasi CSC- diperkaya mekanisme dan driver onkogenik dimana CSC melarikan diri
populasi, seperti CD133, CD24, CD44, EpCAM (molekul radio dan kemoterapi, kita dapat mengembangkan lebih
adhesi sel epitel), THY1, ABCB5 (ATP-mengikat kaset B5), effperawatan efektif yang bisa meningkatkan hasil klinis
dan CD200 [27, 32, 34, 52]. Selain itu, protein intraseluler pasien kanker. Mekanisme kontribusi CSC terhadap
tertentu juga telah digunakan sebagai penanda CSC, seperti kemoresisten termasuk EMT, MDR, dormansi, lingkungan
aldehyde dehydrogenase 1 (ALDH1) yang digunakan untuk tumor, dan sebagainya disebutkan di bawah ini secara
mengkarakterisasi CSCs dalam banyak jenis kanker seperti terperinci dan dirangkum dalam Gambar 2.
leukemia, payudara, usus besar, hati, paru-paru, pankreas, dan
sebagainya [ 12, 53]. Penggunaan penanda permukaan sel 3.1. Epithelial Mesenchymal Transition (EMT). Telah
sebagai CSC penanda kekuatan differ dari masing-masing jenis diindikasikan bahwa penanda transisi mesenchymal (EMT)
kanker tergantung pada karakteristik dan fenotipe mereka. epitel dan penanda sel punca secara bersamaan diekspresikan
Penanda permukaan yang sering digunakan untuk mengisolasi dalam sirkulasi sel tumor dari pasien dengan metastasis [58]
dan induksi EMT atau aktivasi faktor transkripsi EMT (TF) sel-sel yang telah mengalami EMT, dan EMT menginduksi
menganugerahkan fitur seperti batang pada sel kanker [ 59]. generasi angka yang relatif terbatas sel induk kanker dari lebih
Dalam sel-sel induk-seperti payudara manusia tertentu, normal differentiated sel neoplastik
dan neoplastik mengekspresikan penanda yang sama dengan
3 Stem Sel Internasional
Tabel 1: Kanker penanda sel induk pada manusia.
Jenis tumor Penanda sel batang kanker Referensi Kanker paru CD133 +, CD44+, ABCG2, ALDH, CD87+, SP, CD90+ [215-217] Kanker usus besar CD133+,
CD166+, EpCAM+, ALDH, ESA [218, 219] Kanker hati CD133+, CD44+, CD49f+, CD90+, ALDH, ABCG2, CD24+, ESA [51, 219] Kanker payudara CD13
EpCAM+, ALDH-1 [51, 218] Kanker lambung CD133+, CD44+, CD24+ [215, 220-222] Leukemia (AML) CD34+, CD38-, CD123+ [216, 218, 223] Kanker p
α2β1, ABCG2, ALDH [51, 215, 223] Kanker pankreas CD133 +, CD44+, CD24+, ABCG2, ALDH, EpCAM+, ESA [195, 215, 218] Melanoma ABCB5+, CD
kepala dan leher SSEA-1+, CD44+, CD133+ [224-226]
[60]. Sementara itu, ada hubungan antara aktivasi EMT dan resistensi obat [61]. Sebagai contoh,gefisel-sel kanker paru resisten yang d
memperoleh fenotipe EMT [62] melalui aktivasi pensinyalan Notch-1 [63]. Selain itu, potensi invasif yang ditingkatkan, tumorigenis
penanda EMT dapat digunakan untuk memprediksi resistensi cetuximab antibodi anti-EGFR dalam sel [64]. Secara paralel, dibanding
sel epitel, sel-sel mesenchymal telah meningkatkan ekspresi gen yang terlibat dalam metastasis dan invasi dan secarasignifikanlebi
penghambatan EGFR, termasuk erlotinib, gefitinib, dan cetuximab; setidaknya sebagian melalui overekspresi integrin-linked kinase
mesenkim [65]. Selain itu, mediator EMT S100A4 telah terbukti terlibat dalam mempertahankan sifat batang dan tumorigenicity CS
leher kanker [66]. Oleh karena itu, EMT menginduksi sel kanker untuk menunjukkan karakteristik seperti sel punca yang memprom
menyerang jaringan di sekitarnya dan menampilkan resistensi terapeutik [67]. Menariknya, ZEB1, regulator EMT, memainkan peran p
kunci sel induk kanker termasuk regulasi batang dan induksi chemoresistance melalui regulasi transkripsi O-6-Methylguanine DNA M
(MGMT) via miR-200c dan c-MYB pada glioma ganas [68]. Terlepas dari EMT, ekspresi tinggi penanda sel induk seperti Oct4, Nanog
dan Lgr5 telah dianggap untuk memberikan sistance chemore- serta[69-73].
