Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
Year : 2014  |  Volume : 10  |  Issue : 8  |  Page : 233-239

Updates in colorectal cancer stem cell research

1 Institute of Traditional Chinese Medicine Research, Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193; Department of Emergency Medicine, Tianjin Chest Hospital, Tianjin 300060, China
2 Department of Editorial Office, Tianjin Huanhu Hospital, Tianjin 300060, China
3 Institute of Traditional Chinese Medicine Research, Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China

Date of Web Publication17-Feb-2015

Correspondence Address:
Guan-Wei Fan
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.151449

Rights and Permissions
 > Abstract 

Colorectal cancer (CRC) is one of the world most common malignant tumors, also is the main disease, which cause tumor-associated death. Surgery and chemotherapy are the most used treatment of CRC. Recent research reported that, cancer stem cells (CSCs) are considered as the origin of tumor genesis, development, metastasis and recurrence in theory. At present, it has been proved that, CSCs existed in many tumors including CRC. In this review, we summary the identification of CSCs according to the cell surface markers, and the development of drugs that target colorectal cancer stem cells.

Keywords: Biomarker, cancer stem cell, colorectal cancer, target therapy

How to cite this article:
Li CJ, Zhang X, Fan GW. Updates in colorectal cancer stem cell research. J Can Res Ther 2014;10, Suppl S4:233-9

How to cite this URL:
Li CJ, Zhang X, Fan GW. Updates in colorectal cancer stem cell research. J Can Res Ther [serial online] 2014 [cited 2020 Oct 29];10:233-9. Available from: https://www.cancerjournal.net/text.asp?2014/10/8/233/151449

Xueqian Zhang - #Co-first author

 > Introduction Top

Even though the tumor therapy methods are improving, colorectal cancer (CRC) is still the main cause of tumor-related death. [1] Although most CRC patients are treated with surgery to remove the tumor tissue, some of the CRC patients recurred because of the undiscovered minimal residual tumor focus. [2] Other treatment methods such as radiation and chemotherapy are used as adjuvant therapy to treat the residual tumor cells. Whereas these treatments are useless in tumor cells with drug-resistance. [3],[4],[5] Therefore, developing new therapeutic strategies to eliminate tumor is ultimately in need.

Not only in pathogenesis aspects but molecular events aspects, the development of CRC is a multi-step process. [6],[7] The adenoma-carcinoma model of CRC genesis is shown in [Figure 1]. In molecular level, the signal transduction pathways are considered as having important regulation roles. In the research of family CRC syndrome, changes of different key genes were found; later research also revealed that these genes had obvious changes in sporadic cancer. In the tumorigenesis of CRC, Wnt signaling pathway is the cause of hereditary cancer predisposing syndrome and familial adenomatous polyposis (FAP), which plays an important role in the abnormal gene mutation of adenomatous polyposis coli (APC). [8],[9],[10]

Except FAP-related malignant tumor, APC gene mutation is found in 80% sporadic CRC. In these cases, apart from APC gene, genes in Wnt signaling pathway cascade are also found, including β-catenin mutation gene. [11],[12] Meanwhile, in bone morphogenesis protein 4 (BMP4) signal pathway, the mutation of BMP receptor 1A (BMPR1A) and SMAD4 also found in hereditary cancer predisposing syndrome and juvenile polyposis. [13],[14],[15] Then, SMAD4 gene somatic mutation was found in 30% sporadic CRC. [16],[17],[18] In other sporadic tumor, hereditary nonpolyposis CRC mismatch gene mutation repair was found, including MLH1, MSH2, PMS1, PMS2, and MSH6. [19],[20] This kind of genetic heterogeneity also reflects on the phenotypic heterogeneity of CRC, which is characterized as the difference of tumor sits, progress and treatment response.

In molecular level, human cancer can be composed of cells with phenotypic heterogeneity. [21] Otherwise, tumor cell can present functional heterogeneity, such as, the growth characteristics difference of proliferation during in vitro determination, [22] or the difference of tumorigenicity in vivo and maintenance potential of tumor growth. [23] These differences to some extent demonstrate the ongoing gene mutation. This conclusion is the basic of the cancer stem cell (CSC) model. [24] In CSCs theory, only the subset of CSCs can proliferate widely and drive tumor growth that induced morphological and functional diversity daughter cells, including nontumorigenicity cells group. Therefore, CSCs are a small group of cells in tumor tissue with the character of stem cell, such as the potential of self-renew, multi-lineage differentiation and infinite multiplication, [6],[7] they also show characteristics of tumor cell, such as the abnormal of proto-oncogene and tumor suppressor gene, their daughter cells are also incomplete differentiation and with functional defects. When transplant CSCs to animals, they can differentiate into different phenotype cell subpopulation, which is similar to the original tumor but without tumorigenicity. [5],[25],[26],[27],[28],[29],[30] Recent research showed that, CSCs could cause the recovery of CRC. [2],[3],[5],[29] This review summarizes the development of colorectal cancer stem cell (CR-CSC).
Figure 1: The adenoma-carcinoma model of human colorectal carcinogenesis. Adenomatous polyposis coli (APC) or β-catenin mutations initiate the neoplastic process. Tumor progression results from mutations in other genes (e.g., K-ras, Smad 4 and p53) and genomic instability. Patients with familial adenomatous polyposis inherit APC mutations and develop numerous aberrant crypt foci, some of which progress as they acquire other genetic mutations

