Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Tumor Biology
Published in: Tumor Biology 1/2016

01-01-2016 | Review

Cancer stem cells in human digestive tract malignancies

Authors: Fatemeh B. Rassouli, Maryam M. Matin, Morvarid Saeinasab

Published in: Tumor Biology | Issue 1/2016

Login to get access

Abstract

Digestive tract malignancies, including oral, pharyngeal, esophageal, gastric, and colorectal cancers, are among the top 10 most common cancers worldwide. In spite of using various treatment modalities, cancer patients still suffer from recurrence and metastasis of malignant cells. Cancer stem cells (CSCs) are undifferentiated and highly proliferative malignant cells with unique properties mediated by overexpression of stemness markers, metastasis-related proteins, drug transporters, and DNA repair machinery. Due to their salient characteristics, it has been suggested that CSCs are responsible for tumor initiation, progression, invasion, recurrence, and therapy resistance. Exploring different aspects of CSC biology has fueled a great enthusiasm in designing novel therapeutic strategies to help patients. For instance, identification of markers associated with digestive tract CSCs, such as CD44, CD133, CD24, EpCAM, LGR5, ALDH1, and BMI1, has made it possible to develop more accurate diagnosis approaches. In addition, specifically targeting CSCs by their markers imposes fewer side effects and improves therapeutic outcomes. Here, we focus on the current status of CSC biology in digestive tract cancers, with emphasis on CSC markers, and review achieved progress in eradication of digestive tract CSC cells.
Literature
1.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.PubMedCrossRef
2.
3.
Carney DN, Gazdar AF, Bunn Jr PA, Guccion JG. Demonstration of the stem cell nature of clonogenic tumor cells from lung cancer patients. Stem Cells. 1982;1:149–64.PubMed
4.
Enderling H. Cancer stem cells: small subpopulation or evolving fraction? Integr Biol. 2015;7:14–23.CrossRef
5.
6.
Ajani JA, Song S, Hochster HS, Steinberg IB. Cancer stem cells: the promise and the potential. Semin Oncol. 2015;1:S3–17.CrossRef
7.
Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2009;457:608–11.PubMedCrossRef
8.
9.
Richard V, Nair MG, Santhosh Kumar TR, Pillai MR. Side population cells as prototype of chemoresistant, tumor-initiating cells. bioMed Res Int. 2013;2013:517237.PubMedPubMedCentralCrossRef
10.
11.
12.
Imrich S, Hachmeister M, Gires O. EpCAM and its potential role in tumor-initiating cells. Cell Adhes Migr. 2012;6:30–8.CrossRef
13.
Nakata S, Phillips E, Goidts V. Emerging role for leucine-rich repeat-containing G-protein-coupled receptors LGR5 and LGR4 in cancer stem cells. Cancer Manag Res. 2014;6:171–80.PubMedPubMedCentral
14.
Andrews PW, Matin MM, Bahrami AR, Damjanov I, Gokhale P, Draper JS. Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin. Biochem Soc Trans. 2005;33:1526–30.PubMedCrossRef
15.
Liu A, Yu X, Liu S. Pluripotency transcription factors and cancer stem cells: small genes make a big difference. Chin J Cancer. 2013;32:483–7.PubMedPubMedCentral
16.
Siddique HR, Saleem M. Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences. Stem Cells. 2012;30:372–8.PubMedCrossRef
17.
Heidenreich B, Rachakonda PS, Hemminki K, Kumar R. TERT promoter mutations in cancer development. Curr Opin Genet Dev. 2014;24:30–7.PubMedCrossRef
18.
di C, Zhao Y. Multiple drug resistance due to resistance to stem cells and stem cell treatment progress in cancer (Review). Exp Ther Med. 2015;9:289–93.PubMed
19.
Iyama T, Wilson DM. DNA repair mechanisms in dividing and non-dividing cells. DNA Repair (Amst). 2013;12:620–36.CrossRef
20.
21.
Mackenzie IC. Growth of malignant oral epithelial stem cells after seeding into organotypical cultures of normal mucosa. J Oral Pathol Med. 2004;33:71–8.PubMedCrossRef
22.
Locke M, Heywood M, Fawell S, Mackenzie IC. Retention of intrinsic stem cell hierarchies in carcinoma-derived cell lines. Cancer Res. 2005;65:8944–50.PubMedCrossRef
23.
Harper LJ, Piper K, Common J, Fortune F, Mackenzie IC. Stem cell patterns in cell lines derived from head and neck squamous cell carcinoma. J Oral Pathol Med. 2007;36:594–603.PubMedCrossRef
24.
Chen JS, Pardo FS, Wang-Rodriguez J, Chu TS, Lopez JP, Aguilera J, et al. EGFR regulates the side population in head and neck squamous cell carcinoma. Laryngoscope. 2006;116:401–6.PubMedCrossRef
25.
Chiou SH, Yu CC, Huang CY, Lin SC, Liu CJ, Tsai TH, et al. Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clin Cancer Res. 2008;14:4085–95.PubMedCrossRef
26.
Zhang Q, Shi S, Yen Y, Brown J, Ta JQ, Le AD. A subpopulation of CD133(+) cancer stem-like cells characterized in human oral squamous cell carcinoma confer resistance to chemotherapy. Cancer Lett. 2010;289:151–60.PubMedCrossRef
27.
Damek-Poprawa M, Volgina A, Korostoff J, Sollecito TP, Brose MS, O'Malley BW, et al. Targeted inhibition of CD133+ cells in oral cancer cell lines. J Dent Res. 2011;90:638–45.PubMedPubMedCentralCrossRef
28.
Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A. 2007;104:973–8.PubMedPubMedCentralCrossRef
29.
Okamoto A, Chikamatsu K, Sakakura K, Hatsushika K, Takahashi G, Masuyama K. Expansion and characterization of cancer stem-like cells in squamous cell carcinoma of the head and neck. Oral Oncol. 2009;45:633–9.PubMedCrossRef
30.
Chen YC, Chen YW, Hsu HS, Tseng LM, Huang PI, Lu KH, et al. Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. Biochem Biophys Res Commun. 2009;385:307–13.PubMedCrossRef
31.
Clay MR, Tabor M, Owen JH, Carey TE, Bradford CR, Wolf GT, et al. Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase. Head Neck. 2010;32:1195–201.PubMedPubMedCentralCrossRef
32.
Chen YC, Chang CJ, Hsu HS, Chen YW, Tai LK, Tseng LM, et al. Inhibition of tumorigenicity and enhancement of radiochemosensitivity in head and neck squamous cell cancer-derived ALDH1-positive cells by knockdown of Bmi-1. Oral Oncol. 2010;46:158–65.PubMedCrossRef
33.
Chen C, Wei Y, Hummel M, Hoffmann TK, Gross M, Kaufmann AM, et al. Evidence for epithelial-mesenchymal transition in cancer stem cells of head and neck squamous cell carcinoma. PLoS One. 2011;6:e16466.PubMedPubMedCentralCrossRef
34.
Lo WL, Yu CC, Chiou GY, Chen YW, Huang PI, Chien CS, et al. MicroRNA-200c attenuates tumour growth and metastasis of presumptive head and neck squamous cell carcinoma stem cells. J Pathol. 2011;223:482–95.PubMedCrossRef
35.
He Q, Liu Z, Zhao T, Zhao L, Zhou X, Wang A. Bmi1 drives stem-like properties and is associated with migration, invasion, and poor prognosis in tongue squamous cell carcinoma. Int J Biol Sci. 2015;11:1–10.PubMedPubMedCentralCrossRef