3.2. Tingkat Tinggi Perlawanan Multidrug (MDR) atau DetoxifiProteinkasi. Sel-sel populasi samping (SP), yang menunjukkan fenotip
kanker, terdeteksi dalam
4 Stem Cells International
Resistant terhadapdipicu kerusakan DNA.
kematian sel yangMeningkatkan pemulungan ROS Mempromosikan kemampuan perbaikan DNA Mengaktifkan jalur pensinyalan anti-apoptosis
Gambar 2 : jalur sinyal Key danmodifikationdari CSC berkontribusi terhadap perlawanan terhadap kemoterapi. Dalam rangka untuk bertahan hidup
terapi, CSC menampilkan banyak tanggapan termasuk EMT, pembaruan diri, lingkungan tumor, ketenangan, epigenetikyang,modifikasi MDR
Mekanisme kontribusi CSC terhadap resistensi terhadap terapi dirangkum.
Lingkungan tumor (i)

Hipoksia (ii)
Autophagy (iii)
Kanker broblast (CAFs) yang berhubungan dengan kanker Peradangan Sel imun
Mekanisme epigenetik (i)
Modifikasi histone (ii) Metilasi DNA
Menjalani induksi EMT EMT atau aktivasi EMT-faktor transkripsi
(i)
(ii)
(i) (ii)
G1 / S
Kemampuan pembaruan diri
G0
(iv) (v)
G2 / M CSC Diam
Jalur sinyal
Wntpa
Jalur landak
CSC
Ekspresi yang lebih tinggi resistensi multidrug
(MDR) atau detoksifikasi protein Obat-transporter protein: ABCG1, ABCB1 Aldehid dehidrogenase (ALDH)
MRP
berbagai different tumor padat seperti retinoblastoma, roblastoma neutrofil, kanker pencernaan, kanker payudara, kanker paru-paru,
ekspresi tinggi protein pengangkut obat (termasuk MDR1, ABCG2, dan ABCB1) tidak hanya bertindak untuk mengecualikan pewar
juga mengeluarkan obat sitotoksik, yang mengarah pada resistensi tinggi terhadap agen kemoterapi dengan kelangsungan hidup sel ya
kekambuhan penyakit [74-76] ] Alisi et al. menunjukkan bahwa ekspresi berlebih dari protein ABC mungkin merupakan mekanisme p
paling penting untuk CSCs dalam menanggapi agen kemoterapi. Menariknya, telah menunjukkan bahwa PI3K / Aktsecarakhusus m
ABCG2 melalui lokalisasi untuk membran plasma, dan kehilangan PTEN pro motes fenotip SP kanker glioma batang-seperti sel ma
itu, aktivitas aldehida dehidrogenase (ALDH), enzim sitosolik yang bertanggung jawab untuk tion oxida- dari aldehida intraseluler
sel-sel darisecara potensial beracun effEctspeningkatan kadar spesies oksigen reaktif (ROS) [79] , adalah tinggi di kedua normal da
CD38- sel induk leukemia, dan dengan demikian memainkan peran penting dalam perlawanan terhadap kemoterapi [80]. Kegiata
penanda selektif esensial poten- untuk sel induk kanker di berbagaidiffjeniserent kanker, seperti kanker payudara [53], kanker kan
kepala dan leher skuamosa karsinoma sel [82], kanker paru-paru [83 ], dan rhabdomyosarcoma embrional [84]. Antar estingly, model
dan sampel klinis ies stud- menunjukkan bahwa sel-sel induk kanker ALDH1A1-positif mempromosikansignifikanketahanan untuk k
(gefitinib) dan obat antikanker kemoterapi lainnya (cisplatin, etoposid, dan fluorouracil ) dibandingkan sel-sel ALDH1A1-negatif pada
[85]. Selain itu, tingkat ekspresi ALDH1 yang tinggi
respon atau resistensi yang buruk terhadap terapi dengan meningkatkan pembersihan ROS, promosi kemampuan
kemoradioaktif pra operasi pada pasien kanker kerongkongan perbaikan DNA melalui ATM dan fosforilasi CHK1 / CHK2,
yang dapat direseksi [86]. atau aktivasi jalur pensinyalan anti-apoptosis, seperti PI3K /
Akt, WNT / b-catenin, dan Notch jalur pensinyalan [24].
