Cancer stands as a leading global cause of human mortality, predominantly driven by solid tumors that can ravage vital organs. The scientific community has made significant strides in comprehending the molecular and cellular underpinnings of cancer. However, translating these discoveries into effective, targeted therapeutics has proven challenging. This gap highlights the existence of critical bottlenecks hindering the journey from fundamental research findings to fully realized anticancer drugs. Recent insights into cancer biology have illuminated one potential bottleneck: the presence of cancer stem cells (CSCs). These represent a minority subset of cells within a tumor, believed to orchestrate the relentless growth of the entire tumor. The concept of CSCs has gained substantial traction, thanks to advancements in stem cell research. Developing more potent and precise cancer therapies hinges on our ability to identify and understand these cancer-initiating cells within solid tumors. It is essential to discern how CSCs differ from other cancer cells coexisting in the same tissue. This review endeavors to compile the accumulated scientific evidence supporting the existence of CSCs, elucidate the cell surface markers employed for their isolation, dissect the pathways governing their self-renewal and differentiation, and outline future directions for harnessing them as therapeutic targets to eradicate tumor growth comprehensively.
Terskikh AV, Easterday MC, Li L, et al. From hematopoiesis to neuropoiesis: Evidence of overlapping genetic programs. Proc Natl Acad Sci USA 2001;98(14):7934–7939. DOI: 10.1073/pnas.131200898.
Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003;100(7):3983–3988. DOI: 10.1073/pnas.0530291100.
Tang C, Ang BT, Pervaiz S. Cancer stem cell: Target for anti-cancer therapy. FASEB J 2007;21(14):3777–3785. DOI: 10.1096/fj.07-8560rev.
Zhao L, Zhao Y, Bao Q, et al. Clinical implication of targeting of cancer stem cells. Eur Surg Res 2012;49(1):8–15. DOI: 10.1159/000339610.
Bao B, Azmi A, Li Y, et al. Targeting CSCs in tumor microenvironment: The potential role of ROS-associated miRNAs in tumor aggressiveness. Curr Stem Cell Res Ther 2013;9(1):22–35. DOI: 10.2174/1574888x113089990053.
Sell S. Infection, stem cells and cancer signals. Curr Pharm Biotechnol 2011;12(2):182–188. DOI: 10.2174/138920111794295675.
Franco S, Szczesna K, Iliou MS, et al. In vitro models of cancer stem cells and clinical applications. BMC Cancer 2016;16(Suppl2):738. DOI: 10.1186/s12885-016-2774-3.
Ayob AZ, Ramasamy TS. Cancer stem cells as key drivers of tumour progression. J Biomed Sci 2018;25(1):20. DOI: 10.1186/s12929-018-0426-4.
Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 2004;5(7):738–743. DOI: 10.1038/ni1080.
Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: Accumulating evidence and unresolved questions. Nat Rev Cancer 2008;8(10):755–768. DOI: 10.1038/nrc2499.
Iliopoulos D, Hirsch HA, Wang G, et al. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci USA 2011;108(4): 1397–1402. DOI: 10.1073/pnas.1018898108.
Ishiguro T, Ohata H, Sato A, et al. Tumor-derived spheroids: Relevance to cancer stem cells and clinical applications. Cancer Sci 2017;108(3):283–289. DOI: 10.1111/cas.13155.
Ponti D, Costa A, Zaffaroni N, et al. Isolation and In vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 2005;65(13):5506–5511. DOI: 10.1158/0008-5472.CAN-05-0626.
Shackleton M, Vaillant F, Simpson KJ, et al. Generation of a functional mammary gland from a single stem cell. Nature 2006;439(7072): 84–88. DOI: 10.1038/nature04372.
Hassan G, Afify SM, Nair N, et al. Hematopoietic cells derived from cancer stem cells generated from mouse induced pluripotent stem cells. Cancers (Basel) 2019;12(1):82. DOI: 10.3390/cancers12010082.
Schiavone K, Garnier D, Heymann MF, et al. The heterogeneity of osteosarcoma: The role played by cancer stem cells. Adv Exp Med Biol 2019;1139:187–200. DOI: 10.1007/978-3-030-14366-4_11.
Uchida N, Buck DW, He D, et al. Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA 2000;97(26): 14720–14725. DOI: 10.1073/pnas.97.26.14720.
Ignatova TN, Kukekov VG, Laywell ED, et al. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 2002;39(3):193–206. DOI: 10.1002/glia.10094.
Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003;63(18):5821–5828. PMID: 14522905.
Tsai RYL. A molecular view of stem cell and cancer cell self-renewal. Int J Biochem Cell Biol 2004;36(4):684–694. DOI: 10.1016/j.biocel.2003.10.016.
Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature 2004;432(7015):396–401. DOI: 10.1038/nature03128.
Beier D, Hau P, Proescholdt M, et al. CD133+ and CD133− glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 2007;67(9):4010–4005. DOI: 10.1158/0008-5472.CAN-06-4180.
