Colorectal Cancer Stem Cell Biomarkers: Biological Traits and Prognostic
Insights

Atena      Soleimani; Nikoo      Saeedi; Abdulridha   Mohammed   Al-Asady; Elnaz      Nazari; Reyhane      Hanaie; Majid      Khazaei; Elnaz      Ghorbani; Hamed      Akbarzade; Mikhail      Ryzhikov; Amir      Avan; Seyed   Mahdi Hasanian   Mehr
Abstract

Due to self-renewal, differentiation, and limitless proliferation properties, Cancer Stem Cells (CSCs) increase the probability of tumor development. These cells are identified by using CSC markers, which are highly expressed proteins on the cell surface of CSCs. Recently, the therapeutic application of CSCs as novel biomarkers improved both the prognosis and diagnosis outcome of colorectal Cancer. In the present review, we focused on a specific panel of colorectal CSC markers, including LGR5, ALDH, CD166, CD133, and CD44, which offers a targeted and comprehensive analysis of their functions. The selection criteria for these markers cancer were based on their established significance in Colorectal Cancer (CRC) pathogenesis and clinical outcomes, providing novel insights into the CSC biology of CRC. Through this approach, we aim to elevate understanding and stimulate further research for developing effective diagnostic and therapeutic strategies in CRC.
Keywords: LGR5, ALDH, CD166, CD133, CD44, cancer stem cell, colon cancer.
[1]
Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2023. CA Cancer J Clin  2023; 73(3): 233-54.
 [http://dx.doi.org/10.3322/caac.21772] [PMID: 36856579]

[2]
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin  2022; 72(1): 7-33.
 [http://dx.doi.org/10.3322/caac.21708] [PMID: 35020204]

[3]
Morgan E, Arnold M, Gini A, et al. Global burden of colorectal cancer in 2020 and 2040: Incidence and mortality estimates from GLOBOCAN. Gut  2023; 72(2): 338-44.
 [http://dx.doi.org/10.1136/gutjnl-2022-327736] [PMID: 36604116]

[4]
Xi Y, Xu P. Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol  2021; 14(10): 101174.
 [http://dx.doi.org/10.1016/j.tranon.2021.101174] [PMID: 34243011]

[5]
Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut  2017; 66(4): 683-91.
 [http://dx.doi.org/10.1136/gutjnl-2015-310912] [PMID: 26818619]

[6]
Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell  1990; 61(5): 759-67.
 [http://dx.doi.org/10.1016/0092-8674(90)90186-I] [PMID: 2188735]

[7]
Su R, Wu X, Tao L, Wang C. The role of epigenetic modifications in colorectal cancer metastasis. Clin Exp Metastasis  2022; 39(4): 521-39.
 [http://dx.doi.org/10.1007/s10585-022-10163-w] [PMID: 35429301]

[8]
Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and surveillance: Clinical guidelines and rationale? Update based on new evidence. Gastroenterology  2003; 124(2): 544-60.
 [http://dx.doi.org/10.1053/gast.2003.50044] [PMID: 12557158]

[9]
Winawer SJ, Fletcher RH, Miller L, et al. Colorectal cancer screening: Clinical guidelines and rationale. Gastroenterology  1997; 112(2): 594-642.
 [http://dx.doi.org/10.1053/gast.1997.v112.agast970594] [PMID: 9024315]

[10]
Ho MF, Lai VC, Ng DCK, Ng SSM. Prognosis of patients with unresectable stage IV Colon cancer undergoing primary tumor resection: A multicenter study of minimally symptomatic or asymptomatic primary tumor. Asian J Surg  2023; 46(9): 3710-5.
 [http://dx.doi.org/10.1016/j.asjsur.2022.11.127] [PMID: 36522225]

[11]
Park J, Baik H, Kang SH, et al. Comparison between oxaliplatin therapy and capecitabine monotherapy for high-risk stage II – III elderly patients with colon cancer. Asian J Surg  2022; 45(1): 448-55.
 [http://dx.doi.org/10.1016/j.asjsur.2021.07.067] [PMID: 34364765]

[12]
Ishiyama Y, Tachimori Y, Harada T, et al. Oncologic outcomes after laparoscopic versus open multivisceral resection for local advanced colorectal cancer: A meta-analysis. Asian J Surg  2023; 46(1): 6-12.
 [http://dx.doi.org/10.1016/j.asjsur.2022.02.047] [PMID: 35568616]

[13]
Dai S, Zhao W, Yue L, Qian X. A competing risk for nomogram of the role of metastasectomy in patients with colorectal cancer and liver metastases. Asian J Surg  2023; 46(6): 2468-71.
 [http://dx.doi.org/10.1016/j.asjsur.2022.12.066] [PMID: 36567218]

[14]
Ogunwobi OO, Mahmood F, Akingboye A. Biomarkers in colorectal cancer: Current research and future prospects. Int J Mol Sci  2020; 21(15): 5311.
 [http://dx.doi.org/10.3390/ijms21155311] [PMID: 32726923]

[15]
Chen W, Frankel WL. A practical guide to biomarkers for the evaluation of colorectal cancer. Mod Pathol  2019; 32(1) (Suppl. 1): 1-15.
 [http://dx.doi.org/10.1038/s41379-018-0136-1] [PMID: 30600322]

[16]
Ricci-Vitiani L, Fabrizi E, Palio E, De Maria R. Colon cancer stem cells. J Mol Med  2009; 87(11): 1097-104.
 [http://dx.doi.org/10.1007/s00109-009-0518-4] [PMID: 19727638]