Misalnya, CD44, molekul adhesi yang diekspresikan dalam
3.3. Dormansi CSC. Telah dibuktikan bahwa selain
CSC, berinteraksi dengan transporter glutamat-sistin dan
heterogenitas intratumoral yang diprakarsai oleh evolusi
mengendalikan level intraseluler dari glutathione tereduksi
subklon beragam secara genetik, ada juga klon yang berbeda
(GSH); karenanya, CSC yang mengekspresikan CD44 tingkat
secara fungsional, yang ditemukan dengan melacak keturunan
tinggi menunjukkan peningkatan kapasitas untuk sintesis GSH,
sel tunggal menggunakan lentivirus, dalam garis keturunan
menghasilkan pertahanan yang lebih kuat terhadap ROS [89].
genetik pada kanker kolonal [ 87]; dengan demikian, proses-
Menariknya, mirip dengan sel-sel induk jaringan normal,
proses yang menghasilkan keragaman dalam klon genetik ini
CSCs memiliki tingkat ROS yang lebih rendah, yang dikaitkan
mempromosikan sel-sel untuk potensi kelangsungan hidup
dengan peningkatan ekspresi sistem pembilasan radikal bebas,
yang lebih tinggi, terutama selama stres seperti kemoterapi.
yang mengarah ke pertahanan ROS yang lebih tinggi dan
Sebagai contoh, kemoterapi dapat menginduksi pertumbuhan + -/ rendah
tumor dari garis silsilah yang sebelumnya relatif tidak aktif resistensi radioterapi juga [90]. Selain itu,CD44 / CD24
atau berkembang biak yang masih mempertahankan potensi subset CSCpada kanker payudara resisten terhadap radiasi
penyebaran tumor yang kuat, yang mengarah pada melalui aktivasi pensinyalan ATM tetapi tidak tergantung pada
pertumbuhan kanker dan resistensi obat [87]. Demikian pula, perubahan aktivitas perbaikan DNA nonhomologous end
dalam glioblastoma multiforme, ada juga keberadaan subset bergabung (NHEJ) [91]. Demikian pula, CD133-
sel tumor endogen yang relatif diam dengan karakteristik yang mengekspresikan sel tumor yang diisolasi dari kedua
mirip dengan sel punca kanker yang bertanggung jawab untuk xenografts glioma manusia dan pri-mary spesimen pasien
mempertahankan pertumbuhan tumor jangka panjang dan oleh glioblastoma istimewa mengaktifkan pos pemeriksaan
karena itu menyebabkan kekambuhan melalui produksi kerusakan DNA dalam menanggapi radiasi dan perbaikan
populasi sementara yang sangat proliferatif. sel [17]. Secara radiasi kerusakan DNA lebih effectively dari sel-sel tumor
bersamaan, kerusakan yang diinduksi kemoterapi merekrut CD133-negatif [92] . Notch pathway juga mempromosikan
kelompok CSC kandung kemih yang bertahan lama selama radioresistensi sel punca glioma karena penghambatan Notch
periode celah antara siklus kemoterapi menjadi respons dengan gamma-secretase inhibitor (GSIs) menginduksi sel
pembelahan sel yang tak terduga untuk mengisi kembali tumor punca glioma agar lebih peka terhadap radiasi pada dosis yang
residual, mirip dengan mobilisasi perbaikan luka sel-sel batang relevan secara klinis karena pengurangan PI3K yang diinduksi
penduduk jaringan [88 ] oleh radiasi. / Aktivasi Akt dan peningkatan
level isoform apoptosis terpotong dari Mcl-1 (Mcl-1)
sementara tidak mengubah respon kerusakan DNA [93].
3.4. Ketahanan terhadap kematian sel yang disebabkan oleh
kerusakan DNA. CSC dapat resisten terhadap kematian sel
3.5. Lingkungan Tumor. Telah ditunjukkan bahwa lingkungan
yang disebabkan oleh kerusakan DNA melalui beberapa cara.
mikro yang berbeda dari berbagai komposisi seluler adalah
Ini termasuk perlindungan terhadap kerusakan DNA oksidatif
penting untuk melindungi dan mengatur sel-sel induk normal. tahan CSC paru-paru pada mutasi EGFR positif NSCLC oleh
Lingkungan mikro yang setara juga ditemukan dalam CSCs di upregulating ekspresi insulin-like growth factor 1 (IGF1)
mana CSCs didukung dengan baik dalam ceruk histologis, melaluiHIF1α dan mengaktivasi vating IGF1 reseptor (IGF1R)
yang disebut lingkungan mikro CSC [94-96], yang [118]. Menariknya, autophagy diregulasi dalam kanker
mengandung stroma konektif [97-101] dan jaringan pembuluh pankreas pada kondisi mental microenviron- oksigen rendah
darah [102-106]. Lingkungan ini mempercepat CSC dinamika dan kekurangan gizi, mirip dengan tumor hipoksia, dan
divisi, allow- ing mereka untukdiffsel-sel progenitor erentiate kemudian mempromosikan kelangsungan hidup clonogenic
anakserta memperbaharui diri dan mempertahankan CSC di dan migrasi dari pankreas CSCyang tinggi sel[119].