36.
Ma L, Wang H, Yao H, Zhu L, Liu W, Zhou Z. BMI1 expression in oral lichen planus and the risk of progression to oral squamous cell carcinoma. Ann Diagn Pathol. 2013;17:327–30.PubMedCrossRef
37.
Feng JQ, Xu ZY, Shi LJ, Wu L, Liu W, Zhou ZT. Expression of cancer stem cell markers ALDH1 and BMI1 in oral erythroplakia and the risk of oral cancer. J Oral Pathol Med. 2013;42:148–53.PubMedCrossRef
38.
Yamazaki H, Mori T, Yazawa M, Maeshima AM, Matsumoto F, Yoshimoto S, et al. Stem cell self-renewal factors Bmi1 and HMGA2 in head and neck squamous cell carcinoma: clues for diagnosis. Lab Investig. 2013;93:1331–8.PubMedCrossRef
39.
Dang D, Ramos DM. Identification of αvβ6-positive stem cells in oral squamous cell carcinoma. Anticancer Res. 2009;29:2043–9.PubMed
40.
Siu A, Lee C, Dang D, Lee C, Ramos DM. Stem cell markers as predictors of oral cancer invasion. Anticancer Res. 2012;32:1163–6.PubMed
41.
Czerwinski MJ, Desiderio V, Shkeir O, Papagerakis P, Lapadatescu MC, Owen JH, et al. In vitro evaluation of sialyl Lewis X relationship with head and neck cancer stem cells. Otolaryngol Head Neck Surg. 2013;149:97–104.PubMedPubMedCentralCrossRef
42.
Yan M, Yang X, Wang L, Clark D, Zuo H, Ye D, et al. Plasma membrane proteomics of tumour spheres identify CD166 as a novel marker for cancer stem-like cells in head and neck squamous cell carcinoma. Mol Cell Proteomics. 2013;12:3271–84.PubMedPubMedCentralCrossRef
43.
Geng S, Guo Y, Wang Q, Li L, Wang J. Cancer stemlike cells enriched with CD29 and CD44 markers exhibit molecular characteristics with epithelial-mesenchymal transition in squamous cell carcinoma. Arch Dermatol Res. 2013;305:35–47.PubMedCrossRef
44.
Grimm M, Krimmel M, Polligkeit J, Alexander D, Munz A, Kluba S, et al. ABCB5 expression and cancer stem cell hypothesis in oral squamous cell carcinoma. Eur J Cancer. 2012;48:3186–97.PubMedCrossRef
45.
Krishnamurthy S, Dong Z, Vodopyanov D, Imai A, Helman JI, Prince ME, et al. Endothelial cell-initiated signaling promotes the survival and self-renewal of cancer stem cells. Cancer Res. 2010;70:9969–78.PubMedPubMedCentralCrossRef
46.
Han J, Fujisawa T, Husain SR, Puri RK. Identification and characterization of cancer stem cells in human head and neck squamous cell carcinoma. BMC Cancer. 2014;14:173.PubMedPubMedCentralCrossRef
47.
Sun Y, Han J, Lu Y, Yang X, Fan M. Biological characteristics of a cell subpopulation in tongue squamous cell carcinoma. Oral Dis. 2012;18:169–77.PubMedCrossRef
48.
Davis SJ, Divi V, Owen JH, Bradford CR, Carey TE, Papagerakis S, et al. Metastatic potential of cancer stem cells in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 2010;136:1260–6.PubMedPubMedCentralCrossRef
49.
Oh SY, Kang HJ, Kim YS, Kim H, Lim YC. CD44 negative cells in head and neck squamous carcinoma also have stem-cell like traits. Eur J Cancer. 2013;49:272–80.PubMedCrossRef
50.
Cameron SR, Dahler AL, Endo-Munoz LB, Jabbar I, Thomas GP, Leo PJ, et al. Tumor-initiating activity and tumor morphology of HNSCC is modulated by interactions between clonal variants within the tumor. Lab Investig. 2010;90:1594–603.PubMedCrossRef
51.
Song J, Chang I, Chen Z, Kang M, Wang CY. Characterization of side populations in HNSCC: highly invasive, chemoresistant and abnormal Wnt signaling. PLoS One. 2010;5:e11456.PubMedPubMedCentralCrossRef
52.
Dalley AJ, Upton Z, Farah CS. Organotypic culture of normal, dysplastic and squamous cell carcinoma-derived oral cell lines reveals loss of spatial regulation of CD44 and p75\( NTR \) in malignancy. J Oral Pathol Med. 2013;42:37–46.PubMedCrossRef
53.
Koukourakis MI, Giatromanolaki A, Tsakmaki V, Sivridis E. Cancer stem cell phenotype relates to radiochemotherapy outcome in locally advanced squamous cell head-neck cancer. Br J Cancer. 2012;106:846–53.PubMedPubMedCentralCrossRef
54.
Oliveira LR, Oliveira-Costa JP, Araujo IM, Soave DF, Zanetti JS, Soares FA, et al. Cancer stem cell immunophenotypes in oral squamous cell carcinoma. J Oral Pathol Med. 2011;40:135–42.PubMedCrossRef
55.
Rajarajan A, Stokes A, Bloor BK, Ceder R, Desai H, Grafstrom RC, et al. CD44 expression in oro-pharyngeal carcinoma tissues and cell lines. PLoS One. 2012;7:e28776.PubMedPubMedCentralCrossRef
56.
Joshua B, Kaplan MJ, Doweck I, Pai R, Weissman IL, Ailles LE. Frequency of cells expressing CD44, a Head and Neck cancer stem cell marker: correlation with tumor aggressiveness. Head Neck. 2012;34:42–9.PubMedCrossRef
57.
Lin JT, Chang TH, Chang CS, Wang WH, Su BW, Lee KD, et al. Prognostic value of pretreatment CD44 mRNA in peripheral blood of patients with locally advanced head and neck cancer. Oral Oncol. 2010;46:e29–33.PubMedCrossRef
58.
Tsai LL, Yu CC, Chang YC. Markedly increased Oct4 and Nanog expression correlates with cisplatin resistance in oral squamous cell carcinoma. J Oral Pathol Med. 2011;40:621–8.PubMedCrossRef
59.
Chou MY, Hu FW, Yu CH, Yu CC. Sox2 expression involvement in the oncogenicity and radiochemoresistance of oral cancer stemcells. Oral Oncol. 2015;51:31–9.PubMedCrossRef
60.
Hayry V, Makinen LK, Atula T, Sariola H, Makitie A, Leivo I, et al. Bmi-1 expression predicts prognosis in squamous cell carcinoma of the tongue. Br J Cancer. 2010;102:892–7.PubMedPubMedCentralCrossRef
61.
Liu W, Feng JQ, Shen XM, Wang HY, Liu Y, Zhou ZT. Two stem cell markers, ATP-binding cassette, G2 subfamily (ABCG2) and BMI-1, predict the transformation of oral leukoplakia to cancer: a long-term follow-up study. Cancer. 2012;118:1693–700.PubMedCrossRef
62.
Wang J, Guo LP, Chen LZ, Zeng YX, Lu SH. Identification of cancer stem cell-like side population cells in human nasopharyngeal carcinoma cell line. Cancer Res. 2007;67:3716–24.PubMedCrossRef
63.
Zhang Y, Peng J, Zhang H, Zhu Y, Wan L, Chen J, et al. Notch1 signaling is activated in cells expressing embryonic stem cell proteins in human primary nasopharyngeal carcinoma. J Otolaryngol Head Neck Surg. 2010;39:157–66.PubMedPubMedCentral
64.
Zhang H, Liu W, Feng X, Wang L, Jiang X, Liu D, et al. Identification of ABCG2+ cells in nasopharyngeal carcinoma cells. Oncol Rep. 2012;27:1177–87.PubMed
65.
Yu F, Sim ACN, Li C, Li Y, Zhao X, Wang DY, et al. Identification of a subpopulation of nasopharyngeal carcinoma cells with cancer stem-like cell properties by high aldehyde dehydrogenase activity. Laryngoscope. 2013;123:1903–11.PubMedCrossRef
66.
Zhuang HW, Mo TT, Hou WJ, Xiong GX, Zhu XL, Fu QL, et al. Biological characteristics of CD133+ cells in nasopharyngeal carcinoma. Oncol Rep. 2013;30:57–63.PubMedPubMedCentral
67.
Su J, Xu XH, Huang Q, Lu MQ, Li DJ, Xue F, et al. Identification of cancer stem-like CD44+ cells in human nasopharyngeal carcinoma cell line. Arch Med Res. 2011;42:15–21.PubMedCrossRef