Click here to view

 > The identification of colorectal cancer stem cells Top

A large amount of evidence proved that in human CRC tissues, there are CR-CSCs. [27],[28],[29],[31] Meanwhile, CR-CSCs are the main reason of chemotherapy resistance and treatment failure, which prevent the development of clinical oncology.

Recent researchers including Dalerba P, Papailiou J, Zhu L,Vermeulen L,Yeung TM,Takahashi H, et al select or enrich CR-CSCs according to possible stem cell markers, CD133, CD44, CD24, CD166, LGR-5 and aldehyde dehydrogenase-1 (ALDH-1) [29],[30],[32],[33],[34],[35],[36],[37] are current discovered CR-CSCs markers. [Table 1]. In an in vivo research, different amount of cancer cell subpopulations, which were classified according to whether CD133 expression or not, were respectively injected into immune deficiency mice, only CD133 + colon cancer cell subpopulation have tumorigenic ability. CD133 + cells account for 2-25% [27] or 1-6% [28] in CRC tissue, 1 × 10 2[27] or 1.5 × 10 3[28] CD133 + cells can cause tumor, while 1 × l0 5 CD133 cell can't cause tumor. Meanwhile, in other research, 2.5 × 10 5 CD133 cancer cells were injected into 9 mice, only one of them acquired tumor. [27] In addition, research also showed that, unlike CD133 cells, CD133 + colon cancer cell could be alive for at least 1-year as CR-CSC spheres in vivo. However, CD133 as CR-CSCs marker was doubted in the following research of Shmelkov et al. [38] Because they found that CD133 CR-CSC also can cause primary tumor and metastasis tumor, and can be serial cultured in vivo. Conversely, Li et al. [39] agreed to consider CD133 as CR-CSCs marker, in their research, clone population of CD133 + single cell isolated from CRC cell line SW480 has more tumorigenic ability than CD133 cell. Meanwhile, CD133 overexpression cell population have more invasion ability than CD133 down expression cell population. In metastasis tumor, CD133 can be considered as a marker of increased tumorigenic ability. Furthermore, in derived culture of clinical tumor only CD133 + signal cell showed the potential of multi-lineage differentiation. [33]
Table 1: The markers of colorectal cancer stem cells

Click here to view

Dalerba et al. [29] also found another cell population of human CRC with epithelial cell adhesion molecule (EpCAM) (epithelial specific antigen [ESA]) high /CD44 + phenotype had tumorigenic ability. 0.03-38% of the total alive tumor cell expressed both of these markers. Injection nonobese diabetic/severe combined immunodeficient mice with minimal 2 × 10 2 this kind of phenotype cells can cause implant tumor whereas 1 × 10 5 EpCAM low /CD44 cells can't cause tumor. And only one mouse occurred tumor originated from injection of 2 × 10 5 EpCAM low /CD44 cells. However, in this research, long-term cell self-renew ability was not assessed, and tumor cell hierarchy organ xenografts were either not conducted. [29] Interestingly, cells with phenotype of EpCAM high /CD44 + also expressed mesenchymal stem cell marker CD166, which was also found related to the progress of CRC [40] and human malignant melanoma stem cell-like cancer cell [41] in previous research. CD166 also can be considered as a candidate marker of CR-CSCs enrichment. The primary selecting experiment results demonstrate that the tumorigenic cell can be restricted in the ESA high /CD44 + /CD166 + CRC cell population. [29] Moreover, it is proved that two kinds of human colon cancer cell line (HT-29 and CaCO 2 ) express both CD133 and CD44, meanwhile, the tumorigeneic ability of CD133 + /CD44 + cell is higher than cells with one positive marker. [42] In one following research, ALDH-1 is overexpressed in the two hyperplasia colon crypts and colon adenoma of FAP patients. [43] ALDH-1 + cell population showed effective ability to induce xenograft tumor, also can passage in-line in vivo, while ALDH-1 cells don't have this ability. ALDH-1 + cells also represent the subpopulation of CD133 + or CD44 + cells, which means ALDH-1 can be considered as another CR-CSCs marker.