kondisi mental mengembangkan- primitif. Sel-sel dalam
lingkungan mikro CSC mampu menstimulasi jalur pensinyalan 3.5.2. Cancer-Associated Fibroblasts (CAFs). Sudah puncak-
[58], seperti Notch [102, 107, 108] dan Wnt [109-111] yang kasikan bahwa selain ketahanan otonom sel CSC, motherapy
dapat memfasilitasi CSC untuk bermetastasis, menghindari che- istimewa menargetkan non-CSC oleh stimulasi terkait
anoikis, dan mengubah dinamika divisi, mencapai repopulasi kanker fibroblasts (CAFS) yang menciptakan ceruk
dengan pembagian simetris [109, 112-114]. chemoresistant oleh peningkatan sekresi dengan spesialisasi
cific sitokin dan kemokin, termasuk interleukin-17A (IL-17A),
3.5.1. Hipoksia. Jalur pensinyalan Hypoxia dan HIF telah faktor pemeliharaan CSC dengan mempromosikan pembaruan
terbukti berkontribusi pada regulasi dan keberlanjutan CSC diri dan invasi [120]. Telah ditunjukkan sebelumnya bahwa
dan fenotip EMT seperti migrasi sel, invasi, dan angiogenesis CSC bisa differentiate ke dalam sel CAF-seperti (CAFLCs)
[115], melalui peningkatan ekspresi gen tanda tangan VEGF, dan karenanya mereka adalah salah satu sumber utama CAFS
IL-6, dan CSC seperti Nanog, Oct4, dan EZH2, pada kanker yang mendukung pemeliharaan tumor dan kelangsungan hidup
pankreas misalnya [116]. Oleh karena itu, jalur pensinyalan di relung kanker [121]. CAFS diketahui mengeluarkan
HIF juga dapat berperan dalam resistensi CSC terhadap terapi. banyakdifffaktor pertumbuhanerent, sitokin, dan kemokin,
Dalam lingkungan mikro hipoksia, faktor yang diinduksi termasuk faktor pertumbuhan tocyte hepa- (HGF), yang
hipoksia dan faktor hipoksia HIF1-α meningkatkan persistensi mengaktifkan tor MET recep- untuk melindungi CSC dari
sel CML terutama melalui upregulasi faktor yang diinduksi apoptosis dalam menanggapi monoterapi cetuximab
hipoksia 1α (HIF1-α), independen dari aktivitas kinase BCR- menargetkan EGFR di kanker kolorektal metastatik [122].
ABL1 [ 117]. Demikian pula, hipoksia meningkatkan gefitinib
3.5.3.Peradangan.Selain itu, pengobatan jangka panjang sel terhadap kemoterapi dengan mengganggu interaksi sel stroma /
kanker payudara dengan trastuzumabsecarakhusus diperkaya leukemia dalam lingkungan mikro sumsum tulang oleh Akt
CSC yang menunjukkan fenotipe EMT dengan tingkat yang phosphoryla- penghambatan tion dan induksi pembelahan
lebih tinggi dari sitokin yang disekresi IL-6 dibandingkan PARP karena bortomomib di hadapan sel stroma sumsum
dengan sel-sel tua; sebagai akibatnya, sel-sel ini tulang (BMSCs) dalam coculture [128]. Selain itu, CSC dari
mengembangkan resistensi trastuzumab dimediasi oleh tumor chemoresistant memiliki kemampuan unik untuk pro
aktivasi dari IL-6-dimediasi diflumpan balik inflamasi untuk Duce berbagai proinperadangan,sinyal seperti IFN peraturan
memperluas populasi CSC [123]. Demikian pula,TGF- faktor-5 (IRF5), yang bertindak sebagai faktor
autokrinβ pensinyalandan ekspresi IL-8 juga ditingkatkan transkripsispesifikuntuk tumor chemoresistant untuk
setelah pengobatan kemlitaxel obat kemoterapi pada kanker menginduksi Produksi M-CSF, untuk menghasilkan sel
payudara triple-negative, yang mengarah pada pengayaan myeloid imunoregulatori M2-like dari CD14+ monosit, dan
populasi CSC dan kekambuhan tumor [124]. Lebih lanjut, untuk mempromosikan aktivitas tumorigenik dan sel punca
kemokin stroma yang diturunkan faktor stroma yang yang dimediasi sel myeloid dari tumor massal [129].