[17]
Miller SJ, Lavker RM, Sun TT. Interpreting epithelial cancer biology in the context of stem cells: Tumor properties and therapeutic implications. Biochim Biophys Acta  2005; 1756(1): 25-52.
 [PMID: 16139432]

[18]
Alison MR, Islam S, Wright NA. Stem cells in cancer: Instigators and propagators? J Cell Sci  2010; 123(14): 2357-68.
 [http://dx.doi.org/10.1242/jcs.054296] [PMID: 20592182]

[19]
Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer  2005; 5(4): 275-84.
 [http://dx.doi.org/10.1038/nrc1590] [PMID: 15803154]

[20]
Ailles LE, Weissman IL. Cancer stem cells in solid tumors. Curr Opin Biotechnol  2007; 18(5): 460-6.
 [http://dx.doi.org/10.1016/j.copbio.2007.10.007] [PMID: 18023337]

[21]
Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature  2006; 444(7120): 756-60.
 [http://dx.doi.org/10.1038/nature05236] [PMID: 17051156]

[22]
Todaro M, Francipane MG, Medema JP, Stassi G. Colon cancer stem cells: Promise of targeted therapy. Gastroenterology  2010; 138(6): 2151-62.
 [http://dx.doi.org/10.1053/j.gastro.2009.12.063] [PMID: 20420952]

[23]
Markowitz SD, Bertagnolli MM. Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med  2009; 361(25): 2449-60.
 [http://dx.doi.org/10.1056/NEJMra0804588] [PMID: 20018966]

[24]
Vries RGJ, Huch M, Clevers H. Stem cells and cancer of the stomach and intestine. Mol Oncol  2010; 4(5): 373-84.
 [http://dx.doi.org/10.1016/j.molonc.2010.05.001] [PMID: 20598659]

[25]
Vaiopoulos AG, Kostakis ID, Koutsilieris M, Papavassiliou AG. Colorectal cancer stem cells. Stem Cells  2012; 30(3): 363-71.
 [http://dx.doi.org/10.1002/stem.1031] [PMID: 22232074]

[26]
Rey I. Cancer stem cells and signaling pathways in colorectal cancer. Indones J Gastroenterol Hepatol Digest Endosc  2018; 19(1): 37-41.

[27]
Zhang M, Atkinson RL, Rosen JM. Selective targeting of radiation-resistant tumor-initiating cells. Proc Natl Acad Sci USA  2010; 107(8): 3522-7.
 [http://dx.doi.org/10.1073/pnas.0910179107] [PMID: 20133717]

[28]
Clevers H. The cancer stem cell: Premises, promises and challenges. Nat Med  2011; 17(3): 313-9.
 [http://dx.doi.org/10.1038/nm.2304] [PMID: 21386835]

[29]
Gupta PB, Fillmore CM, Jiang G, et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell  2011; 146(4): 633-44.
 [http://dx.doi.org/10.1016/j.cell.2011.07.026] [PMID: 21854987]

[30]
Taniguchi H, Moriya C, Igarashi H, et al. Cancer stem cells in human gastrointestinal cancer. Cancer Sci  2016; 107(11): 1556-62.
 [http://dx.doi.org/10.1111/cas.13069] [PMID: 27575869]

[31]
Parizadeh SM, Jafarzadeh-Esfehani R, Hassanian SM, et al. Targeting cancer stem cells as therapeutic approach in the treatment of colorectal cancer. Int J Biochem Cell Biol  2019; 110: 75-83.
 [http://dx.doi.org/10.1016/j.biocel.2019.02.010] [PMID: 30818083]

[32]
Dahal Lamichane B, Jung SY, Yun J, et al. AGR2 is a target of canonical Wnt/β-catenin signaling and is important for stemness maintenance in colorectal cancer stem cells. Biochem Biophys Res Commun  2019; 515(4): 600-6.
 [http://dx.doi.org/10.1016/j.bbrc.2019.05.154] [PMID: 31178140]

[33]
Shirmohamadi M, Eghbali E, Najjary S, et al. Regulatory mechanisms of microRNAs in colorectal cancer and colorectal cancer stem cells. J Cell Physiol  2020; 235(2): 776-89.
 [http://dx.doi.org/10.1002/jcp.29042] [PMID: 31264216]

[34]
Das PK, Islam F, Lam AK. The roles of cancer stem cells and therapy resistance in colorectal carcinoma. Cells  2020; 9(6): 1392.
 [http://dx.doi.org/10.3390/cells9061392] [PMID: 32503256]

[35]
Kim H, Yu Y, Choi S, et al. Evodiamine eliminates colon cancer stem cells via suppressing Notch and Wnt signaling. Molecules  2019; 24(24): 4520.
 [http://dx.doi.org/10.3390/molecules24244520] [PMID: 31835579]

[36]
Feng HC, Lin JY, Hsu SH, et al. Low folate metabolic stress reprograms DNA methylation-activated sonic hedgehog signaling to mediate cancer stem cell-like signatures and invasive tumour stage-specific malignancy of human colorectal cancers. Int J Cancer  2017; 141(12): 2537-50.
 [http://dx.doi.org/10.1002/ijc.31008] [PMID: 28833104]

[37]
Chang SC, Ding JL. Ubiquitination and SUMOylation in the chronic inflammatory tumor microenvironment. Biochim Biophys Acta Rev Cancer  2018; 1870(2): 165-75.
 [http://dx.doi.org/10.1016/j.bbcan.2018.08.002] [PMID: 30318471]