68.
Lun SW, Cheung ST, Cheung PF, To KF, Woo JK, Choy KW, et al. CD44+ cancer stem-like cells in EBV-associated nasopharyngeal carcinoma. PLoS One. 2012;7:e52426.PubMedPubMedCentralCrossRef
69.
Janisiewicz AM, Shin JH, Murillo-Sauca O, Kwok S, Le QT, Kong C, et al. CD44(+) cells have cancer stem cell-like properties in nasopharyngeal carcinoma. Int Forum Allergy Rhinol. 2012;2:465–70.PubMedCrossRef
70.
Chen J, Zhou J, Lu J, Xiong H, Shi X, Gong L. Significance of CD44 expression in head and neck cancer: a systemic review and meta-analysis. BMC Cancer. 2014;14:15.PubMedPubMedCentralCrossRef
71.
Yang CH, Wang HL, Lin YS, Kumar KPS, Lin HC, Chang CJ, et al. Identification of CD24 as a cancer stem cell marker in human nasopharyngeal carcinoma. PLoS One. 2014;9:e99412.PubMedPubMedCentralCrossRef
72.
Wu A, Luo W, Zhang Q, Yang Z, Zhang G, Li S, et al. Aldehyde dehydrogenase 1, a functional marker for identifying cancer stem cells in human nasopharyngeal carcinoma. Cancer Lett. 2013;330:181–9.PubMedCrossRef
73.
Hou W, He W, Li Y, Ma R, Wang Z, Zhu X, et al. Increased expression of aldehyde dehydrogenase 1 A1 in nasopharyngeal carcinoma is associated with enhanced invasiveness. Eur Arch Otorhinolaryngol. 2014;271:171–9.PubMedCrossRef
74.
Luo WR, Gao F, Li SY, Yao KT. Tumour budding and the expression of cancer stem cell marker aldehyde dehydrogenase 1 in nasopharyngeal carcinoma. Histopathol. 2012;61:1072–81.CrossRef
75.
Haraguchi N, Utsunomiya T, Inoue H, Tanaka F, Mimori K, Barnard GF, et al. Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells. 2006;24:506–13.PubMedCrossRef
76.
Huang SD, Yuan Y, Liu XH, Gong DJ, Bai CG, Wang F, et al. Self-renewal and chemotherapy resistance of p75NTR positive cells in esophageal squamous cell carcinomas. BMC Cancer. 2009;10(9):9.CrossRef
77.
Zhao JS, Li WJ, Ge D, Zhang PJ, Li JJ, Lu CL, et al. Tumor initiating cells in esophageal squamous cell carcinomas express high levels of CD44. PLoS One. 2011;6:e21419.PubMedPubMedCentralCrossRef
78.
Rassouli FB, Matin MM, Bahrami AR, Ghaffarzadegan K, Cheshomi H, Lari S, et al. Evaluating stem and cancerous biomarkers in CD15 + CD44+ KYSE30 cells. Tumour Biol. 2013;34:2909–20.PubMedCrossRef
79.
Le Bras GF, Allison GL, Richards NF, Ansari SS, Washington MK, Andl CD. CD44 upregulation in E-cadherin-negative esophageal cancers results in cell invasion. PLoS One. 2011;6:e27063.PubMedPubMedCentralCrossRef
80.
Wang JL, Yu JP, Sun ZQ, Sun SP. Radiobiological characteristics of cancer stem cells from esophageal cancer cell lines. World J Gastroenterol. 2014;20:18296–305.PubMedPubMedCentralCrossRef
81.
Li JC, Liu D, Yang Y, Wang XY, Pan DL, Qiu ZD, et al. Growth, clonability, and radiation resistance of esophageal carcinoma-derived stem-like cells. Asian Pac J Cancer Prev. 2013;14:4891–6.PubMedCrossRef
82.
Lu C, Xu F, Gu J, Yuan Y, Zhao G, Yu X, et al. Clinical and biological significance of stem-like CD133 + CXCR4+ cells in esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg. 2015;150(2):386–95.PubMedCrossRef
83.
Tang KH, Dai YD, Tong M, Chan YP, Kwan PS, Fu L, et al. A CD90(+) tumor-initiating cell population with an aggressive signature and metastatic capacity in esophageal cancer. Cancer Res. 2013;73:2322–32.PubMedCrossRef
84.
Ajani JA, Wang X, Song S, Suzuki A, Taketa T, Sudo K, et al. ALDH-1 expression levels predict response or resistance to preoperative chemoradiation in respectable esophageal cancer patients. Mol Oncol. 2014;8:142–9.PubMedCrossRef
85.
Honjo S, Ajani JA, Scott AW, Chen Q, Skinner HD, Stroehlein J, et al. Metformin sensitizes chemotherapy by targeting cancer stem cells and the mTOR pathway in esophageal cancer. Int J Oncol. 2014;45:567–74.PubMedPubMedCentral
86.
Bass AJ, Watanabe H, Mermel CH, Yu S, Perner S, Verhaak RG, et al. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet. 2009;41:1238–42.PubMedPubMedCentralCrossRef
87.
Gen Y, Yasui K, Zen Y, Dohi O, Endo M, Tsuji K, et al. SOX2 identified as a target gene for the amplification at 3q26 that is frequently detected in esophageal squamous cell carcinoma. Cancer Genet Cytogenet. 2010;202:82–93.PubMedCrossRef
88.
Rassouli FB, Matin MM, Bahrami AR, Ghaffarzadegan K, Sisakhtnezhad S, Cheshomi H, et al. SOX2 expression in gastrointestinal cancers of Iranian patients. Int J Biol Markers. 2015. doi:10.​5301/​jbm.​5000137.PubMed
89.
Wang Z, Qiao Q, Chen M, Li X, Wang Z, Liu C, et al. miR-625 down-regulation promotes proliferation and invasion in esophageal cancer by targeting SOX2. FEBS Lett. 2014;588:915–21.PubMedCrossRef
90.
Forghanifard MM, Ardalan Khales S, Javdani-Mallak A, Rad A, Farshchian M, Abbaszadegan MR. Stemness state regulators SALL4 and SOX2 are involved in progression and invasiveness of esophageal squamous cell carcinoma. Med Oncol. 2014;31:922–7.PubMedCrossRef
91.
Nagaraja V, Eslick GD. Forthcoming prognostic markers for esophageal cancer: a systematic review and meta-analysis. J Gastrointest Oncol. 2014;5:67–76.PubMedPubMedCentral
92.
DiMaio MA, Kwok S, Montgomery KD, Lowe AW, Pai RK. Immunohistochemical panel for distinguishing esophageal adenocarcinoma from squamous cell carcinoma: a combination of p63, cytokeratin 5/6, MUC5AC, and anterior gradient homolog 2 allows optimal subtyping. Hum Pathol. 2012;43:1799–807.PubMedPubMedCentralCrossRef
93.
Wang Q, He W, Lu C, Wang Z, Wang J, Giercksky KE, et al. Oct3/4 and Sox2 are significantly associated with an unfavorable clinical outcome in human esophageal squamous cell carcinoma. Anticancer Res. 2009;29:1233–41.PubMed
94.
Vaiphei K, Sinha SK, Kochhar R. Comparative analysis of Oct4 in different histological subtypes of esophageal squamous cell carcinomas in different clinical conditions. Asian Pac J Cancer Prev. 2014;15:3519–24.PubMedCrossRef
95.
Du Q, Yan W, Burton VH, Hewitt SM, Wang L, Hu N, et al. Validation of esophageal squamous cell carcinoma candidate genes from high-throughput transcriptomic studies. Am J Cancer Res. 2013;3:402–10.PubMedPubMedCentral
96.
Minato T, Yamamoto Y, Seike J, Yoshida T, Yamai H, Takechi H, et al. Aldehyde dehydrogenase 1 expression is associated with poor prognosis in patients with esophageal squamous cell carcinoma. Ann Surg Oncol. 2013;20:209–17.PubMedCrossRef
97.
Liu WK, Fu Q, Li YM, Jiang XY, Zhang MP, Zhang ZX. The relationship between cyclooxygenase-2, CD44v6, and nm23H1 in esophageal squamous cell carcinoma. Onkologie. 2009;32:574–8.PubMedCrossRef
98.
Shen WD, Ji Y, Liu PF, Xiang B, Chen GQ, Huang B, et al. Correlation of E-cadherin and CD44v6 expression with clinical pathology in esophageal carcinoma. Mol Med Rep. 2012;5:817–21.PubMed