O'Brien CA, Pollett A, Gallinger S, et al. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007;445(7123):106–110. DOI: 10.1038/nature05372.
Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature 2007;445(7123):111–115. DOI: 10.1038/nature05384.
Shmelkov SV, Butler JM, Hooper AT, 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(6):2111–2120. DOI: https://doi.org/10.1172/JCI34401.
Dalerba P, Dylla SJ, Park IK, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA 2007;104(24):10158–10163. DOI: 10.1073/pnas.0703478104.
Medema JP. Cancer stem cells: The challenges ahead. Nat Cell Biol 2013;15(4):338–344. DOI: 10.1038/ncb2717.
Akbarzadeh M, Maroufi NF, Tazehkand AP, et al. Current approaches in identification and isolation of cancer stem cells. J Cell Physiol 2019;234(9):14759–14772. DOI: 10.1002/jcp.28271.
Dobbin ZC, Landen CN. Isolation and characterization of potential cancer stem cells from solid human tumors—potential applications. Curr Protoc Pharmacol 2013;63:14.28.1–14.28.19. DOI: 10.1002/0471141755.ph1428s63.
Kondo T, Setoguchi T, Taga T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA 2004;101(3):781–786. DOI: 10.1073/pnas.0307618100.
Goodell MA, Brose K, Paradis G, et al. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996;183(4):1797–1806. DOI: 10.1084/jem.183.4.1797.
Zhou S, Schuetz JD, Bunting KD, et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 2001;7(9):1028–1034. DOI: 10.1038/nm0901-1028.
Haraguchi N, Utsunomiya T, Inoue H, et al. Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells 2006;24(3):506–513. DOI: 10.1634/stemcells.2005-0282.
Balicki D. Moving forward in human mammary stem cell biology and breast cancer prognostication using ALDH1. Cell Stem Cell 2007;1(5):485–487. DOI: 10.1016/j.stem.2007.10.015.
Liu W Hui, Qian N Song, Li R, et al. Replacing Hoechst33342 with Rhodamine123 in isolation of cancer stem-like cells from the MHCC97 cell line. Toxicol In Vitro 2010;24(2):538–545. DOI: 10.1016/j.tiv.2009.11.008.
Ginestier C, Hur MH, Charafe-Jauffret E, et al. ALDH1 Is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007;1(5):555–567. DOI: 10.1016/j.stem.2007.08.014.
Bandhavkar S. Cancer stem cells: A metastasizing menace! Cancer Med 2016;5(4):649–655. DOI: 10.1002/cam4.629.
Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3(7):730–737. DOI: 10.1038/nm0797-730.
Snyder V, Reed-Newman TC, Arnold L, et al. Cancer stem cell metabolism and potential therapeutic targets. Front Oncol 2018;8:203. DOI: 10.3389/fonc.2018.00203.
Oishi N, Wang XW. Novel therapeutic strategies for targeting liver cancer stem cells. Int J Biol Sci 2011;7(5):517–535. DOI: 10.7150/ijbs.7.517.
Effendi K, Yamazaki K, Fukuma M, et al. Overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) represents a typical wnt/β-catenin pathway-activated hepatocellular carcinoma. Liver Cancer 2014;3(3–4):451–457. DOI: 10.1159/000343873.
Chao MP, Weissman IL, Majeti R. The CD47–SIRPα pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol 2012;24(2):225–232. DOI: 10.1016/j.coi.2012.01.010.
Kaur S, Singh G, Kaur K. Cancer stem cells: An insight and future perspective. J Cancer Res Ther 2014;10(4):846–852. DOI: 10.4103/0973-1482.139264.
Tu L, Foltz G, Lin E, et al. Targeting stem cells-clinical implications for cancer therapy. Curr Stem Cell Res Ther 2009;4(2):147–153. DOI: 10.2174/157488809788167373.
Mikhail S. Stem cells in gastrointestinal cancers: The road less travelled. World J Stem Cells 2014;6(5):606. DOI: 10.4252/wjsc.v6.i5.606.
Wicha MS, Liu S, Dontu G. Cancer stem cells: An old idea—a paradigm shift. Cancer Res 2006;66(4):1883–1890. DOI: 10.1158/0008-5472.CAN-05-3153.
Kavyasudha C, Joseph JP, Jayaraj R, et al. Conventional and emerging markers in stem cell isolation and characterization. In 201913:1–14. DOI: https://doi.org/10.1007/5584_2019_475.
Xiong J, Yan L, Zou C, et al. Integrins regulate stemness in solid tumor: An emerging therapeutic target. J Hematol Oncol 2021;14(1):177. DOI: 10.1186/s13045-021-01192-1.
Jaggupilli A, Elkord E. Significance of CD44 and CD24 as cancer stem cell markers: An enduring ambiguity. Clin Dev Immunol 2012;2012:708036. DOI: 10.1155/2012/708036.
Fulawka L, Donizy P, Halon A. Cancer stem cells – the current status of an old concept: Literature review and clinical approaches. Biol Res 2014;47(1):66. DOI: 10.1186/0717-6287-47-66.
Kent L. Culture and maintenance of human embryonic stem cells. J Vis Exp 2009 Dec 22;(34):1427. DOI: 10.3791/1427.
McKee C, Chaudhry GR. Advances and challenges in stem cell culture. Colloids Surf B Biointerfaces 2017;159:62–77. DOI: 10.1016/j.colsurfb.2017.07.051.
Celià-Terrassa T, Jolly MK. Cancer stem cells and epithelial-to-mesenchymal transition in cancer metastasis. Cold Spring Harb Perspect Med 2020;10(7):a036905. DOI: 10.1101/cshperspect.a036905.
Brungs D, Aghmesheh M, Vine KL, et al. Gastric cancer stem cells: Evidence, potential markers, and clinical implications. J Gastroenterol 2016;51(4):313–326. DOI: 10.1007/s00535-015-1125-5.
Nieto MA. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol 2011;27(1):347–376. DOI: 10.1146/annurev-cellbio-092910-154036.
Mani SA, Guo W, Liao MJ, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008;133(4):704–715. DOI: 10.1016/j.cell.2008.03.027.
Xu MH, Gao X, Luo D, et al. EMT and acquisition of stem cell-like properties are involved in spontaneous formation of tumorigenic hybrids between lung cancer and bone marrow-derived mesenchymal stem cells. PLoS One 2014;9(2):e87893. DOI: 10.1371/journal.pone.0087893.
Wang H, Unternaehrer JJ. Epithelial-mesenchymal transition and cancer stem cells: At the crossroads of differentiation and dedifferentiation. Dev Dyn 2019;248(1):10–20. DOI: 10.1002/dvdy.24678.
Batlle E, Clevers H. Cancer stem cells revisited. Nat Med 2017;23(10):1124–1134. DOI: 10.1038/nm.4409.
Vincent Z, Urakami K, Maruyama K, et al. CD133-positive cancer stem cells from colo205 human colon adenocarcinoma cell line show resistance to chemotherapy and display a specific metabolomic profile. Genes Cancer 2014;5(7–8):250–260. DOI: 10.18632/genesandcancer.23.
Lindeman GJ, Visvader JE. Insights into the cell of origin in breast cancer and breast cancer stem cells. Asia Pac J Clin Oncol 2010;6(2):89–97. DOI: 10.1111/j.1743-7563.2010.01279.x.
Garza-Treviño EN, Said-Fernández SL, Martínez-Rodríguez HG. Understanding the colon cancer stem cells and perspectives on treatment. Cancer Cell Int 2015;15(1):2. DOI: 10.1186/s12935-015-0163-7.
Raggi C, Mousa HS, Correnti M, et al. Cancer stem cells and tumor-associated macrophages: A roadmap for multitargeting strategies. Oncogene 2016;35(6):671–682. DOI: 10.1038/onc.2015.132.
Roato I, Ferracini R. Cancer stem cells, bone and tumor microenvironment: Key players in bone metastases. Cancers (Basel) 2018;10(2):56. DOI: 10.3390/cancers10020056.
Klimkiewicz K, Weglarczyk K, Collet G, et al. A 3D model of tumour angiogenic microenvironment to monitor hypoxia effects on cell interactions and cancer stem cell selection. Cancer Lett 2017;396: 10–20. DOI: 10.1016/j.canlet.2017.03.006.
Frentzas S, Lum C, Chen TY. Angiogenesis and its role in the tumour microenvironment: A target for cancer therapy. Current Cancer Treatment. 2020. DOI: 10.5772/intechopen.89667.
Markowska A, Sajdak S, Markowska J, et al. Angiogenesis and cancer stem cells: New perspectives on therapy of ovarian cancer. Eur J Med Chem 2017;142:87–94. DOI: 10.1016/j.ejmech.2017.06.030.
O'Brien CS, Farnie G, Howell SJ, et al. Breast cancer stem cells and their role in resistance to endocrine therapy. Horm Cancer 2011;2(2):91–103. DOI: 10.1007/s12672-011-0066-6.
Fujita K, Akita M. Tumor angiogenesis: A focus on the role of cancer stem cells. Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy. 2017. DOI: 10.5772/66402.
Tsujii M. Search for novel target molecules for the effective treatment or prevention of colorectal cancer. Digestion 2012;85(2):99–102. DOI: 10.1159/000334678.
Safa AR, Saadatzadeh MR, Cohen-Gadol AA, et al. Glioblastoma stem cells (GSCs) epigenetic plasticity and interconversion between differentiated non-GSCs and GSCs. Genes Dis 2015;2(2):152–163. DOI: 10.1016/j.gendis.2015.02.001.
Shih JY, Yang PC. The EMT regulator slug and lung carcinogenesis. Carcinogenesis 2011;32(9):1299–1304. DOI: 10.1093/carcin/bgr110.