[38]
Ylä-Herttuala S. The pharmacology of gene therapy. Mol Ther  2017; 25(8): 1731-2.
 [http://dx.doi.org/10.1016/j.ymthe.2017.07.007] [PMID: 28739283]

[39]
Smith DC, Eisenberg PD, Manikhas G, et al. A phase I dose escalation and expansion study of the anticancer stem cell agent demcizumab (anti-DLL4) in patients with previously treated solid tumors. Clin Cancer Res  2014; 20(24): 6295-303.
 [http://dx.doi.org/10.1158/1078-0432.CCR-14-1373] [PMID: 25324140]

[40]
Wei F, Zhang T, Deng SC, et al. PD-L1 promotes colorectal cancer stem cell expansion by activating HMGA1-dependent signaling pathways. Cancer Lett  2019; 450: 1-13.
 [http://dx.doi.org/10.1016/j.canlet.2019.02.022] [PMID: 30776481]

[41]
Imperial R, Ahmed Z, Toor OM, et al. Comparative proteogenomic analysis of right-sided colon cancer, left-sided colon cancer and rectal cancer reveals distinct mutational profiles. Mol Cancer  2018; 17(1): 177.
 [http://dx.doi.org/10.1186/s12943-018-0923-9] [PMID: 30577807]

[42]
Barker N, van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature  2007; 449(7165): 1003-7.
 [http://dx.doi.org/10.1038/nature06196] [PMID: 17934449]

[43]
Haegebarth A, Clevers H. Wnt signaling, lgr5, and stem cells in the intestine and skin. Am J Pathol  2009; 174(3): 715-21.
 [http://dx.doi.org/10.2353/ajpath.2009.080758] [PMID: 19197002]

[44]
Kozovska Z, Gabrisova V, Kucerova L. Colon cancer: Cancer stem cells markers, drug resistance and treatment. Biomed Pharmacother  2014; 68(8): 911-6.
 [http://dx.doi.org/10.1016/j.biopha.2014.10.019] [PMID: 25458789]

[45]
Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature  2001; 414(6859): 105-11.
 [http://dx.doi.org/10.1038/35102167] [PMID: 11689955]

[46]
Fumagalli A, Oost KC, Kester L, Morgner J, Bornes L, Bruens L. Plasticity of Lgr5-negative cancer cells drives metastasis in colorectal cancer. Cell stem cell  2020; 26(4): 569-78.
 [http://dx.doi.org/10.1016/j.stem.2020.02.008]

[47]
Jang BG, Kim HS, Chang WY, Bae JM, Kim WH, Kang GH. Expression profile of LGR5 and its prognostic significance in colorectal cancer progression. Am J Pathol  2018; 188(10): 2236-50.
 [http://dx.doi.org/10.1016/j.ajpath.2018.06.012] [PMID: 30036518]

[48]
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(8): 791-9.
 [http://dx.doi.org/10.1016/j.biopha.2013.08.001] [PMID: 24138824]

[49]
Han Y, Xue X, Jiang M, et al. LGR5, a relevant marker of cancer stem cells, indicates a poor prognosis in colorectal cancer patients: A meta-analysis. Clin Res Hepatol Gastroenterol  2015; 39(2): 267-73.
 [http://dx.doi.org/10.1016/j.clinre.2014.07.008] [PMID: 25193236]

[50]
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(1): 244.
 [http://dx.doi.org/10.1186/1477-7819-10-244] [PMID: 23153436]

[51]
Liu Z, Dai W, Jiang L, Cheng Y. Over-expression of LGR5 correlates with poor survival of colon cancer in mice as well as in patients. Neoplasma  2014; 61(2): 177-85.
 [http://dx.doi.org/10.4149/neo_2014_016] [PMID: 24063790]

[52]
Salehizadeh S, Hasanzad M, Kadijani AA, Akbari A. The expression analysis of intestinal cancer stem cell marker lgr5 in colorectal cancer patients and the correlation with histopathological markers. J Gastrointest Cancer  2020; 51(2): 591-9.

[53]
Ding H, Wang C. Role of Lgr5-positive cells in colorectal cancer. Tumour Biol  2015; 36(9): 6759-64.
 [http://dx.doi.org/10.1007/s13277-015-3357-7] [PMID: 25835970]

[54]
Jia H, Xiang L, Wang Z, Zhou Q. A study on the mechanism of low-expressed cancer stem cell marker lgr5 in inhibition of the proliferation and invasion of colorectal carcinoma. Cell Biochem Biophys  2015; 73(2): 393-7.
 [http://dx.doi.org/10.1007/s12013-015-0640-6] [PMID: 27352328]

[55]
Nagata H, Ishihara S, Abe H, et al. LGR5 expression predicts peritoneal recurrence after curative resection of primary colon cancer. Br J Cancer  2019; 120(10): 996-1002.
 [http://dx.doi.org/10.1038/s41416-019-0442-5] [PMID: 31000786]

[56]
Armstrong L, Stojkovic M, Dimmick I, et al. Phenotypic characterization of murine primitive hematopoietic progenitor cells isolated on basis of aldehyde dehydrogenase activity. Stem Cells  2004; 22(7): 1142-51.
 [http://dx.doi.org/10.1634/stemcells.2004-0170] [PMID: 15579635]

[57]
Magni M, Shammah S, Schiró R, Mellado W, Dalla-Favera R, Gianni AM. Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer. Blood  1996; 87(3): 1097-103.
 [http://dx.doi.org/10.1182/blood.V87.3.1097.bloodjournal8731097] [PMID: 8562935]

[58]
Huang EH, Hynes MJ, Zhang T, 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(8): 3382-9.
 [http://dx.doi.org/10.1158/0008-5472.CAN-08-4418] [PMID: 19336570]

[59]
Carpentino JE, Hynes MJ, Appelman HD, et al. Aldehyde dehydrogenase-expressing colon stem cells contribute to tumorigenesis in the transition from colitis to cancer. Cancer Res  2009; 69(20): 8208-15.
 [http://dx.doi.org/10.1158/0008-5472.CAN-09-1132] [PMID: 19808966]

[60]
Zhou F, Mu YD, Liang J, et al. Aldehyde dehydrogenase 1: A specific cancer stem cell marker for human colorectal carcinoma. Mol Med Rep  2015; 11(5): 3894-9.
 [http://dx.doi.org/10.3892/mmr.2015.3195] [PMID: 25585687]

[61]
Chen J, Xia Q, Jiang B, et al. Prognostic value of cancer stem cell marker ALDH1 expression in colorectal cancer: A systematic review and meta-analysis. PLoS One  2015; 10(12): e0145164.
 [http://dx.doi.org/10.1371/journal.pone.0145164] [PMID: 26682730]

[62]
Yang W, Wang Y, Wang W, Chen Z, Bai G. Expression of aldehyde dehydrogenase 1A1 (ALDH1A1) as a prognostic biomarker in colorectal cancer using immunohistochemistry. Med Sci Monit  2018; 24: 2864-72.
 [http://dx.doi.org/10.12659/MSM.910109] [PMID: 29748529]

[63]
Hessman CJ, Bubbers EJ, Billingsley KG, Herzig DO, Wong MH. Loss of expression of the cancer stem cell marker aldehyde dehydrogenase 1 correlates with advanced-stage colorectal cancer. Am J Surg  2012; 203(5): 649-53.
 [http://dx.doi.org/10.1016/j.amjsurg.2012.01.003] [PMID: 22405917]

[64]
Khorrami S, Zavaran Hosseini A, Mowla SJ, Malekzadeh R. Verification of ALDH activity as a biomarker in colon cancer stem cells-derived HT-29 cell line. Iran J Cancer Prev  2015; 8(5): e3446.
 [http://dx.doi.org/10.17795/ijcp-3446] [PMID: 26634106]

[65]
Mohamed SY, Kaf RM, Ahmed MM, Elwan A, Ashour HR, Ibrahim A. The prognostic value of cancer stem cell markers (Notch1, ALDH1, and CD44) in primary colorectal carcinoma. J Gastrointest Cancer  2019; 50(4): 824-37.
 [http://dx.doi.org/10.1007/s12029-018-0156-6] [PMID: 30136202]

[66]
Miraglia S, Godfrey W, Yin AH, et al. A novel five-transmembrane hematopoietic stem cell antigen: Isolation, characterization, and molecular cloning. Blood  1997; 90(12): 5013-21.
 [http://dx.doi.org/10.1182/blood.V90.12.5013] [PMID: 9389721]

[67]
Pilati P, Mocellin S, Bertazza L, et al. Prognostic value of putative circulating cancer stem cells in patients undergoing hepatic resection for colorectal liver metastasis. Ann Surg Oncol  2012; 19(2): 402-8.
 [http://dx.doi.org/10.1245/s10434-011-2132-2] [PMID: 22071867]

[68]
Catalano V, Di Franco S, Iovino F, Dieli F, Stassi G, Todaro M. CD133 as a target for colon cancer. Expert Opin Ther Targets  2012; 16(3): 259-67.
 [http://dx.doi.org/10.1517/14728222.2012.667404] [PMID: 22385077]

[69]
Horst D, Scheel SK, Liebmann S, 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(4): 427-34.
 [http://dx.doi.org/10.1002/path.2597] [PMID: 19621338]

[70]
Pohl A, El-Khoueiry A, Yang D, et al. Pharmacogenetic profiling of CD133 is associated with response rate (RR) and progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC), treated with bevacizumab-based chemotherapy. Pharmacogenomics J  2013; 13(2): 173-80.
 [http://dx.doi.org/10.1038/tpj.2011.61] [PMID: 22231565]

[71]
Shih T, Lindley C. Bevacizumab: An angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther  2006; 28(11): 1779-802.
 [http://dx.doi.org/10.1016/j.clinthera.2006.11.015] [PMID: 17212999]

[72]
Sanders MA, Majumdar AP. Colon cancer stem cells: Implications in carcinogenesis. Front Biosci  2011; 16(1): 1651-62.
 [http://dx.doi.org/10.2741/3811] [PMID: 21196254]

[73]
Stanisavljević L, Myklebust MP, Leh S, Dahl O. LGR5 and CD133 as prognostic and predictive markers for fluoropyrimidine-based adjuvant chemotherapy in colorectal cancer. Acta Oncol  2016; 55(12): 1425-33.
 [http://dx.doi.org/10.1080/0284186X.2016.1201215] [PMID: 27435662]

[74]
Shikina A, Shinto E, Hashiguchi Y, et al. Differential clinical benefits of 5-fluorouracil-based adjuvant chemotherapy for patients with stage III colorectal cancer according to CD133 expression status. Jpn J Clin Oncol  2014; 44(1): 42-8.
 [http://dx.doi.org/10.1093/jjco/hyt168] [PMID: 24244031]

[75]
Li R, Dong H, Zhu J, Yi H, Liu S. Overexpression of CD133 confers poor prognosis in colorectal cancer: A systematic review and meta-analysis. Int J Clin Exp Med  2019; 12(2): 1492-502.