Recent research using lineage-tracing experiments in mice cancer model revealed that CR-CSCs could come from stem cell in physiological tissue. For example, using the latest intestinal stem cell marker LGR5, [44] Barker et al. proved that the regulation of Wnt signal on APC was lost in LGR5 + cell instead of LGR5 cells, which induced the progress of intestinal adenoma. [45] It is also demonstrated that in CD133 + cells, internal Wnt signaling pathway was activated though mutated β-catenin, which induced the damage of colon crypts structure and the disproportionate expansion of CD133 + cell in intestinal crypt stem cell. Therefore, some potential marker or marker group exist in the enriched CR-CSCs cells.

Especially when considering future therapy design, identification of the function of CSC surface marker is an important problem to solve. Du et al. [46] proved that CD133 knock-out have no effect on the formation of in vitro clone or in vivo xenotransplanted tumor, indicating that CD133 can be considered as the passive marker of CR-CSCs. However, knockout CD44 can induce limited colony formation, and significantly reduce the formation of xenotransplanted tumor, which strongly implied that CD44 plays a role in CRC tumorigenesis. These data support a single genetic model independently; knocking out CD44 in APC min/+ mice can limit the progress of intestinal adenoma. [47] CD44 transmembrane glycoprotein is a cell adhesion molecular, which transmit extracellular matrix signal from hyaluronic acid into the cell. [48] Wnt signaling pathway can regulate the expression of CD44, and the modulation of Wnt signaling pathway may also regulate CR-CSCs. [49],[50],[51]

 > Drug-Resistance of Colorectal Cancer Stem Cells Top

Traditional cancer therapies, including chemotherapy and radiotherapy, depend on the rapid cycling cell cycle and aim at specific cell division phase, such as 5-fluoroucil (5-FU), the inhibitor of thymidylate synthase in cell mitotic S-stage, and oxaliplatin, a platinum compounds agent. [52] Nevertheless, there is evidence that showed drug-resistance exists in CR-CSCs, which may be associated with the slow growth of CR-CSCs in G0 stage. A large sample of clinical research conducted in 501 human CRC patients demonstrated that, tumors with CD133 overexpression showed more resistance in 5-FU based chemotherapy and the expression of CD133 related to poor prognosis. [37] In oxaliplatin treated SW620 and LoVo CRC cells, overexpression of CD133 was also observed. [53] Recently, Dallas et al. found that the high concentration of 5-FU or oxaliplatin treated human HT-29 CRC cells showed enrichment of CD133 + and CD44 + CR-CSCs and decreased in vitro proliferation. Insulin-like growth factor receptor I (IGF-1R) is overexpressed in chemoresistant HT-29 cell line, treatment with IGF-1R inhibitor AVE-1642 can inhibit the growth of in vivo xenograft model. [54] Todaro et al. [55] reported that human CD133 + CR-CSCs can regulate death receptor and inhibit chemotherapy-induced cell apoptosis through specifically expressed interleukin-4 (IL-4). Treated CD133 + CR-CSCs with anti-IL-4 neutralizing antibody can increase the sensibility of 5-FU or oxaliplatin-based therapy. [55] Cammareri et al. [56] reported other mechanism of CD133 + CR-CSCs 5-FU and oxaliplatin resistance: Aurora-A kinase, a regulator of mitosis affecting the process of cell cycle, is overexpressed in CR-CSCs; and Aurora-A silence can result in the growth inhibition, down-regulation of the apoptosis protein expression and increase of chemotherapy sensitivity, which then induce the death of CR-CSCs. MicroRNAs (miRNA) also play a role in the regulation of cell proliferation and can regulate CR-CSCs specific signal pathway to increase CR-CSCs drug-resistance. For example, miRNA-140 inhibits the proliferation of CD133 +high /CD44 +high human CRC cells through regulating histone deacetylase 4, leading to resistance to methotrexate (MTX) and 5-FU. [57] Though inhibiting cell proliferate and regulating nuclear and centrosomal protein DTL to block cell cycle and induce cell G2 stage retardation, miRNA-215 can increase the resistance of CD133 + CD44 + CRC to MTX and tomudex. [58] It is meaningful to study this invasion cancer cell subpopulation with specific targets and their drug-resistance mechanism, and to improve the effect of traditional cancer therapy and treatment method. [5]