99.
Okamoto H, Fujishima F, Nakamura Y, Zuguchi M, Ozawa Y, Takahashi Y, et al. Significance of CD133 expression in esophageal squamous cell carcinoma. World J Surg Oncol. 2013;11:51.PubMedPubMedCentralCrossRef
100.
Hang D, Dong HC, Ning T, Dong B, Hou DL, Xu WG. Prognostic value of the stem cell markers CD133 and ABCG2 expression in esophageal squamous cell carcinoma. Dis Esophagus. 2012;25:638–44.PubMedCrossRef
101.
Honing J, Pavlov KV, Meijer C, Smit JK, Boersma-van Ek W, Karrenbeld A, et al. Loss of CD44 and SOX2 expression is correlated with a poor prognosis in esophageal adenocarcinoma patients. Ann Surg Oncol. 2014;21:S657–64.PubMedCrossRef
102.
He XT, Cao XF, Ji L, Zhu B, Lv J, Wang DD, et al. Association between Bmi1 and clinicopathological status of esophageal squamous cell carcinoma. World J Gastroenterol. 2009;15:2389–94.PubMedPubMedCentralCrossRef
103.
Liu WL, Guo XZ, Zhang LJ, Wang JY, Zhang G, Guan S, et al. Prognostic relevance of Bmi-1 expression and autoantibodies in esophageal squamous cell carcinoma. BMC Cancer. 2010;10:467.PubMedPubMedCentralCrossRef
104.
Stoecklein NH, Siegmund A, Scheunemann P, Luebke AM, Erbersdobler A, Verde PE, et al. Ep-CAM expression in squamous cell carcinoma of the esophagus: a potential therapeutic target and prognostic marker. BMC Cancer. 2006;6:165.PubMedPubMedCentralCrossRef
105.
Wang Y, Zhe H, Gao P, Zhang N, Li G, Qin J. Cancer stem cell marker ALDH1 expression is associated with lymph node metastasis and poor survival in esophageal squamous cell carcinoma: a study from high incidence area of northern China. Dis Esophagus. 2012;25:560–5.PubMedCrossRef
106.
Du Y, Shi L, Wang T, Liu Z, Wang Z. Nanog siRNA plus cisplatin may enhance the sensitivity of chemotherapy in esophageal cancer. J Cancer Res Clin Oncol. 2012;138:1759–67.PubMedCrossRef
107.
Yoshikawa R, Nakano Y, Tao L, Koishi K, Matsumoto T, Sasako M, et al. Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy. Br J Cancer. 2008;98:1670–4.PubMedPubMedCentralCrossRef
108.
Mori Y, Okumura T, Tsunoda S, Sakai Y, Shimada Y. Gli-1 expression is associated with lymph node metastasis and tumor progression in esophageal squamous cell carcinoma. Oncol. 2006;70:378–89.CrossRef
109.
Sano A, Kato H, Sakurai S, Sakai M, Tanaka N, Inose T, et al. CD24 expression is a novel prognostic factor in esophageal squamous cell carcinoma. Ann Surg Oncol. 2009;16:506–14.PubMedCrossRef
110.
Gao G, Sun Z, Wenyong L, Dongxia Y, Zhao R, Zhang X. A preliminary study of side population cells in human gastric cancer cell line HGC-27. Ann Transplant. 2015;20:147–53.PubMedCrossRef
111.
Fukuda K, Saikawa Y, Ohashi M, Kumagai K, Kitajima M, Okano H, et al. Tumor initiating potential of side population cells in human gastric cancer. Int J Oncol. 2009;34:1201–7.PubMed
112.
She JJ, Zhang PG, Wang X, Che XM, Wang ZM. Side population cells isolated from KATO III human gastric cancer cell line have cancer stem cell-like characteristics. World J Gastroenterol. 2012;18:4610–7.PubMedPubMedCentralCrossRef
113.
Li R, Wu X, Wei H, Tian S. Characterization of side population cells isolated from the gastric cancer cell line SGC-7901. Oncol Lett. 2013;5:877–83.PubMedPubMedCentral
114.
Ehata S, Johansson E, Katayama R, Koike S, Watanabe A, Hoshino Y, et al. Transforming growth factor-beta decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells. Oncogene. 2011;30:1693–705.PubMedCrossRef
115.
Sun M, Zhou W, Zhang YY, Wang DL, Wu XL. CD44+ gastric cancer cells with stemness properties are chemoradioresistant and highly invasive. Oncol Lett. 2013;5:1793–8.PubMedPubMedCentral
116.
Takaishi S, Okumura T, Tu S, Wang SS, Shibata W, Vigneshwaran R, et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells. 2009;27:1006–20.PubMedPubMedCentralCrossRef
117.
Chen W, Zhang X, Chu C, Cheung WL, Ng L, Lam S, et al. Identification of CD44+ cancer stem cells in human gastric cancer. Hepato-Gastroenterology. 2013;60:949–54.PubMed
118.
Liu J, Ma L, Xu J, Liu C, Zhang J, Liu J, et al. Spheroid body-forming cells in the human gastric cancer cell line MKN-45 possess cancer stem cell properties. Int J Oncol. 2013;42:453–9.PubMed
119.
Yu D, Shin HS, Choi G, Lee YC. Proteomic analysis of CD44(+) and CD44(-) gastric cancer cells. Mol Cell Biochem. 2014;396:213–20.PubMedCrossRef
120.
Han ME, Jeon TY, Hwang SH, Lee YS, Kim HJ, Shim HE, et al. Cancer spheres from gastric cancer patients provide an ideal model system for cancer stem cell research. Cell Mol Life Sci. 2011;68:3589–605.PubMedCrossRef
121.
Chen T, Yang K, Yu J, Meng W, Yuan D, Bi F, et al. Identification and expansion of cancer stem cells in tumor tissues and peripheral blood derived from gastric adenocarcinoma patients. Cell Res. 2012;22:248–58.PubMedCrossRef
122.
Zhang C, Li C, He F, Cai Y, Yang H. Identification of CD44 + CD24+ gastric cancer stem cells. J Cancer Res Clin Oncol. 2011;137:1679–86.PubMedCrossRef
123.
Nishikawa S, Konno M, Hamabe A, Hasegawa S, Kano Y, Fukusumi T, et al. Surgically resected human tumors reveal the biological significance of the gastric cancer stem cell markers CD44 and CD26. Oncol Lett. 2015;9:2361–7.PubMedPubMedCentral
124.
Liu J, Ma L, Xu J, Liu C, Zhang J, Liu J, et al. Co-expression of CD44 and ABCG2 in spheroid body-forming cells of gastric cancer cell line MKN45. Hepato gastroenterol. 2013;60:975–80.
125.
Wang X, Zou F, Deng H, Fu Z, Li Y, Wu L, et al. Characterization of sphere-forming cells with stem-like properties from the gastric cancer cell lines MKN45 and SGC7901. Mol Med Rep. 2014;10:2937–41.PubMed
126.
Ghaffarzadehgan K, Jafarzadeh M, Raziee HR, Sima HR, Esmaili-Shandiz E, Hosseinnezhad H, et al. Expression of cell adhesion molecule CD44 in gastric adenocarcinoma and its prognostic importance. World J Gastroenterol. 2008;14:6376–81.PubMedPubMedCentralCrossRef
127.
Xie JW, Huang CM, Zheng CH, Li P, Wang JB, Lin JX, et al. Expression tumor stem cell surface marker CD44 in gastric cancer and its significance. Zhonghua Wei Chang Wai Ke Za Zhi. 2013;16:1107–12.PubMed
128.
Chen Y, Fu Z, Xu S, Xu Y, Xu P. The prognostic value of CD44 expression in gastric cancer: a meta-analysis. Biomed Pharmacother. 2014;68:693–7.PubMedCrossRef
129.
Cao X, Cao D, Jin M, Jia Z, Kong F, Ma H, et al. CD44 but not CD24 expression is related to poor prognosis in non-cardia adenocarcinoma of the stomach. BMC Gastroenterol. 2014;12(14):157.CrossRef
130.
Xu GF, Zhang WJ, Sun Q, Xu X, Zou X, Guan W. Combined epithelial-mesenchymal transition with cancer stem cell-like marker as predictors of recurrence after radical resection for gastric cancer. World J Surg Oncol. 2014;12:368.PubMedPubMedCentralCrossRef