diturunkan 1a (SDF-1a) dan reseptor serumpunnya CXCR4
memainkan peran penting dalam migrasi sel hematopoietik ke 3.5.4. Sel Kekebalan Tubuh. Telah diindikasikan sebelumnya
lingkungan mikro sumsum tulang [125, 126], jadi SDF-1A / bahwa makrofag terkait-tumor (TAMs) dapat mempromosikan
CXCR4 interaksi memediasi resistensi sel leukemia terhadap kemoresistensi pada kedua garis sel myeloma dan sel myeloma
apoptosis yang diinduksi kemoterapi [127], dan dengan primer dari apoptosis yang diinduksi oleh obat kemoterapi atau
demikian penghambatan CXCR4 dengan inhibitor seperti obat kemoterapi secara langsung dengan berinteraksi dengan
AMD3100 dapat meningkatkan sensitivitas sel leukemia sel-sel ganas dalam lingkungan mikro tumor dan melemahkan
aktivasi dan pembelahan dari pensinyalan apoptosis yang dalam berbagai jenis kanker, termasuk karsinoma nasofaring
tergantung caspase [130]. Selain itu, TAM juga secara [136], melanoma [137], adenokarsinoma pankreas [138],
langsung menginduksi sifat CSC sel tumor pankreas dengan kanker ovarium [139], dan karsinoma hepatoselular [140].
mengaktifkan transduser sinyal dan aktivator transkripsi 3 Lebih jauh lagi, anggota PcG lainnya EZH2, subunit katalitik
(STAT3) dan dengan demikian menghambatantitumor CD8 + dari kompleks penekan polycomb 2 (PRC2) yang memetilasi
respon limfosit TT dalam respon kemoterapi [131]. Selain itu, histon H3 pada lisin 27 (H3K27me) dan memunculkan
pada adenokarsinoma duktus pankreas, sel kanker mensekresi pembungkaman gen, juga berpartisipasi dalam kemoterapi
faktor penstimulasi koloni 1 (CSF1) untuk menarik dan kanker kanker pankreas dengan membungkam gen penekan
menstimulasi reseptor CSF- (CSF1R-) yang mengekspresikan tumor p27 melalui metilasi histone H3 -lysine 27 (H3K27)
TAM untuk mengekspresikan tingkat tinggi sitidin deaminase [141]. Selain itu, EZH2 melindungi GSC dari kematian sel
(CDA), suatu enzim intraseluler yang mengkatalisasi enzim yang diinduksi radiasi dan akibatnya mempromosikan
bentuk bioaktif dari tabibin dan oleh karena itu melindungi sel-kelangsungan hidup GSC dan radioresisten melalui regulator
sel kanker dari kemoterapi [132]. hulu mitosis kinase embrionik leucine-ritsleting kinase ibu
(MELK) [142]. Selain itu, penghambatan EZH2 peka BRG1
3.6. Epigenetik. Selain itu, resistensi obat CSC-dimediasi dan EGFR hilangnya fungsi tumor mutan untuk topoisomerase
diatur oleh mekanisme epigenetik juga, termasuk histone II (TopoII) inhibitor etoposide dengan peningkatan fase S,
modifikasi dan metilasi DNA. Pertama, DNA metilasi tidak bridging anafase, dan apoptosis [143]. Menariknya, EZH2 dan
berubah selama TGF-ßEMT -dimediasi tetapi perubahan BMI1 diindikasikan berkorelasi terbalik dengan tanda tangan
epigenetik lain seperti lysine-spesifikdeaminase-1- prognosis dan mutasi TP53 pada kanker payudara [144].
pengurangan global (Lsd1-) tergantung Kedua, asetilasi histone terlibat dalam regulasi aktivasi
dari tanda heterochromatin H3-lys9 dimethylation transkripsi dan chemoresistance dari CSC juga. Pengobatan
(H3K9Me2), meningkat dari tanda euchromatin H3-lys4 dengan HDAC inhibitor (HDACi) effectively menargetkan
trimethylation (H3K4Me3) dan tanda transkripsi H3-lys36 diam kronis myelogenous Kemia leu- (CML) stem sel yang
trimethylation (H3K36Me3) ditemukan; terutama, H3K4Me3 tahan terhadap tyrosine kinase inhibitor imatinib mesylate
mungkin berkontribusi terhadap chemoresistance yang diatur (IM) [145]. Demikian pula, pretreatment dengan inhibitor
Lsd1 [133]. Selain itu, KDM1A, sebuah flavin yang me- HDAC dapat membuat peka sel-sel seperti batang prostat
sembilan dinucleotide- (FAD-) tergantunglysine- untuk pengobatan radiasi melalui peningkatan kerusakan DNA
spesifikdemethylasesecarakhusus dengan monomethyl- dan dan mengurangi kelangsungan hidup klonogenik [146].
dimethyl- histon H3 lisin-4 (H3K4) dan lisin-9 (H3K9) sub Vorinostat, inhibitor HDAC melalui merangsang tination
Strate, merupakan regulator penting dari MLL-Af9 sel ubiqui- dan degradasi lisosom, downregulates ekspresi dan
leukemia induk (LSC) potensi onkogenik dengan menghalangi signaling dari ketiga reseptor EGFR, ErbB2, dan ErbB3
differenti- asi [134]. Selain itu, B-cell-spesifikfiintegrasic bersama-sama dengan pengembalian EMT di EGFR TKI
Moloney murine leukemia virus situs 1 (BMI1), salah satu gefisel tinib-tahan dan karena itu meningkatkan antitumor
dari beberapa protein peredam epigenetik milik kelompok effect gefitinib dalam karsinoma sel skuamosa kepala dan leher
Polycomb (PCG), diperlukan untuk pembaruan diri dari kedua [147]. Menariknya, NANOG meningkatkan pengaturan
sel induk dewasa dan banyak CSC melalui berbagai jalur histone deacetylases 1 (HDAC1) melalui pengikatan ke daerah
utama, seperti pertumbuhan independen-pelabuhan, jalur Wnt promotor dan mengurangi asetilasi H3 nada K14 dan K27;
dan Notch [135]. BMI-1 telah diindikasikan terlibat dalam sebagai hasilnya, ia menginduksi tidak hanya fitur seperti
perlindungan sel kanker dari apoptosis atau resistensi obat batang melalui represi epigenetik sel. Sel
6 Stem SelInternasional
Stem Sel Internasional 7
Aktivasi penghambat siklus CDKN2D dan CDKN1B tetapi juga dari Wnt /β-catenin dan ATP-mengikat k
imun dan chemoresistance me
(ABCG2) pada kanker ovarium [164]. upregulation by epigenetic silencing of E3 ubiquitin-ligase
Secondly, Hh pathway could regulate autophagy in CML TRIM17 and NOXA [148].
cells and then inhibition of the Hh pathway and autophagy Third, many tumor suppressor genes have been shown to
simultaneously could sharply reduce cell viability and signif- be epigenetically silenced in chemoresistant cancers by DNA
icantly induce apoptosis of imatinib-sensitive or -resistant methylation on CpG promoter regions. For instance, tumor
BCR-ABL+ cells via downregulating the kinase activity of suppressor insulin-like growth factor binding protein-3
the BCR-ABL oncoprotein [165]. Concomitantly, the expres- (IGFBP-3), which is involved in controlling cell growth,
sion of sonic hedgehog (SHH) and glioma-associated onco- transformation, and survival, is specifically downregulated
gene homolog 1 (GLI1), the well-known signaling pathway through promoter-hypermethylation and results in acquired
molecules involved in the drug resistance, is higher in resistance to chemotherapy in many different types of cancer
enriched CD44+/Musashi-1+ gastric cancer stem cells and [149]. In addition, loss of DNA mismatch repair (MMR)
consequently enhances the drug resistance via high drug gene hMLH1 via full hypermethylation of the hMLH1 pro-
efflux pump activity [166]. In glioma, CD133 + CSC popula- moter [150] is highly correlated with the ability of arresting
tion, which contributes to the chemoresistance of therapy cell death and cell cycle after DNA damage induced by che-
such as temozolomide (TMZ) treatment, overexpresses genes motherapy and poor survival prediction for cancer patients
involved in Notch and SHH pathways and activates these [151], hence plays a role in drug resistance in ovarian [152]
pathways [167]. and breast cancers [153].
Last but not least, chemotherapy such as oxaliplatin induces Notch-1 receptor and its downstream target Hes-1 3.7. Signaling Pathway
Che
activity by increasing gamma-secretase activity in colon can- mentioned, normal stem cells and CSCs have similar charac-
cer cells; hence, inhibition of Notch-1 signaling by gamma- teristics such as self-renewal and differentiation. They also
secretase inhibitors (GSIs) sensitizes colon cancer cells to share numbers of key signaling pathway to maintain its exis-
chemotherapy [168]. Moreover, Notch signaling pathway tence. For example, Notch signaling was highly expressed in
and Notch3 in particular play an essential role in the regula- the hematopoietic tumors such as T-ALL and solid tumors
tion of CSC maintenance and chemoresistance to platinum such as non-small-cell lung carcinoma (NSCLC), breast can-
in ovarian cancer therapy [169]. Similarly, the enrichment cer, and glioblastoma [154–156]. Activation of Hedgehog sig-
of CD133+ cells in lung adenocarcinoma after cisplatin naling which in normal condition plays important roles in
induction leads to multidrug resistance through activation embryonic development and tissue regeneration also has
of Notch signaling as higher levels of cleaved Notch1 been found to be involved in the regulation of various cancer
(NICD1) are detected [170]. Furthermore, it has been shown stem cells, such as pancreatic cancer, leukemias, and basal
that gefitinib-acquired resistant lung adenocarcinoma cells cell carcinoma (BCC) [157]. Another signaling pathway such
undergo EMT by activation of Notch-1 signaling via as WNT, TGFβ, PI3K/Akt, EGFR, and JAK/STAT, as well as
Notch-1 receptor intracellular domain (N1IC), the activated transcriptional regulators including OCT4, Nanog, YAP/
form of the Notch-1 receptor [63]. TAZ, and Myc are also commonly activated in various cancer
Besides, there are also some molecules which act as the stem cells to regulate their self-renewal and differentiation
integration of various pathways involved in the control of state [21, 158]. CSCs have been indicated to display many
stem cell fate across tissues; for example, CYP26, a primary characteristics of embryonic or tissue stem cells and develop-
retinoid-inactivating enzyme through retinoid and Hedge- mental signaling pathways such as Wnt, HH, and Notch that
hog pathways, limits the retinoic acid concentration, there- are highly conserved embryonically and control self-renewal
fore leading to drug resistance in the stem cell niche [171]. of stem cells [159]. Therefore, activation of these pathways may play an imp
expansion of CSCs and hence the resistance to therapy [160]. Here, several represen-
4. CSC-Based Therapy
tatives are explained.