In the treatment of metastasis cancer, chemotherapy effect also impacted by different mechanism induced primary or secondary tumors, this phenomenon is called multi-drug-resistance (MDR). [59] Reduce the enriched drug in the tumor is the most studied in tumor MDR mechanism. It is found that part of the tumor cells express adenosine triphosphate (ATP) depended on drug efflux transporter p-glycoprotein (P-gp, MDR1, ABCB1). [60],[61] In clinical, the overexpression of ABCB1 is found in CRC, kidney, adrenal hepatocellular tumor, and acute myeloid leukemia. [59] However, till now, the relation between ABC transduction and CR-CSCs has not been identified. It is reported that human MDR family-ABCB5 expressed in human skin [62] and human malignant melanoma. [41],[62] Meanwhile, the analysis of ABCB5-mRNA revealed that its expression also exist in normal colonic tissue and other CRC tissue. [41] Notably, in CD133 + stem cell phenotype-expressing tumor cells in malignant melanoma cultures and clinical primary and metastatic melanomas, the specific expression of ABCB5 was found. [41] In a multi-center drug selecting research (NCI-60) supported by National Cancer Institute, it is found that lots of cancer cell lines express ABCB5, which is related to the chemotherapy drug-resistance. [41],[63] In CD133 + stem cell phenotype-expressing melanoma cells, ABCB5 can mediate doxorubicin resistance through drug efflux transport. [41] Follow-up research have identified that ABCB5 mediated doxorubicin resistance in melanoma and liver cancer cells, [64],[65] furthermore, in melanoma cells, ABCB5 resisted to camptothecin and 5-FU, which are two commonly used anti-CRC drugs. [63] Because the expression of ABCB5 means drug-resistance, [41],[63],[64],[65],[66] it is evidenced that in solid malignant tumor, there are novel, potential and key relations among CSCs, tumor development and chemotherapy resistance. ABCB5 + CSCs may be the main factor of malignant disease development and chemotherapy resistance. Therefore, target CSCs therapy is a new treatment strategy in metastasis tumor. [5] All these results indicated that, ABCB5 expression is closely related to the CSCs-driven cancer, [41],[65],[67] ABCB5 expressing or not in CRC may represent another drug-resistant mechanism. [68] Therapies target CR-CSCs subpopulation with tumorigenicity and chemotherapy resistance can improve the therapy efficacy in these malignant tumors. [41]

Some research suggested that CSC is resistant to radiotherapy, such as, compared with CD133 tumor cell, the chemotherapy resistance increased in CD133 + human brain glioma stem cell, meanwhile, CD133 + tumor cells presented preferentially activation of DNA damage checkpoint in response to radiotherapy-induced DNA damage and repair. [69] The exact relationship between CR-CSCs and chemotherapy in still unclear, several research demonstrated that, in CRC, CD133 + CR-CSCs survived after adjuvant chemoradiotherapy. [70] As the radiation dose increasing, the expression of CD133 also increased in vitro. [71]

 > Colorectal cancer stem cells target therapy Top

Recent researches provide new target therapy strategy for advanced colon cancer [Table 2]. The purpose of this therapy is to damage the necessary way of tumor growth, survival and metastasis, and specific cytotoxic. [72],[73] Currently, there are two targets of this therapy, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). EGFR is a member of ErbB family, which is abnormally activated in many tumors. [74] VEGF promotes angiogenesis through inducing epithelial cell growth and differentiation, VEGF expresses in 40-60% colon cancer, the activation process is related to tumor development and metastasis. [75],[76] Some clinical trials indicated that, in addition to 5-FU therapy, target therapy including anti-EGFR (such as cetuximab) and anti-VEGF monoclonal antibody (bevacizumab) could increase the survival of advance colon cancer patients for over 20 months. [73],[77] Therefore, treatment targeting to specific cell population after chemotherapy is feasible to eradicate tumor successfully.
Table 2: Novel targeting approaches against colorectal cancer stem cells

Click here to view

Recent discoveries of specific molecular signaling pathway in chemotherapy resistance, self-renew and tumorigenicity provide potential targets for the future treatment of CR-CSCs. The role of Wnt/β-catenin signaling pathway in maintaining the phenotype of intestinal crypt stem cell has been evidenced. APC function loss or β-catenin mutation induced Wnt signaling disorder are the leading causes of most CRC. [78],[79] Recent findings revealed that LGR5, a marker of intestinal stem cell, could regulate CRC cell proliferation and survival through targeting the Wnt/β-catenin signaling pathway. [80],[81] CD44v6 is found expressed in all CR-CSCs, inhibition of phosphatidylinositol 3-kinase selectively killed CD44v6 CR-CSCs and decreased metastatic growth. [82] Meanwhile, Notch signaling pathway is overexpressed in CR-CSCs, and plays a role in CR-CSCs tumorigenicity and self-renew by inhibiting cell cycle kinase inhibitor p27 and transcription factor ATOH1. [83] In APC min CRC model, γ-secretase inhibition mediated Notch signaling dysfunction induced the APC min proliferating cells in intestinal adenoma turning into goblet cells, then leading to the growth stagnation of tumor cells. [84] BMP4 plays a key role in the development of physiological intestinal crypts. [85] Mutation of BMP4 signaling pathway (SMAD4 and BMPRIA) or blocking the BMP4 signaling pathway by expression of BMP4 antistatic agent, Noggin, induced the development of intestinal crypts, cancer susceptibility syndrome, and juvenile polyposis syndrome. [86] The expression of BMPR2 and SMAD4 were also found in an immunohistochemical analysis of 72 sporadic CRC patients, revealing that blocking BMP4 signaling pathway can potentially contribute to the formation of colorectal tumor. [87] In this aspect, Lombardo et al. demonstrated that, BMP4 could induce the differentiation of CD133 + CR-CSCs, improving the sensitivity of oxaliplatin and 5-FU in the treatment of xenografted tumor. [88] It is reported that, actin-binding peptide thymosin β4 (Tβ4) is overexpressed in CD133 + CR-CSCs. Targeting Tβ4 can damage the growth and migration of CR-CSCs in vitro, also, though regulating integrin-linked kinase/Akt transduction cascades in vivo can reduce the tumor size of CD133 + CR-CSCs based xenografts in mice. [89]