131.
Nosrati A, Naghshvar F, Khanari S. Cancer stem cell markers CD44, CD133 in primary gastric adenocarcinoma. Int J Mol Cell Med. 2014;3:279–86.PubMedPubMedCentral
132.
Wang W, Dong LP, Zhang N, Zhao CH. Role of cancer stem cell marker CD44 in gastric cancer: a meta-analysis. Int J Clin Exp Med. 2014;7:5059–66.PubMedPubMedCentral
133.
Wu Y, Li Z, Zhang C, Yu K, Teng Z, Zheng G, et al. CD44 family proteins in gastric cancer: a meta-analysis and narrative review. Int J Clin Exp Med. 2015;8:3595–606.PubMedPubMedCentral
134.
Hirata K, Suzuki H, Imaeda H, Matsuzaki J, Tsugawa H, Nagano O, et al. CD44 variant 9 expression in primary early gastric cancer as a predictive marker for recurrence. Br J Cancer. 2013;109:379–86.PubMedPubMedCentralCrossRef
135.
Go SI, Ko GH, Lee WS, Kim RB, Lee JH, Jeong SH, et al. CD44 variant 9 serves as a poor prognostic marker in early gastric cancer, but not in advanced gastric cancer. Cancer Res Treat. 2015. doi:10.​4143/​crt.​2014.​227.
136.
Xie JW, Chen PC, Zheng CH, Li P, Wang JB, Lin JX, et al. Evaluation of the prognostic value and functional roles of CD44v6 in gastric cancer. J Cancer Res Clin Oncol. 2015;141(10):1809–17.PubMedCrossRef
137.
Wang L, Li HG, Wen JM, Peng TS, Zeng H, Wang LY. Expression of CD44v3, erythropoietin and VEGF-C in gastric adenocarcinomas: correlations with clinicopathological features. Tumori. 2014;100:321–7.PubMed
138.
Lau WM, Teng E, Chong HS, Lopez KA, Tay AY, Salto Tellez M, et al. CD44v8-10 is a cancer specific marker for gastric cancer stem cells. Cancer Res. 2014;74:2630–41.PubMedCrossRef
139.
Smith LM, Nesterova A, Ryan MC, Duniho S, Jonas M, Anderson M, et al. CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers. Br J Cancer. 2008;99:100–9.PubMedPubMedCentralCrossRef
140.
Zhao P, Li Y, Lu Y. Aberrant expression of CD133 protein correlates with Ki-67 expression and is a prognostic marker in gastric adenocarcinoma. BMC Cancer. 2010;10:218.PubMedPubMedCentralCrossRef
141.
Lee HH, Seo KJ, An CH, Kim JS, Jeon HM. CD133 expression is correlated with chemoresistance and early recurrence of gastric cancer. J Surg Oncol. 2012;106:999–1004.PubMedCrossRef
142.
Wen L, Chen XZ, Yang K, Chen ZX, Zhang B, Chen JP, et al. Prognostic value of cancer stem cell marker CD133 expression in gastric cancer: a systematic review. PLoS One. 2013;8:e59154.PubMedPubMedCentralCrossRef
143.
Hashimoto K, Aoyagi K, Isobe T, Kouhuji K, Shirouzu K. Expression of CD133 in the cytoplasm is associated with cancer progression and poor prognosis in gastric cancer. Gastric Cancer. 2014;17:97–106.PubMedCrossRef
144.
Wang T, Ong CW, Shi J, Srivastava S, Yan B, Cheng CL, et al. Sequential expression of putative stem cell markers in gastric carcinogenesis. Br J Cancer. 2011;105:658–65.PubMedPubMedCentralCrossRef
145.
Jiang Y, He Y, Li H, Li HN, Zhang L, Hu W, et al. Expressions of putative cancer stem cell markers ABCB1, ABCG2, and CD133 are correlated with the degree of differentiation of gastric cancer. Gastric Cancer. 2012;15:440–50.PubMedCrossRef
146.
Chen S, Hou JH, Feng XY, Zhang XS, Zhou ZW, Yun JP, et al. Clinicopathologic significance of putative stem cell marker, CD44 and CD133, in human gastric carcinoma. J Surg Oncol. 2013;107:799–806.PubMedCrossRef
147.
Katsuno Y, Ehata S, Yashiro M, Yanagihara K, Hirakawa K, Miyazono K. Coordinated expression of REG4 and aldehyde dehydrogenase 1 regulating tumourigenic capacity of diffuse-type gastric carcinoma-initiating cells is inhibited by TGF-β. J Pathol. 2012;228:391–404.PubMedCrossRef
148.
Wakamatsu Y, Sakamoto N, Oo HZ, Naito Y, Uraoka N, Anami K, et al. Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer. Pathol Int. 2012;62:112–9.PubMedCrossRef
149.
Tian T, Zhang Y, Wang S, Zhou J, Xu S. Sox2 enhances the tumorigenicity and chemoresistance of cancer stem-like cells derived from gastric cancer. J Biomed Res. 2012;26:336–45.PubMedPubMedCentralCrossRef
150.
Matsuoka J, Yashiro M, Sakurai K, Kubo N, Tanaka H, Muguruma K, et al. Role of the stemness factors Sox2, Oct3/4, and Nanog in gastric carcinoma. J Surg Res. 2010;174:130–5.PubMedCrossRef
151.
Zhang X, Yu H, Yang Y, Zhu R, Bai J, Peng Z, et al. SOX2 in gastric carcinoma, but not Hath1, is related to patients' clinicopathological features and prognosis. J Gastrointest Surg. 2010;14:1220–6.PubMedCrossRef
152.
Wu C, Xie Y, Gao F, Wang Y, Guo Y, Tian H, et al. Lgr5 expression as stem cell marker in human gastric gland and its relatedness with other putative cancer stem cell markers. Gene. 2013;525:18–25.PubMedCrossRef
153.
Simon E, Petke D, Boger C, Behrens HM, Warneke V, Ebert M, et al. The spatial distribution of LGR5+ cells correlates with gastric cancer progression. PLoS One. 2012;7:e35486.PubMedPubMedCentralCrossRef
154.
Jiang J, Zhang Y, Chuai S, Wang Z, Zheng D, Xu F, et al. Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype. Oncogene. 2012;31:671–82.PubMedCrossRef
155.
Zhan YY, He JP, Chen HZ, Wang WJ, Cai JC. Orphan receptor TR3 is essential for the maintenance of stem-like properties in gastric cancer cells. Cancer Lett. 2013;329:37–44.PubMedCrossRef
156.
Ohkuma M, Haraguchi N, Ishii H, Mimori K, Tanaka F, Kim HM, et al. Absence of CD71 transferrin receptor characterizes human gastric adenosquamous carcinoma stem cells. Ann Surg Oncol. 2012;19:1357–64.PubMedCrossRef
157.
Vermeulen L, Snippert HJ. Stem cell dynamics in homeostasis and cancer of the intestine. Nat Rev Cancer. 2014;14:468–80.PubMedCrossRef
158.
Xiong B, Ma L, Hu X, Zhang C, Cheng Y. Characterization of side population cells isolated from the colon cancer cell line SW480. Int J Oncol. 2014;45:1175–83.PubMed
159.
Xie ZY, Lv K, Xiong Y, Guo WH. ABCG2-meditated multidrug resistance and tumor-initiating capacity of side population cells from colon cancer. Oncol Res Treat. 2014;3:666–8.CrossRef
160.
Burkert J, Otto WR, Wright NA. Side populations of gastrointestinal cancers are not enriched in stem cells. J Pathol. 2008;214:564–73.PubMedCrossRef
161.
O'Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumor growth in immunodeficient mice. Nature. 2007;445:106–10.PubMedCrossRef
162.
Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445:111–5.PubMedCrossRef
163.
Ieta K, Tanaka F, Haraguchi N, Kita Y, Sakashita H, Mimori K, et al. Biological and genetic characteristics of tumor-initiating cells in colon cancer. Ann Surg Oncol. 2008;15:638–48.PubMedCrossRef
164.
Botchkina IL, Rowehl RA, Rivadeneira DE, Karpeh MS, Crawford H, Dufour A, et al. Phenotypic subpopulations of metastatic colon cancer stem cells: genomic analysis. Cancer Genomics Proteomics. 2009;6:19–29.PubMed
165.