Owing to the ability of CSCs to develop chemo- and radiore- First, it has been indicated that activation of Wnt/β-
sistance which play key roles in the malignant progression, catenin signaling enhances the chemoresistance to IFN-α/5-
metastasis, and cancer recurrence, it is suggested that target- FU combination therapy [161]. OV6+ HCC cells, a subpopu-
ing cancer stem cells offers an ultimate goal to overcome a lation of less differentiated progenitor-like cells in HCC cell
poor prognosis, leading to a better patient survival [15, 22]. lines and primary HCC tissues, have been shown to be
Selective targeting of CSC signaling networks that are essen- endogenously active Wnt/β-catenin signaling and resistant
tial for self-renewal, proliferation, and differentiation to to standard chemotherapy [162]. In addition, in neuroblas-
maintain their stem cell properties provides a new challenge toma, amplification and upregulation of frizzled-1 Wnt
in the development of cancer treatments [19, 172]. Over the receptor (FZD1) activate the Wnt/β-catenin pathway in che-
last decades, it was suggested that the combination of con- moresistant cancer cells by nuclear β-catenin translocation
ventional therapy and targeted therapy against CSC-specific and transactivation of Wnt target genes such as multidrug
pathways gives rise a better consequence compared to mono- resistance gene (MDR1), which is known to mediate the
therapy in removal of both bulk tumor and CSC population resistance to chemotherapy [163]. Furthermore, c-Kit, a stem
(Figure 1) [19]. Thus, targeting essential pathways in the cell factor (SCF) receptor, mediates chemoresistance through
CSCs such as Notch, Wnt, and Hedgehog (HH) is being
developed to block the self-renewal of CSCs [21]. Lately, using microRNA [184–190].
some classes of Notch pathway inhibitors have been reported Accumulating evidence suggests that miRNA and
to enter a clinical trial, accompanied by a substantial variety of other groups of long noncoding RNA (lncRNA) play important
targets, mechanism of action, and drug classes [19, 21]. The roles in the regulation of CSCs properties such as self-renewal,
major class of Notch inhibitor is the γ-secretase inhibitors asymmetric cell division, tumor initiation, drug resistance, and
(GSIs). GSI works by inhibiting the final proteolytic cleavage disease recurrence [186, 187, 189, 191–193].The usage of
of Notch receptors, which results in the release of the active miRNA as CSC-based therapeutic agents is reported; for
intracellular fragment. It was the first class of Notch pathway example, mir-22 that targets TET2 in leukemia (AML and
inhibitor that enters a clinical trial in the cancer field [159, MDS) and breast cancer [194], Let-7 to target RAS and
173, 174]. HMGA2 in breast cancer [195], mir-128 to target BMI-1 in
HH pathway is shown to be involved in several brain cancer [191], mir-200 to target ZEB1/ZEB2, BMI-1, and
essential developmental pathways such as tissue patterning SUZ12 in breast cancer [189, 196, 197], and some other
during embryonic development and the repair of normal miRNA in the colon cancer and prostate cancer have been
tissues and epithelial-to-mesenchymal transition [175]. reported to reduce cancer malignancy [198–202].
Vismode- gib, a drug targeting HH pathway, was approved by Finally, cancer immunotherapy may be a breakthrough
the Euro- pean Medicines Agency (EMA) in 2013 and the US for targeting specifically CSCs in cancer patients. For cancer
FDA in 2012 for the therapy of metastatic BCC patients or immunotherapy, several effectors, including natural killer (NK)
locally advanced BCC patients that are not candidates for cells and γδT cells in innate immunity, antibodies in acquired
surgery or radiotherapy [176, 177]. humoral immunity, CSC-based dendritic cells, and CSC-
Targeting Wnt signaling has also shown promising primed cytotoxic T lymphocytes (CTLs) in acquired cellular
results related to carcinogenesis, tumor invasiveness, and immunity, which are able to recognize and kill CSCs may be
metastasis [159]. Wnt3A-neutralizing mAb was shown to have suitable candidates to improve the efficacy of cancer treatment.
antiproliferation and proapoptotic effects in prostate cancer A variety of immunotherapeutic strategies that specifically
mouse model [178]. And anti-Fz10 radio-labeled mAb is being target CSCs using these effector cells have been reported. In
evaluated in a phase I trial for the synovial sarcoma therapy. addition, identification of specific antigens or genetic
Vantictumab (OMP-18R5, a mAb that blocks five Fz receptors alterations in CSCs plays an important role in finding targets
such as Fz1, Fz2, Fz5, Fz7, and Fz8) [179–181] and OMP- for immunotherapy. These include CSC markers (ALDH
54F28 [181] (a mAb that blocks fusion protein decoy receptor [203], CD44 [204, 205], CD133 [206], EpCAM [207], and
such as truncated Fz8) are under investigation in phase I HER2 [208]), CSC niche interaction (TAM [209]), tumor
studies in advanced-stage solid tumors [182]. microenvironment (immune cells/myeloid- derived suppressor
Targeting CSCs through the EMT pathways also cells), cytokines (IL1 [210], IL6 [211], and IL8 [212]), and
provides a new challenge in the cancer therapy study. This immune checkpoint (CTLA-4 [213] or PD1/PDL1 [214]).
therapy is developed in order to prevent cancer aggressiveness
and acquired drug resistance of cancer stem cells [183, 184]. 5. Conclusion
Lately, the finding of therapeutic agents to EMT-based CSC
therapy indicated three general target groups [184, 185]. These CSCs possess stem cell-like features found in cancer and have
include a group involved in the regulation of EMT important implications for the chemoresistance and cancer
extracellular inducer such as TGF-β, EGF, Axl-Gas6 path- relapse, a notion that remains somewhat controversial. With a
ways, hypoxia, and extracellular matrix components. Another small subpopulation in the malignant cell pool, the contri-
group is the transcription factors (TFs) that promote EMT bution of CSCs is remarkable in cancer therapy, as shown by
transcriptome including Twist1, Snail1, Zeb1/2, T-box TF intensive studies in recent decades. These cells can be identi-
Brachyury as well as its downstream effectors of EMT, such as fied based on the presence of surface biomarkers, enhanced
E-Cadherin, N-Cadherin, vimentin, and HoxA9. The last one is spheroid or colony formation in vitro and augmented tumor-
targeting regulators of EMT-TFs and epigenetic regulator 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 crucial role in tumor promising strategies for suppressing tumor relapse and
recurrence after anticancer therapy. To survive following metastasis, recent technological advances made it easier than
cancer treatment, CSCs seem to be able to manifest several before to find mechanisms contributing to drug resistance.
responses such as EMT, induction of signaling pathways that Also, the recent therapeutic strategy of combining molecules
regulate self-renewal or influence tumor environments, specifically targeting CSCs with conventional che-
expression of drug transporters or detoxifica- tion proteins, and motherapeutic drugs could possibly be a better direction for
so forth to protect them from devastating effects caused by anticancer therapy and may therefore achieve better survival
therapeutic agents. Thus, the development of anticancer rates of cancer patients (Figure 1) [19]. Besides, as some cell
therapeutics that target CSCs is not only limited to the finding surface biomarkers and signaling pathways are similar
of inhibitor of CSC pathways and cell surface markers but also between CSCs and normal stem cells, it is also essentially
to the development of EMT and CSCs microenvironment- required to develop novel therapeutic agents targeting only
related inhibitors. Though the molecular mechanisms CSCs to avoid off-target effects on noncancerous cells or
underlying the resistance of CSCs to chemotherapy and normal stem cells.
radiation still require further studies in order to develop
Conflicts of Interest no. 19, pp. 1441–1454, 2007. [8] DA Senthebane, A. Rowe, NE
Thomford et al., “The role of tumor microenvironment in
The authors declare no conflict of interest. chemoresistance: to survive, keep your enemies closer,”
International Journal of Molecular Sciences, vol. 18, tidak. 7, 2017.
[9] A. Fesler, S. Guo, H. Liu, N. Wu, and J. Ju, “Overcoming
Authors' Contributions chemoresistance in cancer stem cells with the help of microRNAs in
colorectal cancer,” Epigenomics, vol. 9, tidak. 6, pp. 793–796, 2017.
Lan Thi Hanh Phi and Ita Novita Sari contributed equally to [10] R. Di Fiore, R. Drago-Ferrante, F. Pentimalli et al., “Micro-
the work. 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–
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cancer stem cells overcomes chemoresistance and inhibits
This work was supported by the Soonchunhyang University metastases in squamous cell carcinoma,” Cell Stem Cell, vol. 20,
Research Fund and Global Research Development Center tidak. 5, pp. 621–634.e6, 2017. [12] JE Visvader and GJ Lindeman,
“Cancer stem cells in solid tumours: accumulating evidence and
(NRF-2016K1A4A3914725).
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