In a word, these data demonstrated the efficacy of CSCs therapy, providing new approaches to discover new mechanism of cancer treatment resistance by detection of more invasive cancer and cancer cell subpopulation proliferation. If researches limited to unclassified tumor cells, the discovery of new therapy method is impossible.

 > Future prospective Top

Despite the observed proliferation of CR-CSCs is very slow, the knowledge of the metabolism character of CR-CSCs remains limited. Metabolomics that is an emerging research field, points out the way. Warburg effect, which believes that cancer cells utilize glycolysis as ATP energy source in priority instead of fatty acid oxidation, also can be applied as broad-spectrum anticancer drugs. [90],[91] A recent research of Akao et al. found the primary evidence of the metabolomics changes in drug-resistance cells. SIRT1, the key regulator, is overexpressed in 5-FU resistance DLD-1 cells. [92] In addition, there are many approaches for high throughput screening CR-CSCs, such as RNA interference library, drug screening libraries, mass spectrometry analysis, differentiation therapy, microarray chip and gene therapy, paved the way for future identifying different characteristics of CR-CSCs related molecular signal pathways and the effective methods to eradicate tumors.

 > Conclusion Top

Since the first report of CR-CSCs in 2007, there are great advancements in the identification CR-CSCs and targeting CR-CSCs treatments. At present, although a large amount of research have been done, more novel molecular characters of CR-CSCs are still to be explored in the future. Patient oriented new therapy strategy is under development. Once the efficacy of targeting CR-CSCs and tumor side population cells therapy were identified and verified, the survival of patients can be obviously improved.

 > Acknowledgements Top

We thank the financial supports from the National Natural Science Foundation of China (81001659, 81273891), and Tianjin Innovative teams in Colleges and Universities (TD12-50-31)