Schneider M, Huber J, Hadaschik B, Siegers GM, Fiebig HH, Schuler J. Characterization of colon cancer cells: a functional approach characterizing CD133 as a potentialstem cell marker. BMC Cancer. 2012;12:96.PubMedPubMedCentralCrossRef
166.
Du L, Wang H, He L, Zhang J, Ni B, Wang X, et al. CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res. 2008;14:6751–60.PubMedCrossRef
167.
Horst D, Scheel SK, Liebmann S, Neumann J, Maatz S, Kirchner T, et al. The cancer stem cell marker CD133 has high prognostic impact but unknown functional relevance for the metastasis of human colon cancer. J Pathol. 2009;219:427–34.PubMedCrossRef
168.
Elsaba TM, Martinez-Pomares L, Robins AR, Crook S, Seth R, Jackson D, et al. The stem cell marker CD133 associates with enhanced colony formation and cell motility in colorectal cancer. PLoS One. 2010;5:e10714.PubMedPubMedCentralCrossRef
169.
Wang C, Xie J, Guo J, Manning HC, Gore JC, Guo N. Evaluation of CD44 and CD133 as cancer stem cell markers for colorectal cancer. Oncol Rep. 2012;28:1301–8.PubMedPubMedCentral
170.
Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, et al. CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors. J Clin Invest. 2008;118:2111–20.PubMedPubMedCentral
171.
Artells R, Moreno I, Diaz T, Martinez F, Gel B, Navarro A, et al. Tumor CD133 mRNA expression and clinical outcome in surgically resected colorectal cancer patients. Eur J Cancer. 2010;46:642–9.PubMedCrossRef
172.
Wang Q, Chen ZG, Du CZ, Wang HW, Yan L, Gu J. Cancer stem cell marker CD133+ tumor cells and clinical outcome in rectal cancer. Histopathol. 2009;55:284–93.CrossRef
173.
Choi D, Lee HW, Hur KY, Kim JJ, Park GS, Jang SH, et al. Cancer stem cell markers CD133 and CD24 correlate with invasiveness and differentiation in colorectal adenocarcinoma. World J Gastroenterol. 2009;15:2258–64.PubMedPubMedCentralCrossRef
174.
Horst D, Kriegl L, Engel J, Kirchner T, Jung A. CD133 expression is an independent prognostic marker for low survival in colorectal cancer. Br J Cancer. 2008;99:1285–9.PubMedPubMedCentralCrossRef
175.
Horst D, Kriegl L, Engel J, Jung A, Kirchner T. CD133 and nuclear beta-catenin: the marker combination to detect high risk cases of low stage colorectal cancer. Eur J Cancer. 2009;45:2034–40.PubMedCrossRef
176.
Horst D, Kriegl L, Engel J, Kirchner T, Jung A. Prognostic significance of the cancer stem cell markers CD133, CD44, and CD166 in colorectal cancer. Cancer Investig. 2009;27:844–50.CrossRef
177.
Florianova L, Orain M, Tetu B, Doillon CJ. Histological study of stem-like cells in human colon adenocarcinoma at different stages of the disease. Biotech Histochem. 2013;88:222–34.PubMedCrossRef
178.
Kawamoto A, Tanaka K, Saigusa S, Toiyama Y, Morimoto Y, Fujikawa H, et al. Clinical significance of radiation-induced CD133 expression in residual rectal cancer cells after chemoradiotherapy. Exp Ther Med. 2012;3:403–9.PubMed
179.
Pitule P, Cedikova M, Daum O, Vojtisek J, Vycital O, Hosek P, et al. Immunohistochemical detection of cancer stem cell related markers CD44 and CD133 in metastatic colorectal cancer patients. BioMed Res Int. 2014;2014:432139.PubMedPubMedCentralCrossRef
180.
Jing F, Kim HJ, Kim CH, Kim YJ, Lee JH, Kim HR. Colon cancer stem cell markers CD44 and CD133 in patients with colorectal cancer and synchronous hepatic metastases. Int J Oncol. 2015;46:1582–8.PubMed
181.
Chu P, Clanton DJ, Snipas TS, Lee J, Mitchell E, Nguyen ML, et al. Characterization of a subpopulation of colon cancer cells with stem cell-like properties. Int J Cancer. 2009;124:1312–21.PubMedCrossRef
182.
Fan X, Ouyang N, Teng H, Yao H. Isolation and characterization of spheroid cells from the HT29 colon cancer cell line. Int J Colorectal Dis. 2011;26:1279–85.PubMedCrossRef
183.
Yeung TM, Gandhi SC, Wilding JL, Muschel R, Bodmer WF. Cancer stem cells from colorectal cancer-derived cell lines. Proc Natl Acad Sci U S A. 2010;107:3722–7.PubMedPubMedCentralCrossRef
184.
Fan CW, Chen T, Shang YN, Gu YZ, Zhang SL, Lu R, et al. Cancer-initiating cells derived from human rectal adenocarcinoma tissues carry mesenchymal phenotypes and resist drug therapies. Cell Death Dis. 2013;4:e828.PubMedPubMedCentralCrossRef
185.
Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A. 2007;104:10158–63.PubMedPubMedCentralCrossRef
186.
Sahlberg SH, Spiegelberg D, Glimelius B, Stenerlow B, Nestor M. Evaluation of cancer stem cell markers CD133, CD44, CD24: association with AKT isoforms and radiation resistance in colon cancer cells. PLoS One. 2014;9:e94621.PubMedPubMedCentralCrossRef
187.
Haraguchi N, Ohkuma M, Sakashita H, Matsuzaki S, Tanaka F, Mimori K, et al. CD133 + CD44+ population efficiently enriches colon cancer initiating cells. Ann Surg Oncol. 2008;15:2927–33.PubMedCrossRef
188.
Chen KL, Pan F, Jiang H, Chen JF, Pei L, Xie FW, et al. Highly enriched CD133(+)CD44(+) stem-like cells with CD133(+)CD44(high) metastatic subset in HCT116 colon cancer cells. Clin Exp Metastasis. 2011;28:751–63.PubMedCrossRef
189.
Fang DD, Kim YJ, Lee CN, Aggarwal S, McKinnon K, Mesmer D, et al. Expansion of CD133(+) colon cancer cultures retaining stem cell properties to enable cancer stem cell target discovery. Br J Cancer. 2010;102:1265–75.PubMedPubMedCentralCrossRef
190.
Rowehl RA, Burke S, Bialkowska AB, Pettet DW, Rowehl L, Li E, et al. Establishment of highly tumorigenic human colorectal cancer cell line (CR4) with properties of putative cancer stem cells. PLoS One. 2014;9:e99091.PubMedPubMedCentralCrossRef
191.
Todaro M, Gaggianesi M, Catalano V, Benfante A, Iovino F, Biffoni M, et al. CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell. 2014;14:342–56.PubMedCrossRef
192.
Peng J, Lu JJ, Zhu J, Xu Y, Lu H, Lian P, et al. Prediction of treatment outcome by CD44v6 after total mesorectal excision in locally advanced rectal cancer. Cancer J. 2008;14:54–61.PubMedCrossRef
193.
Saito S, Okabe H, Watanabe M, Ishimoto T, Iwatsuki M, Baba Y, et al. CD44v6 expression is related to mesenchymal phenotype and poor prognosis in patients with colorectal cancer. Oncol Rep. 2013;29:1570–8.PubMed
194.
Kimura Y, Goi T, Nakazawa T, Hirono Y, Katayama K, Urano T, et al. CD44variant exon 9 plays an important role in colon cancer initiating cells. Oncotarget. 2013;4:785–91.PubMedPubMedCentralCrossRef
195.
Katoh S, Goi T, Naruse T, Ueda Y, Kurebayashi H, Nakazawa T, et al. Cancer stem cell marker in circulating tumor cells: expression of CD44 variant exon 9 is strongly correlated to treatment refractoriness, recurrence and prognosis of human colorectal cancer. Anticancer Res. 2015;35:239–44.PubMed
196.