[76]
Wang BB, Li ZJ, Zhang FF, Hou HT, Yu JK, Li F. Clinical significance of stem cell marker CD133 expression in colorectal cancer. Histol Histopathol  2016; 31(3): 299-306.
 [PMID: 26442717]

[77]
Wang K, Xu J, Zhang J, Huang J. Prognostic role of CD133 expression in colorectal cancer: A meta-analysis. BMC Cancer  2012; 12(1): 573.
 [http://dx.doi.org/10.1186/1471-2407-12-573] [PMID: 23216926]

[78]
Pals ST, Hogervorst F, Keizer GD, Thepen T, Horst E, Figdor CC. Identification of a widely distributed 90-kDa glycoprotein that is homologous to the Hermes-1 human lymphocyte homing receptor. J Immunol  1989; 143(3): 851-7.

[79]
Screaton GR, Bell MV, Jackson DG, Cornelis FB, Gerth U, Bell JI. Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons. Proc Natl Acad Sci USA  1992; 89(24): 12160-4.
 [http://dx.doi.org/10.1073/pnas.89.24.12160] [PMID: 1465456]

[80]
Wielenga VJM, van der Neut R, Offerhaus GJA, Pals ST. CD44 glycoproteins in colorectal cancer: Expression, function, and prognostic value. Adv Cancer Res  1999; 77: 169-87.
 [http://dx.doi.org/10.1016/S0065-230X(08)60787-3] [PMID: 10549358]

[81]
Huh JW, Kim HR, Kim YJ, et al. Expression of standard CD44 in human colorectal carcinoma: Association with prognosis. Pathol Int  2009; 59(4): 241-6.
 [http://dx.doi.org/10.1111/j.1440-1827.2009.02357.x] [PMID: 19351367]

[82]
Lee SY, Kim KA, Kim CH, Kim YJ, Lee JH, Kim HR. CD44-shRNA recombinant adenovirus inhibits cell proliferation, invasion, and migration, and promotes apoptosis in HCT116 colon cancer cells. Int J Oncol  2017; 50(1): 329-36.
 [http://dx.doi.org/10.3892/ijo.2016.3801] [PMID: 27959393]

[83]
Wielenga VJ, Heider KH, Offerhaus GJ, et al. Expression of CD44 variant proteins in human colorectal cancer is related to tumor progression. Cancer Res  1993; 53(20): 4754-6.
 [PMID: 7691404]

[84]
Wielenga VJ, van der Voort R, Mulder JW, et al. CD44 splice variants as prognostic markers in colorectal cancer. Scand J Gastroenterol  1998; 33(1): 82-7.
 [http://dx.doi.org/10.1080/00365529850166257] [PMID: 9489913]

[85]
Katoh S, Goi T, Naruse 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(1): 239-44.
 [PMID: 25550556]

[86]
Miyoshi S, Tsugawa H, Matsuzaki J, et al. Inhibiting xCT improves 5-fluorouracil resistance of gastric cancer induced by CD44 variant 9 expression. Anticancer Res  2018; 38(11): 6163-70.
 [http://dx.doi.org/10.21873/anticanres.12969] [PMID: 30396933]

[87]
Ozawa M, Ichikawa Y, Zheng Y-W, et al. Prognostic significance of CD44 variant 2 upregulation in colorectal cancer. Br J Cancer  2014; 111(2): 365-74.
 [http://dx.doi.org/10.1038/bjc.2014.253] [PMID: 24921913]

[88]
Nakano M, Taguchi R, Kikushige Y, et al. RHAMM marks proliferative subpopulation of human colorectal cancer stem cells. Cancer Sci  2023; 114(7): 2895-906.
 [http://dx.doi.org/10.1111/cas.15795] [PMID: 36945114]

[89]
Gerger A, Zhang W, Yang D, et al. Common cancer stem cell gene variants predict colon cancer recurrence. Clin Cancer Res  2011; 17(21): 6934-43.
 [http://dx.doi.org/10.1158/1078-0432.CCR-11-1180] [PMID: 21918173]

[90]
Tachezy M, Zander H, Gebauer F, et al. Activated leukocyte cell adhesion molecule (CD166)-Its prognostic power for colorectal cancer patients. J Surg Res  2012; 177(1): e15-20.
 [http://dx.doi.org/10.1016/j.jss.2012.02.013] [PMID: 22482754]

[91]
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(11): 1160-4.
 [http://dx.doi.org/10.1136/jcp.2004.016238] [PMID: 15509676]

[92]
Ribeiro KB, da Silva Zanetti J, Ribeiro-Silva A, et al. KRAS mutation associated with CD44/CD166 immunoexpression as predictors of worse outcome in metastatic colon cancer. Cancer Biomark  2016; 16(4): 513-21.
 [http://dx.doi.org/10.3233/CBM-160592] [PMID: 27062566]

[93]
Shafaei S, Sharbatdaran M, Kamrani G, Khafri S. The association between CD166 detection rate and clinicopathologic parameters of patients with colorectal cancer. Caspian J Intern Med  2013; 4(4): 768-72.
 [PMID: 24294471]

[94]
Hansen AG, Freeman TJ, Arnold SA, et al. Elevated ALCAM shedding in colorectal cancer correlates with poor patient outcome. Cancer Res  2013; 73(10): 2955-64.
 [http://dx.doi.org/10.1158/0008-5472.CAN-12-2052] [PMID: 23539446]

[95]
Rey I, Lindarto D, Yusuf F, Putra A. CD166 as cancer stem cells marker based on colorectal cancer location and individual characteristic. J Kedokteran Syiah Kuala 2022.