 > References Top

Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29.  Back to cited text no. 1
Markowitz SD, Bertagnolli MM. Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med 2009;361:2449-60.  Back to cited text no. 2
Zhou BB, Zhang H, Damelin M, Geles KG, Grindley JC, Dirks PB. Tumour-initiating cells: Challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov 2009;8:806-23.  Back to cited text no. 3
Siegel D. Changes in colonoscopy: New tricks for an old dog. J Interv Gastroenterol 2013;3:57-58.  Back to cited text no. 4
Frank NY, Schatton T, Frank MH. The therapeutic promise of the cancer stem cell concept. J Clin Invest 2010;120:41-50.  Back to cited text no. 5
Zoratto F, Rossi L, Verrico M, Papa A, Basso E, Zullo A, et al. Focus on genetic and epigenetic events of colorectal cancer pathogenesis: Implications for molecular diagnosis. Tumour Biol 2014;35:6195-206.  Back to cited text no. 6
Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759-67.  Back to cited text no. 7
Kinzler KW, Nilbert MC, Vogelstein B, Bryan TM, Levy DB, Smith KJ, et al. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science 1991;251:1366-70.  Back to cited text no. 8
Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991;253:665-9.  Back to cited text no. 9
Farkas SA, Vymetalkova V, Vodickova L, Vodicka P, Nilsson TK. DNA methylation changes in genes frequently mutated in sporadic colorectal cancer and in the DNA repair and Wnt/ß-catenin signaling pathway genes. Epigenomics 2014;6:179-91.  Back to cited text no. 10
Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 1997;275:1787-90.  Back to cited text no. 11
Deming DA, Leystra AA, Nettekoven L, Sievers C, Miller D, Middlebrooks M, et al. PIK3CA and APC mutations are synergistic in the development of intestinal cancers. Oncogene 2014;33:2245-54.  Back to cited text no. 12
Howe JR, Bair JL, Sayed MG, Anderson ME, Mitros FA, Petersen GM, et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 2001;28:184-7.  Back to cited text no. 13
Howe JR, Roth S, Ringold JC, Summers RW, Järvinen HJ, Sistonen P, et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 1998;280:1086-8.  Back to cited text no. 14
Cheah PY, Wong YH, Chau YP, Loi C, Lim KH, Lim JF, et al. Germline bone morphogenesis protein receptor 1A mutation causes colorectal tumorigenesis in hereditary mixed polyposis syndrome. Am J Gastroenterol 2009;104:3027-33.  Back to cited text no. 15
Thiagalingam S, Lengauer C, Leach FS, Schutte M, Hahn SA, Overhauser J, et al. Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. Nat Genet 1996;13:343-6.  Back to cited text no. 16
Fleming NI, Jorissen RN, Mouradov D, Christie M, Sakthianandeswaren A, Palmieri M, et al. SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer. Cancer Res 2013;73:725-35.  Back to cited text no. 17
Schwenter F, Faughnan ME, Gradinger AB, Berk T, Gryfe R, Pollett A, et al. Juvenile polyposis, hereditary hemorrhagic telangiectasia, and early onset colorectal cancer in patients with SMAD4 mutation. J Gastroenterol 2012;47:795-804.  Back to cited text no. 18
Bellacosa A, Genuardi M, Anti M, Viel A, Ponz de Leon M. Hereditary nonpolyposis colorectal cancer: Review of clinical, molecular genetics, and counseling aspects. Am J Med Genet 1996;62:353-64.  Back to cited text no. 19
Müller A, Korabiowska M, Brinck U. Review. DNA-mismatch repair and hereditary nonpolyposis colorectal cancer syndrome. In Vivo 2003;17:55-9.  Back to cited text no. 20
Bruce WR, van der Gaag H. A quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo. Nature 1963;199:79-80.  Back to cited text no. 21
Hamburger AW, Salmon SE. Primary bioassay of human tumor stem cells. Science 1977;197:461-3.  Back to cited text no. 22
Brunschwig A, Southam CM, Levin AG. Host resistance to cancer. Clinical experiments by homotransplants, autotransplants and admixture of autologous leucocytes. Ann Surg 1965;162:416-25.  Back to cited text no. 23
Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001;414:105-11.  Back to cited text no. 24
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003;100:3983-8.  Back to cited text no. 25
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature 2004;432:396-401.  Back to cited text no. 26
O′Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007;445:106-10.  Back to cited text no. 27
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.  Back to cited text no. 28
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.  Back to cited text no. 29
Papailiou J, Bramis KJ, Gazouli M, Theodoropoulos G. Stem cells in colon cancer. A new era in cancer theory begins. Int J Colorectal Dis 2011;26:1-11.  Back to cited text no. 30
Lu J, Ye X, Fan F, Xia L, Bhattacharya R, Bellister S, et al. Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell 2013;23:171-85.  Back to cited text no. 31
Zhu L, Gibson P, Currle DS, Tong Y, Richardson RJ, Bayazitov IT, et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 2009;457:603-7.  Back to cited text no. 32
Vermeulen L, Todaro M, de Sousa Mello F, Sprick MR, Kemper K, Perez Alea M, et al. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc Natl Acad Sci U S A 2008;105:13427-32.  Back to cited text no. 33
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.  Back to cited text no. 34
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.  Back to cited text no. 35
Pang R, Law WL, Chu AC, Poon JT, Lam CS, Chow AK, et al. A subpopulation of CD26+cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell 2010;6:603-15.  Back to cited text no. 36
Ong CW, Kim LG, Kong HH, Low LY, Iacopetta B, Soong R, et al. CD133 expression predicts for non-response to chemotherapy in colorectal cancer. Mod Pathol 2010;23:450-7.  Back to cited text no. 37
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.  Back to cited text no. 38
Li G, Liu C, Yuan J, Xiao X, Tang N, Hao J, et al. CD133(+) single cell-derived progenies of colorectal cancer cell line SW480 with different invasive and metastatic potential. Clin Exp Metastasis 2010;27:517-27.  Back to cited text no. 39
Weichert W, Knösel T, Bellach J, Dietel M, Kristiansen G. ALCAM/CD166 is overexpressed in colorectal carcinoma and correlates with shortened patient survival. J Clin Pathol 2004;57:1160-4.  Back to cited text no. 40
Frank NY, Margaryan A, Huang Y, Schatton T, Waaga-Gasser AM, Gasser M, et al. ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res 2005;65:4320-33.  Back to cited text no. 41
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.  Back to cited text no. 42
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.  Back to cited text no. 43
Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007;449:1003-7.  Back to cited text no. 44
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.  Back to cited text no. 45
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.  Back to cited text no. 46
Zeilstra J, Joosten SP, Dokter M, Verwiel E, Spaargaren M, Pals ST. Deletion of the WNT target and cancer stem cell marker CD44 in Apc(Min/+) mice attenuates intestinal tumorigenesis. Cancer Res 2008;68:3655-61.  Back to cited text no. 47
Ponta H, Sherman L, Herrlich PA. CD44: From adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 2003;4:33-45.  Back to cited text no. 48
Ishimoto T, Oshima H, Oshima M, Kai K, Torii R, Masuko T, et al. CD44+slow-cycling tumor cell expansion is triggered by cooperative actions of Wnt and prostaglandin E2 in gastric tumorigenesis. Cancer Sci 2010;101:673-8.  Back to cited text no. 49
Dissanayake SK, Wade M, Johnson CE, O′Connell MP, Leotlela PD, French AD, et al. The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition. J Biol Chem 2007;282:17259-71.  Back to cited text no. 50
Vermeulen L, De Sousa E Melo F, van der Heijden M, Cameron K, de Jong JH, Borovski T, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 2010;12:468-76.  Back to cited text no. 51
Long H, Zhang S, Liu C, Shi J, Tao L, Situ D, et al. Characterization of a stem cell population in lung cancer cell line Glc-82. Thorac Cancer 2012;3:8-18.  Back to cited text no. 52
Kahi CJ. Chromocolonoscopy for colorectal cancer screening: Dive into the Big Blue. J Interv Gastroenterol 2012;2:112-13.  Back to cited text no. 53
Dallas NA, Xia L, Fan F, Gray MJ, Gaur P, van Buren G 2 nd , 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.  Back to cited text no. 54
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.  Back to cited text no. 55
Cammareri P, Scopelliti A, Todaro M, Eterno V, Francescangeli F, Moyer MP, et al. Aurora - A is essential for the tumorigenic capacity and chemoresistance of colorectal cancer stem cells. Cancer Res 2010;70:4655-65.  Back to cited text no. 56
Song B, Wang Y, Xi Y, Kudo K, Bruheim S, Botchkina GI, et al. Mechanism of chemoresistance mediated by miR-140 in human osteosarcoma and colon cancer cells. Oncogene 2009;28:4065-74.  Back to cited text no. 57
Song B, Wang Y, Titmus MA, Botchkina G, Formentini A, Kornmann M, et al. Molecular mechanism of chemoresistance by miR-215 in osteosarcoma and colon cancer cells. Mol Cancer 2010;9:96.  Back to cited text no. 58
Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: Role of ATP-dependent transporters. Nat Rev Cancer 2002;2:48-58.  Back to cited text no. 59
Ejendal KF, Hrycyna CA. Multidrug resistance and cancer: The role of the human ABC transporter ABCG2. Curr Protein Pept Sci 2002;3:503-11.  Back to cited text no. 60
Riordan JR, Deuchars K, Kartner N, Alon N, Trent J, Ling V. Amplification of P-glycoprotein genes in multidrug-resistant mammalian cell lines. Nature 1985;316:817-9.  Back to cited text no. 61
Frank NY, Pendse SS, Lapchak PH, Margaryan A, Shlain D, Doeing C, et al. Regulation of progenitor cell fusion by ABCB5 P-glycoprotein, a novel human ATP-binding cassette transporter. J Biol Chem 2003;278:47156-65.  Back to cited text no. 62
Huang Y, Anderle P, Bussey KJ, Barbacioru C, Shankavaram U, Dai Z, et al. Membrane transporters and channels: Role of the transportome in cancer chemosensitivity and chemoresistance. Cancer Res 2004;64:4294-301.  Back to cited text no. 63
Elliott AM, Al-Hajj MA. ABCB8 mediates doxorubicin resistance in melanoma cells by protecting the mitochondrial genome. Mol Cancer Res 2009;7:79-87.  Back to cited text no. 64
Cheung ST, Cheung PF, Cheng CK, Wong NC, Fan ST. Granulin-epithelin precursor and ATP-dependent binding cassette (ABC) B5 regulate liver cancer cell chemoresistance. Gastroenterology 2011;140:344-55.  Back to cited text no. 65
Fukunaga-Kalabis M, Martinez G, Nguyen TK, Kim D, Santiago-Walker A, Roesch A, et al. Tenascin-C promotes melanoma progression by maintaining the ABCB5-positive side population. Oncogene 2010;29:6115-24.  Back to cited text no. 66
