Demystifying the Differences Between Tumor-Initiating Cells and Cancer Stem Cells in Colon Cancer
Purpose of Review
Tumor-initiating cells and cancer stem cells refer to a subpopulation of self-renewing cells involved in tumor initiation and tumor maintenance, respectively. With this review, we aimed to define the functional and molecular differences between both cell types in the context of colon cancer.
Recent evidence suggests that the two major stem cell populations in the normal intestinal crypt have tumor-initiating capacity and could be the cell-of-origin in colon cancer. Activation of the Wnt/β-catenin pathway (an early event in mouse intestinal carcinogenesis) in the crypt base columnar stem cells and reserve stem cells leads to adenoma formation, supporting a role in tumor initiation. On the other hand, colon cancer stem cells express several membrane markers facilitating their isolation by FACS and are associated with treatment resistance and higher metastatic potential.
Tumor-initiating cells and cancer stem cells express distinct markers, display discrete biological functions, and can be studied using different molecular and cellular approaches. While cancer stem cells may be derived from tumor-initiating cells, these terms are not necessarily interchangeable and more likely reflect a specific cell state.
KeywordsColon cancer Tumor-initiating cells Cancer stem cells Cancer relapse Cell-of-origin Drug resistance
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 7.Fodde R. The APC gene in colorectal cancer. Eur J Cancer Oxf Engl 1990. 2002;38(7):867–71.Google Scholar
- 10.Sherwood L. Fundamentals of human physiology. 4th ed. Belmont: Brooks/Cole Cengage Learning; 2012.Google Scholar
- 25.• Montgomery RK, Carlone DL, Richmond CA, Farilla L, Kranendonk ME, Henderson DE, et al. Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proc Natl Acad Sci U S A. 2011;108(1):179–84 Identification of Tert+ reserve ISCs in the intestine.PubMedCrossRefGoogle Scholar
- 28.Li N, Nakauka-Ddamba A, Tobias J, Jensen ST, Lengner CJ. Mouse label-retaining cells are molecularly and functionally distinct from reserve intestinal stem cells. Gastroenterology. 2016;151(2):298–310Google Scholar
- 36.•• Asfaha S, Hayakawa Y, Muley A, Stokes S, Graham TA, Ericksen RE, et al. Krt19(+)/Lgr5(−) cells are radioresistant cancer-initiating stem cells in the colon and intestine. Cell Stem Cell. 2015;16(6):627–38 Identification of Krt19+/Lgr5- ISCs in the intestine and demonstration that they can act as TICs. PubMedPubMedCentralCrossRefGoogle Scholar
- 37.•• Giroux V, Stephan J, Chatterji P, Rhoades B, Wileyto EP, Klein-Szanto AJ, et al. Mouse intestinal Krt15+ crypt cells are radio-resistant and tumor initiating. Stem Cell Rep. 2018;10(6):1947–58 Identification of Krt15+ ISCs in the intestine and demonstration that they can act as TICs. CrossRefGoogle Scholar
- 54.•• Powell AE, Vlacich G, Zhao ZY, McKinley ET, Washington MK, Manning HC, et al. Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis. Am J Physiol Liver Physiol. 2014;307(1):G16–23 Demonstration that Lrig+ cells can act as TICs in colon cancer.Google Scholar
- 59.Dylla SJ, Beviglia L, Park I-K, Chartier C, Raval J, Ngan L, et al. Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS ONE [Internet]. 2008;3(6) [cited 2018 Sep 28] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2413402/.
- 69.•• 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(8):3382–9 Demonstration that ALDH1 marks CSCs in colon cancer. PubMedPubMedCentralCrossRefGoogle Scholar
- 74.•• Pang R, Law WL, Chu ACY, Poon JT, Lam CSC, Chow AKM, et al. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell. 2010;6(6):603–15 Demonstration that CD26 marks CSCs in colon cancer with high metastatic capacities. PubMedCrossRefPubMedCentralGoogle Scholar
- 79.•• 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(3):342–56 Demonstration that CD44v6+ cells are colon CSCs with high metastatic capacities. PubMedCrossRefPubMedCentralGoogle Scholar
- 81.Qureshi-Baig K, Ullmann P, Haan S, Letellier E. Tumor-initiating cells: a criTICal review of isolation approaches and new challenges in targeting strategies. Mol Cancer [Internet]. 2017;16 [cited 2018 Sep 28] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314476/.