[96]
Hadjimichael C, Chanoumidou K, Papadopoulou N, Arampatzi P, Papamatheakis J, Kretsovali A. Common stemness regulators of embryonic and cancer stem cells. World J Stem Cells  2015; 7(9): 1150-84.
 [http://dx.doi.org/10.4252/wjsc.v7.i9.1150] [PMID: 26516408]

[97]
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell  2006; 126(4): 663-76.
 [http://dx.doi.org/10.1016/j.cell.2006.07.024] [PMID: 16904174]

[98]
Amini S, Fathi F, Mobalegi J, Sofimajidpour H, Ghadimi T. The expressions of stem cell markers: OCT4, Nanog, Sox2, nucleostemin, Bmi, Zfx, Tcl1, Tbx3, Dppa4, and Esrrb in bladder, colon, and prostate cancer, and certain cancer cell lines. Anat Cell Biol  2014; 47(1): 1-11.
 [http://dx.doi.org/10.5115/acb.2014.47.1.1] [PMID: 24693477]

[99]
Shi G, Jin Y. Role of OCT4 in maintaining and regaining stem cell pluripotency. Stem Cell Res Ther  2010; 1(5): 39.
 [http://dx.doi.org/10.1186/scrt39] [PMID: 21156086]

[100]
Zhang Q, Han Z, Zhu Y, Chen J, Li W. The role and specific mechanism of OCT4 in cancer stem cells: A review. Int J Stem Cells  2020; 13(3): 312-25.
 [http://dx.doi.org/10.15283/ijsc20097] [PMID: 32840233]

[101]
Dai X, Ge J, Wang X, Qian X, Zhang C, Li X. OCT4 regulates epithelial-mesenchymal transition and its knockdown inhibits colorectal cancer cell migration and invasion. Oncol Rep  2013; 29(1): 155-60.
 [http://dx.doi.org/10.3892/or.2012.2086] [PMID: 23076549]

[102]
Beiraghdar M, Talebi A, Kianersi K. Comparison of gene expression of SOX2 and OCT4 in normal tissue, polyps, and colon adenocarcinoma using immunohistochemical staining. Adv Biomed Res  2015; 4(1): 234.
 [http://dx.doi.org/10.4103/2277-9175.167958] [PMID: 26645019]

[103]
Neumann J, Bahr F, Horst D, et al. SOX2 expression correlates with lymph-node metastases and distant spread in right-sided colon cancer. BMC Cancer  2011; 11(1): 518.
 [http://dx.doi.org/10.1186/1471-2407-11-518] [PMID: 22168803]

[104]
Avery S, Inniss K, Moore H. The regulation of self-renewal in human embryonic stem cells. Stem Cells Dev  2006; 15(5): 729-40.
 [http://dx.doi.org/10.1089/scd.2006.15.729] [PMID: 17105408]

[105]
Masui S, Nakatake Y, Toyooka Y, et al. Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol  2007; 9(6): 625-35.
 [http://dx.doi.org/10.1038/ncb1589] [PMID: 17515932]

[106]
Ibrahim EE, Babaei-Jadidi R, Saadeddin A, et al. Embryonic NANOG activity defines colorectal cancer stem cells and modulates through AP1- and TCF-dependent mechanisms. Stem Cells  2012; 30(10): 2076-87.
 [http://dx.doi.org/10.1002/stem.1182] [PMID: 22851508]

[107]
Pan G, Thomson JA. Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res  2007; 17(1): 42-9.
 [http://dx.doi.org/10.1038/sj.cr.7310125] [PMID: 17211451]

[108]
Leng Z, Tao K, Xia Q, et al. Krüppel-like factor 4 acts as an oncogene in colon cancer stem cell-enriched spheroid cells. PLoS One  2013; 8(2): e56082.
 [http://dx.doi.org/10.1371/journal.pone.0056082] [PMID: 23418515]

[109]
Roudi R, Barodabi M, Madjd Z, Roviello G, Corona SP, Panahi M. Expression patterns and clinical significance of the potential cancer stem cell markers OCT4 and NANOG in colorectal cancer patients. Mol Cell Oncol  2020; 7(5): 1788366.
 [http://dx.doi.org/10.1080/23723556.2020.1788366] [PMID: 32944642]

[110]
Gentric G, Mieulet V, Mechta-Grigoriou F. Heterogeneity in cancer metabolism: New concepts in an old field. Antioxid Redox Signal  2017; 26(9): 462-85.
 [http://dx.doi.org/10.1089/ars.2016.6750] [PMID: 27228792]

[111]
Paldino E, Tesori V, Casalbore P, Gasbarrini A, Puglisi MA. Tumor initiating cells and chemoresistance: Which is the best strategy to target colon cancer stem cells?  Biomed Res Int  2014; 2014: 859871.
 [http://dx.doi.org/10.1155/2014/859871]

[112]
Menendez J, Joven J, Cufí S, et al. The Warburg effect version 2.0: Metabolic reprogramming of cancer stem cells. Cell Cycle  2013; 12(8): 1166-79.
 [http://dx.doi.org/10.4161/cc.24479] [PMID: 23549172]

[113]
Wang M, Han D, Yuan Z, et al. Long non-coding RNA H19 confers 5-Fu resistance in colorectal cancer by promoting SIRT1-mediated autophagy. Cell Death Dis  2018; 9(12): 1149.
 [http://dx.doi.org/10.1038/s41419-018-1187-4] [PMID: 30451820]

[114]
Zu G, Ji A, Zhou T, Che N. Clinicopathological significance of SIRT1 expression in colorectal cancer: A systematic review and meta analysis. Int J Surg  2016; 26: 32-7.
 [http://dx.doi.org/10.1016/j.ijsu.2016.01.002] [PMID: 26763348]

[115]
Su BC, Xiao KM, Wang K, Yang SF, Huang ZX, Luo JW. ATGL promotes colorectal cancer growth by regulating autophagy process and SIRT1 expression. Med Oncol  2023; 40(12): 350.
 [http://dx.doi.org/10.1007/s12032-023-02148-w] [PMID: 37935950]

[116]
Yu DF, Jiang SJ, Pan ZP, et al. Expression and clinical significance of Sirt1 in colorectal cancer. Oncol Lett  2016; 11(2): 1167-72.
 [http://dx.doi.org/10.3892/ol.2015.3982] [PMID: 26893713]

[117]
Wang XW, Jiang YH, Ye W, Shao CF, Xie JJ, Li X. SIRT1 promotes the progression and chemoresistance of colorectal cancer through the p53/miR-101/KPNA3 axis. Cancer Biol Ther  2023; 24(1): 2235770.
 [http://dx.doi.org/10.1080/15384047.2023.2235770] [PMID: 37575080]

[118]
Yang Y, Yuan H, Zhao L, et al. Targeting the miR-34a/LRPPRC/MDR1 axis collapse the chemoresistance in P53 inactive colorectal cancer. Cell Death Differ  2022; 29(11): 2177-89.
 [http://dx.doi.org/10.1038/s41418-022-01007-x] [PMID: 35484333]

[119]
Qiao PF, Yao L, Zeng ZL. Catalpol-mediated microRNA-34a suppresses autophagy and malignancy by regulating SIRT1 in colorectal cancer. Oncol Rep  2020; 43(4): 1053-66.
 [http://dx.doi.org/10.3892/or.2020.7494] [PMID: 32323786]

[120]
Zhang Q, Wang J, Li N, et al. miR-34a increases the sensitivity of colorectal cancer cells to 5-fluorouracil in vitro and in vivo. Am J Cancer Res  2018; 8(2): 280-90.
 [PMID: 29511598]

[121]
Lucena-Cacace A, Otero-Albiol D, Jiménez-García MP, Muñoz- Galvan S, Carnero A. NAMPT is a potent oncogene in colon cancer progression that modulates cancer stem cell properties and resistance to therapy through Sirt1 and PARP. Clin Cancer Res  2018; 24(5): 1202-15.
 [http://dx.doi.org/10.1158/1078-0432.CCR-17-2575] [PMID: 29203587]

[122]
Yao J, Yang J, Yang Z, et al. FBXW11 contributes to stem-cell- like features and liver metastasis through regulating HIC1-mediated SIRT1 transcription in colorectal cancer. Cell Death Dis  2021; 12(10): 930.
 [http://dx.doi.org/10.1038/s41419-021-04185-7] [PMID: 34642302]

[123]
Chen X, Sun K, Jiao S, et al. High levels of SIRT1 expression enhance tumorigenesis and associate with a poor prognosis of colorectal carcinoma patients. Sci Rep  2014; 4(1): 7481.
 [http://dx.doi.org/10.1038/srep07481] [PMID: 25500546]

[124]
Ashrafizadeh M, Mirzaei S, Hushmandi K, et al. Therapeutic potential of AMPK signaling targeting in lung cancer: Advances, challenges and future prospects. Life Sci  2021; 278: 119649.
 [http://dx.doi.org/10.1016/j.lfs.2021.119649] [PMID: 34043989]

[125]
Ananthram KJ, Rajeev M, Aneesh TP. Insights into the role of mTOR/AMPK as a potential target for anticancer therapy. Curr Drug Ther  2021; 16(4): 299-312.
 [http://dx.doi.org/10.2174/1574885516666210812092321]

[126]
Ng CAW, Jiang AA, Toh EMS, et al. Metformin and colorectal cancer: A systematic review, meta-analysis and meta-regression. Int J Colorectal Dis  2020; 35(8): 1501-12.
 [http://dx.doi.org/10.1007/s00384-020-03676-x] [PMID: 32592092]

[127]
Ashamalla M, Youssef I, Yacoub M, Jayarangaiah A, Gupta N, Ray J. Obesity, diabetes and gastrointestinal malignancy: The role of metformin and other anti-diabetic therapy. Glob J Obes  2018; 5(2): 8.