Wilson BJ, Saab KR, Ma J, Schatton T, Pütz P, Zhan Q, et al. ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit. Cancer Res 2014;74:4196-207.  Back to cited text no. 67
Farawela HM, Khorshied MM, Kassem NM, Kassem HA, Zawam HM. The clinical relevance and prognostic significance of adenosine triphosphate ATP-binding cassette (ABCB5) and multidrug resistance (MDR1) genes expression in acute leukemia: An Egyptian study. J Cancer Res Clin Oncol 2014;140:1323-30.  Back to cited text no. 68
Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006;444:756-60.  Back to cited text no. 69
Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Koike Y, et al. Clinical significance of CD133 and hypoxia inducible factor-1a gene expression in rectal cancer after preoperative chemoradiotherapy. Clin Oncol (R Coll Radiol) 2011;23:323-32.  Back to cited text no. 70
Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Kawamoto A, et al. Immunohistochemical features of CD133 expression: Association with resistance to chemoradiotherapy in rectal cancer. Oncol Rep 2010;24:345-50.  Back to cited text no. 71
Seal BS, Sullivan SD, Ramsey SD, Shermock KM, Ren J, Kreilick C, et al. Systemic therapy for colorectal cancer: Patterns of chemotherapy and biologic therapy use in nationally representative US claims database. BioDrugs 2014;28:229-36.  Back to cited text no. 72
Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med 2005;352:476-87.  Back to cited text no. 73
Chen X, Liu Y, Yang HW, Zhou S, Cheng C, Zheng MW, et al. SKLB-287, a?novel oral multikinase inhibitor of EGFR and VEGFR2, exhibits potent antitumor activity in LoVo colorectal tumor model. Neoplasma 2014;61:514-22.  Back to cited text no. 74
Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 1995;55:3964-8.  Back to cited text no. 75
Fan F, Wey JS, McCarty MF, Belcheva A, Liu W, Bauer TW, et al. Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene 2005;24:2647-53.  Back to cited text no. 76
Feng QY, Wei Y, Chen JW, Chang WJ, Ye LC, Zhu DX, et al. Anti-EGFR and anti-VEGF agents: Important targeted therapies of colorectal liver metastases. World J Gastroenterol 2014;20:4263-75.  Back to cited text no. 77
Wu WK, Wang XJ, Cheng AS, Luo MX, Ng SS, To KF, et al. Dysregulation and crosstalk of cellular signaling pathways in colon carcinogenesis. Crit Rev Oncol Hematol 2013;86:251-77.  Back to cited text no. 78
Zhang K, Civan J, Mukherjee S, Patel F, Yang H. Genetic variations in colorectal cancer risk and clinical outcome. World J Gastroenterol 2014;20:4167-77.  Back to cited text no. 79
Hsu HC, Liu YS, Tseng KC, Tan BC, Chen SJ, Chen HC. LGR5 regulates survival through mitochondria-mediated apoptosis and by targeting the Wnt/ß-catenin signaling pathway in colorectal cancer cells. Cell Signal 2014;26:2333-42.  Back to cited text no. 80
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.  Back to cited text no. 81
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.  Back to cited text no. 82
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.  Back to cited text no. 83
van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H, et al. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 2005;435:959-63.  Back to cited text no. 84
Whissell G, Montagni E, Martinelli P, Hernando-Momblona X, Sevillano M, Jung P, et al. The transcription factor GATA6 enables self-renewal of colon adenoma stem cells by repressing BMP gene expression. Nat Cell Biol 2014;16:695-707.  Back to cited text no. 85
Haramis AP, Begthel H, van den Born M, van Es J, Jonkheer S, Offerhaus GJ, et al. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science 2004;303:1684-6.  Back to cited text no. 86
Kodach LL, Bleuming SA, Musler AR, Peppelenbosch MP, Hommes DW, van den Brink GR, et al. The bone morphogenetic protein pathway is active in human colon adenomas and inactivated in colorectal cancer. Cancer 2008;112:300-6.  Back to cited text no. 87
Lombardo Y, Scopelliti A, Cammareri P, Todaro M, Iovino F, Ricci-Vitiani L, et al. Bone morphogenetic protein 4 induces differentiation of colorectal cancer stem cells and increases their response to chemotherapy in mice. Gastroenterology 2011;140:297-309.  Back to cited text no. 88
Ricci-Vitiani L, Mollinari C, di Martino S, Biffoni M, Pilozzi E, Pagliuca A, et al. Thymosin beta4 targeting impairs tumorigenic activity of colon cancer stem cells. FASEB J 2010;24:4291-301.  Back to cited text no. 89
Kim JW, Dang CV. Cancer′s molecular sweet tooth and the Warburg effect. Cancer Res 2006;66:8927-30.  Back to cited text no. 90
Bui T, Thompson CB. Cancer′s sweet tooth. Cancer Cell 2006;9:419-20.  Back to cited text no. 91
Akao Y, Noguchi S, Iio A, Kojima K, Takagi T, Naoe T. Dysregulation of microRNA-34a expression causes drug-resistance to 5-FU in human colon cancer DLD-1 cells. Cancer Lett 2011;300:197-204.  Back to cited text no. 92


  [Figure 1]

  [Table 1], [Table 2]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>The identificati...>Colorectal cance...>Future prospective>Conclusion>Acknowledgements>Drug-Resistance ...>Article Figures>Article Tables
  In this article

 Article Access Statistics
    PDF Downloaded344    
    Comments [Add]    

Recommend this journal