Giampieri R, Scartozzi M, Loretelli C, Piva F, Mandolesi A, Lezoche G, et al. Cancer stem cell gene profile as predictor of relapse in high risk stage II and stage III, radically resected colon cancer patients. PLoS One. 2013;8:e72843.PubMedPubMedCentralCrossRef
197.
Saigusa S, Inoue Y, Tanaka K, Toiyama Y, Matsushita K, Kawamura M, et al. Clinical significance of LGR5 and CD44 expression in locally advanced rectal cancer after preoperative chemoradiotherapy. Int J Oncol. 2012;41:1643–52.PubMed
198.
Gerger A, Zhang W, Yang D, Bohanes P, Ning Y, Winder T, et al. Common cancer stem cell gene variants predict colon cancer recurrence. Clin Cancer Res. 2011;17:6934–43.PubMedCrossRef
199.
Kemper K, Prasetyanti PR, De Lau W, Rodermond H, Clevers H, Medema JP. Monoclonal antibodies against Lgr5 identify human colorectal cancer stem cells. Stem Cells. 2012;30:2378–86.PubMedCrossRef
200.
Rao GH, Liu HM, Li BW, Hao JJ, Yang YL, Wang MR, et al. Establishment of a human colorectal cancer cell line P6C with stem cell properties and resistance to chemotherapeutic drugs. Acta Pharmacol Sin. 2013;34:793–804.PubMedPubMedCentralCrossRef
201.
Kobayashi S, Yamada-Okabe H, Suzuki M, Natori O, Kato A, Matsubara K, et al. LGR5-positive colon cancer stem cells interconvert with drug-resistant LGR5-negative cells and are capable of tumor reconstitution. Stem Cells. 2012;30:2631–44.PubMedCrossRef
202.
Liu YS, Hsu HC, Tseng KC, Chen HC, Chen SJ. Lgr5 promotes cancer stemness and confers chemoresistance through ABCB1 in colorectal cancer. Biomed Pharmacother. 2013;67:791–9.PubMedCrossRef
203.
Al-Kharusi MR, Smartt HJM, Greenhough A, Collard TJ, Emery ED, Williams AC, et al. LGR5 promotes survival in human colorectal adenoma cells and is upregulated by PGE2: implications for targeting adenoma stem cells with NSAIDs. Carcinogenesis. 2013;34:1150–7.PubMedPubMedCentralCrossRef
204.
Hsu HC, Liu YS, Tseng KC, Hsu CL, Liang Y, Yang TS, et al. Overexpression of Lgr5 correlates with resistance to 5-FU-based chemotherapy in colorectal cancer. Int J Colorectal Dis. 2013;28:1535–46.PubMedCrossRef
205.
Hirsch D, Barker N, McNeil N, Hu Y, Camps J, McKinnon K, et al. LGR5 positivity defines stem-like cells in colorectal cancer. Carcinogenesis. 2014;35:849–58.PubMedCrossRef
206.
Valladares-Ayerbes M, Blanco-Calvo M, Reboredo M, Orenzo-Patino MJ, Iglesias-Diaz P, Haz M, et al. Evaluation of the adenocarcinoma-associated gene AGR2 and the intestinal stem cell marker LGR5 as biomarkers in colorectal cancer. Int J Mol Sci. 2012;13:436787.CrossRef
207.
Uchida H, Yamazaki K, Fukuma M, Yamada T, Hayashida T, Hasegawa H, et al. Overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 in colorectal cancer. Cancer Sci. 2010;101:1731–7.PubMedCrossRef
208.
Takahashi H, Ishii H, Nishida N, Takemasa I, Mizushima T, Ikeda M, et al. Significance of Lgr5 + ve cancer stem cells in the colon and rectum. Ann Surg Oncol. 2011;18:1166–74.PubMedCrossRef
209.
Wu XS, Xi HQ, Chen L. Lgr5 is a potential marker of colorectal carcinoma stem cells that correlates with patient survival. World J Surg Oncol. 2012;10:244.PubMedPubMedCentralCrossRef
210.
Gao F, Chen J, Wu H, Shi J, Chen M, Fan XS, et al. Lgr5 over-expression is positively related to the tumor progression and HER2 expression in stage pTNM IV colorectal cancer. Int J Clin Exp Pathol. 2014;7:1572–9.PubMedPubMedCentral
211.
He S, Zhou H, Zhu X, Hu S, Fei M, Wan D, et al. Expression of Lgr5, a marker of intestinal stem cells, in colorectal cancer and its clinicopathological significance. Biomed Pharmacother. 2014;68:507–13.PubMedCrossRef
212.
Chai N, Zhang W, Wang Y, Zhou Z, Zhang Y, Liu H, et al. Lgr5 and CD44 expressions in different types of intestinal polyps and colorectal cancer. Nan Fang Yi Ke Da Xue Xue Bao. 2013;33:972–6.PubMed
213.
Takeda K, Kinoshita I, Shimizu Y, Matsuno Y, Shichinohe T, Dosaka-Akita H. Expression of LGR5, an intestinal stem cell marker, during each stage of colorectal tumorigenesis. Anticancer Res. 2011;31:263–70.PubMed
214.
Fan XS, Wu HY, Yu HP, Zhou Q, Zhang YF, Huang Q. Expression of Lgr5 in human colorectal carcinogenesis and its potential correlation with beta-catenin. Int J Colorectal Dis. 2010;25:583–90.PubMedCrossRef
215.
Ziskin JL, Dunlap D, Yaylaoglu M, Fodor IK, Forrest WF, Patel R, et al. In situ validation of an intestinal stem cell signature in colorectal cancer. Gut. 2013;62:1012–23.PubMedCrossRef
216.
Navarro-Alvarez N, Kondo E, Kawamoto H, Hassan W, Yuasa T, Kubota Y, et al. Isolation and propagation of a human CD133(-) colon tumor-derived cell line with tumorigenic and angiogenic properties. Cell Transplant. 2010;19:865–77.PubMedPubMedCentralCrossRef
217.
Kreso A, van Galen P, Pedley NM, Lima-Fernandes E, Frelin C, Davis T, et al. Self-renewal as a therapeutic target in human colorectal cancer. Nat Med. 2014;20:29–36.PubMedCrossRef
218.
Tateishi K, Ohta M, Kanai F, Guleng B, Tanaka Y, Asaoka Y, et al. Dysregulated expression of stem cell factor Bmi1 in precancerous lesions of the gastrointestinal tract. Clin Cancer Res. 2006;12:6960–6.PubMedCrossRef
219.
Du J, Li Y, Li J, Zheng J. Polycomb group protein Bmi1 expression in colon cancers predicts the survival. Med Oncol. 2010;27:1273–6.PubMedCrossRef
220.
Li D, Tang H, Fan J, Yan DW, Zhou CZ, Li SX, et al. Expression level of Bmi-1 oncoprotein is associated with progression and prognosis in colon cancer. J Cancer Res Clin Oncol. 2010;136:997–1006.PubMedCrossRef
221.
Pun JCS, Chan JYJ, Chun BKM, Ng KW, Tsui SY, Wan TM, et al. Plasma Bmi1 mRNA as a potential prognostic biomarker for distant metastasis in colorectal cancer patients. Mol Clin Oncol. 2014;2:817–20.PubMedPubMedCentral
222.
Dylla SJ, Beviglia L, Park IK, Chartier C, Raval J, Ngan L, et al. Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS One. 2008;3:e2428.PubMedPubMedCentralCrossRef
223.
Huang EH, Hynes MJ, Zhang T, Ginestier C, Dontu G, Appelman H, et al. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res. 2009;69:3382–9.PubMedPubMedCentralCrossRef
224.
Fitzgerald TL, Rangan S, Dobbs L, Starr S, Sigounas G. The impact of aldehyde dehydrogenase 1 expression on prognosis for metastatic colon cancer. J Surg Res. 2014;192:82–9.PubMedCrossRef
225.
Langan RC, Mullinax JE, Ray S, Raiji MT, Schaub N, Xin HW, et al. A pilot study assessing the potential role of non-CD133 colorectal cancer stem cells as biomarkers. J Cancer. 2012;3:231–40.PubMedPubMedCentralCrossRef
226.
Weichert W, Denkert C, Burkhardt M, Gansukh T, Bellach J, Altevogt P, et al. Cytoplasmic CD24 expression in colorectal cancer independently correlates with shortened patient survival. Clin Cancer Res. 2005;11:6574–81.PubMedCrossRef
227.
228.