[128]
León-González AJ, Jiménez-Vacas JM, Fuentes-Fayos AC, et al. Role of metformin and other metabolic drugs in the prevention and therapy of endocrine-related cancers. Curr Opin Pharmacol  2021; 60: 17-26.
 [http://dx.doi.org/10.1016/j.coph.2021.06.002] [PMID: 34311387]

[129]
Zhang Y, Guan M, Zheng Z, Zhang Q, Gao F, Xue Y. Effects of metformin on CD133+ colorectal cancer cells in diabetic patients. PLoS One  2013; 8(11): e81264.
 [http://dx.doi.org/10.1371/journal.pone.0081264] [PMID: 24278407]

[130]
Kim SH, Kim SC, Ku JL. Metformin increases chemo-sensitivity via gene downregulation encoding DNA replication proteins in 5- Fu resistant colorectal cancer cells. Oncotarget  2017; 8(34): 56546-57.
 [http://dx.doi.org/10.18632/oncotarget.17798] [PMID: 28915611]

[131]
Sethy C, Kundu CN. 5-Fluorouracil (5-FU) resistance and the new strategy to enhance the sensitivity against cancer: Implication of DNA repair inhibition. Biomed Pharmacother  2021; 137: 111285.
 [http://dx.doi.org/10.1016/j.biopha.2021.111285] [PMID: 33485118]

[132]
Lee J, Choi EA, Kim YS, et al. Metformin usage and the risk of colorectal cancer: A national cohort study. Int J Colorectal Dis  2021; 36(2): 303-10.
 [http://dx.doi.org/10.1007/s00384-020-03765-x] [PMID: 32968891]

[133]
Canha MI, Ramos G, Prata R, Lages Martins P, Viúla Ramos M, Coimbra J. Is metformin associated with a lower prevalence of polyps, adenomas, and colorectal carcinoma in patients with diabetes mellitus? J Gastrointest Cancer  2023; 1-9.
 [http://dx.doi.org/10.1007/s12029-023-00989-2] [PMID: 37987968]

[134]
Jahanafrooz Z, Mosafer J, Akbari M, Hashemzaei M, Mokhtarzadeh A, Baradaran B. Colon cancer therapy by focusing on colon cancer stem cells and their tumor microenvironment. J Cell Physiol  2020; 235(5): 4153-66.
 [http://dx.doi.org/10.1002/jcp.29337] [PMID: 31647128]

[135]
Zhang R, Qi F, Zhao F, et al. Cancer-associated fibroblasts enhance tumor-associated macrophages enrichment and suppress NK cells function in colorectal cancer. Cell Death Dis  2019; 10(4): 273.
 [http://dx.doi.org/10.1038/s41419-019-1435-2] [PMID: 30894509]

[136]
Luo S, Yang G, Ye P, et al. Macrophages are a double-edged sword: molecular crosstalk between tumor-associated macrophages and cancer stem cells. Biomolecules  2022; 12(6): 850.
 [http://dx.doi.org/10.3390/biom12060850] [PMID: 35740975]

[137]
Lin CC, Liao TT, Yang MH. Immune adaptation of colorectal cancer stem cells and their interaction with the tumor microenvironment. Front Oncol  2020; 10: 588542.
 [http://dx.doi.org/10.3389/fonc.2020.588542] [PMID: 33312953]

[138]
Ishimoto T, Izumi D, Sakamoto Y, Miyamoto Y, Baba H. Molecular insights into colorectal cancer stem cell regulation by environmental factors. J Cancer Metastasis Treat  2015; 1(3): 156-62.
 [http://dx.doi.org/10.4103/2394-4722.165532]

[139]
Tauriello DVF, Batlle E. Targeting the microenvironment in advanced colorectal cancer. Trends Cancer  2016; 2(9): 495-504.
 [http://dx.doi.org/10.1016/j.trecan.2016.08.001] [PMID: 28741478]

[140]
Shi J, Fan L, Li B, Pan H. Molecular mechanism of integrin αvβ6 in liver metastasis of colon cancer based on SDF-1/CXCR4. Cell Mol Biol  2022; 67(5): 88-95.
 [http://dx.doi.org/10.14715/cmb/2021.67.6.12] [PMID: 35818267]

[141]
Sun L, Li Q, Guo Y, et al. Extract of Caulis Spatholobi, a novel platelet inhibitor, efficiently suppresses metastasis of colorectal cancer by targeting tumor cell-induced platelet aggregation. Biomed Pharmacother  2020; 123: 109718.
 [http://dx.doi.org/10.1016/j.biopha.2019.109718] [PMID: 31918208]

[142]
Zou W, Zhao J, Li Y, et al. Rat bone marrow-derived mesenchymal stem cells promote the migration and invasion of colorectal cancer stem cells. OncoTargets Ther  2020; 13: 6617-28.
 [http://dx.doi.org/10.2147/OTT.S249353] [PMID: 32764957]

[143]
Shimokawa M, Ohta Y, Nishikori S, et al. Visualization and targeting of LGR5+ human colon cancer stem cells. Nature  2017; 545(7653): 187-92.
 [http://dx.doi.org/10.1038/nature22081] [PMID: 28355176]

[144]
Huang JL, Oshi M, Endo I, Takabe K. Clinical relevance of stem cell surface markers CD133, CD24, and CD44 in colorectal cancer. Am J Cancer Res  2021; 11(10): 5141-54.
 [PMID: 34765317]

[145]
Sadeghi A, Roudi R, Mirzaei A, Zare Mirzaei A, Madjd Z, Abolhasani M. CD44 epithelial isoform inversely associates with invasive characteristics of colorectal cancer. Biomarkers Med  2019; 13(6): 419-26.
 [http://dx.doi.org/10.2217/bmm-2018-0337] [PMID: 30942083]
Cite As
Current Pharmaceutical Design

Colorectal Cancer Stem Cell Biomarkers: Biological Traits and Prognostic Insights

Abstract