Li L, Bellows CF. Doublecortin-like kinase 1 exhibits cancer stem cell-like characteristics in a human colon cancer cell line. Chin J Cancer Res. 2013;25:134–42.PubMedPubMedCentral
229.
Nakanishi Y, Seno H, Fukuoka A, Ueo T, Yamaga Y, Maruno T, et al. Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nat Genet. 2013;45:98–103.PubMedCrossRef
230.
Saiki Y, Ishimaru S, Mimori K, Takatsuno Y, Nagahara M, Ishii H, et al. Comprehensive analysis of the clinical significance of inducing pluripotent stemness-related gene expression in colorectal cancer cells. Ann Surg Oncol. 2009;16:2638–44.PubMedCrossRef
231.
Chang CJ, Chien Y, Lu KH, Chang SC, Chou YC, Huang CS, et al. Oct4-related cytokine effects regulate tumorigenic properties of colorectal cancer cells. Biochem Biophys Res Commun. 2011;415:245–51.PubMedCrossRef
232.
Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Ioue Y, et al. Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol. 2009;16:3488–98.PubMedCrossRef
233.
Lu B, Fang Y, Xu J, Xu F, Xu E, Huang Q, et al. Analysis of SOX9 expression in colorectal cancer. Am J Clin Pathol. 2008;130:897–904.PubMedCrossRef
234.
Matheu A, Collado M, Wise C, Manterola L, Cekaite L, Tye AJ, et al. Oncogenicity of the developmental transcription factor Sox9. Cancer Res. 2012;72:1301–15.PubMedPubMedCentralCrossRef
235.
Candy PA, Phillips MR, Redfern AD, Colley SM, Davidson JA, Stuart LM, et al. Notch-induced transcription factors are predictive of survival and 5-fluorouracil response in colorectal cancer patients. Br J Cancer. 2013;109:1023–30.PubMedPubMedCentralCrossRef
236.
Huang MY, Chen HC, Yang IP, Tsai HL, Wang TN, Juo SH, et al. Tumorigenesis and tumor progression related gene expression profiles in colorectal cancer. Cancer Biomark. 2013;13:269–79.PubMedCrossRef
237.
Moserle L, Ghisi M, Amadori A, Indraccolo S. Side population and cancer stem cells: therapeutic implications. Cancer Lett. 2010;288:1–9.PubMedCrossRef
238.
Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell. 2007;1:389–402.PubMedCrossRef
239.
Dallas NA, Xia L, Fan F, Gray MJ, Gaur P, van Buren G, et al. Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res. 2009;69:1951–7.PubMedPubMedCentralCrossRef
240.
Subramaniam V, Vincent IR, Gilakjan M, Jothy S. Suppression of human colon cancer tumors in nude mice by siRNA CD44 gene therapy. Exp Mol Pathol. 2007;83:332–40.PubMedCrossRef
241.
Golubovskaya V, O'Brien S, Ho B, Heffler M, Conroy J, Hu Q, et al. Down-regulation of ALDH1A3, CD44 or MDR1 sensitizes resistant cancer cells to FAK autophosphorylation inhibitor Y15. J Cancer Res Clin Oncol. 2015;141(9):1613–31.PubMedCrossRef
242.
Xu ZY, Tang JN, Xie HX, Du YA, Huang L, Yu PF, et al. 5-Fluorouracil chemotherapy of gastric cancer generates residual cells with properties of cancer stem cells. Int J Biol Sci. 2015;11:284–94.PubMedPubMedCentralCrossRef
243.
Markman JL, Rekechenetskiy A, Holler E, Ljubimova JY. Nanomedicine therapeutic approaches to overcome cancer drug resistance. Adv Drug Deliv Rev. 2013;65:1866–79.PubMedCrossRef
244.
Bourseau-Guilmain E, Bejaud J, Griveau A, Lautram N, Hindre F, Weyland M, et al. Development and characterization of immunonanocarriers targeting the cancer stem cell marker AC133. Int J Pharm. 2011;423:93–101.PubMedCrossRef
245.
Liu C, Zhao G, Liu J, Ma N, Chivukula P, Perelman L, et al. Novel biodegradable lipid nanocomplex for siRNA delivery significantly improving the chemosensitivity of human colon cancer stem cells to paclitaxel. J Control Release. 2009;140:277–83.PubMedCrossRef
246.
Liu Q, Li RT, Qian HQ, Wei J, Xie L, Shen J, et al. Targeted delivery of miR-200c/DOC to inhibit cancer stem cells and cancer cells by the gelatinases-stimuli nanoparticles. Biomaterials. 2013;34:7191–203.PubMedCrossRef
247.
248.
Lampropoulos P, Zizi-Sermpetzoglou A, Rizos S, Kostakis A, Nikiteas N, Papavassiliou AG. TGF-beta signalling in colon carcinogenesis. Cancer Lett. 2012;314:1–7.PubMedCrossRef
249.
Thenappan A, Li Y, Shetty K, Johnson L, Reddy EP, Mishra L. New therapeutics targeting colon cancer stem cells. Curr Colorectal Cancer Rep. 2009;5:209.PubMedPubMedCentralCrossRef
250.
Mao J, Fan S, Ma W, Fan P, Wang B, Zhang J, et al. Roles of Wnt/beta-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment. Cell Death Dis. 2014;5:e1039.PubMedPubMedCentralCrossRef
251.
Hwang WL, Jiang JK, Yang SH, Huang TS, Lan HY, Teng HW, et al. MicroRNA-146a directs the symmetric division of Snail-dominant colorectal cancer stem cells. Nat Cell Biol. 2014;16:268–80.PubMedCrossRef
252.
Patel S. Exploring novel therapeutic targets in GIST: focus on the PI3K/Akt/mTOR pathway. Curr Oncol Rep. 2013;15:386–95.PubMedCrossRef
253.
254.
Saqui-Salces M, Merchant JL. Hedgehog signaling and gastrointestinal cancer. Biochim Biophys Acta. 1803;2010:786–95.
255.
Jin G, Westphalen CB, Hayakawa Y, Worthley DL, Asfaha S, Yang X, et al. Progastrin stimulates colonic cell proliferation via CCK2R- and β-arrestin-dependent suppression of BMP2. Gastroenterol. 2013;145:820–30.CrossRef
256.
Batsaikhan BE, Yoshikawa K, Kurita N, Iwata T, Takasu C, Kashihara H, et al. Cyclopamine decreased the expression of Sonic Hedgehog and its downstream genes in colon cancer stem cells. Anticancer Res. 2014;34:6339–44.PubMed
257.
Yu S, Zhang R, Liu F, Wang H, Wu J, Wang Y. Notch inhibition suppresses nasopharyngeal carcinoma by depleting cancer stem-like side population cells. Oncol Rep. 2012;28:561–6.PubMed
258.
Sikandar SS, Pate KT, Anderson S, Dizon D, Edwards RA, Waterman ML, et al. NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer. Cancer Res. 2010;70:1469–78.PubMedPubMedCentralCrossRef
Metadata
Title
Cancer stem cells in human digestive tract malignancies
Authors
Fatemeh B. Rassouli
Maryam M. Matin
Morvarid Saeinasab
Publication date
01-01-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 1/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4155-y

Other articles of this Issue 1/2016

Tumor Biology 1/2016 Go to the issue

Review

MicroRNAs, TGF-β signaling, and the inflammatory microenvironment in cancer

Original Article

Risk factors for skeletal-related events (SREs) and factors affecting SRE-free survival for nonsmall cell lung cancer patients with bone metastases

Original Article

Radiation-related lymphopenia as a new prognostic factor in limited-stage small cell lung cancer

Original Article

Delivery of miR-155 to retinal pigment epithelial cells mediated by Burkitt’s lymphoma exosomes

Review

The role of TWIST1 in epithelial-mesenchymal transition and cancers

Research Article

Imperatorin acts as a cisplatin sensitizer via downregulating Mcl-1 expression in HCC chemotherapy
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits