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Published in: Molecular Cancer 1/2017

Open Access 01-12-2017 | Review

Intra-tumor heterogeneity from a cancer stem cell perspective

Authors: Pramudita R. Prasetyanti, Jan Paul Medema

Published in: Molecular Cancer | Issue 1/2017

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Abstract

Tumor heterogeneity represents an ongoing challenge in the field of cancer therapy. Heterogeneity is evident between cancers from different patients (inter-tumor heterogeneity) and within a single tumor (intra-tumor heterogeneity). The latter includes phenotypic diversity such as cell surface markers, (epi)genetic abnormality, growth rate, apoptosis and other hallmarks of cancer that eventually drive disease progression and treatment failure. Cancer stem cells (CSCs) have been put forward to be one of the determining factors that contribute to intra-tumor heterogeneity. However, recent findings have shown that the stem-like state in a given tumor cell is a plastic quality. A corollary to this view is that stemness traits can be acquired via (epi)genetic modification and/or interaction with the tumor microenvironment (TME). Here we discuss factors contributing to this CSC heterogeneity and the potential implications for cancer therapy.
Literature
1.
go back to reference Shapiro JR, Yung WKA, Shapiro WR. Isolation, karyotype, and clonal growth of heterogeneous subpopulations of human malignant gliomas. Cancer Res. 1981;41:2349–59.PubMed Shapiro JR, Yung WKA, Shapiro WR. Isolation, karyotype, and clonal growth of heterogeneous subpopulations of human malignant gliomas. Cancer Res. 1981;41:2349–59.PubMed
2.
go back to reference Yung WKA, Shapiro JR, Shapiro WR. Heterogeneous chemosensitivities of subpopulations of human glioma cells in culture. Cancer Res. 1982;42:992–8.PubMed Yung WKA, Shapiro JR, Shapiro WR. Heterogeneous chemosensitivities of subpopulations of human glioma cells in culture. Cancer Res. 1982;42:992–8.PubMed
8.
go back to reference Sottoriva A, Verhoeff JJC, Borovski T, McWeeney SK, Naumov L, Medema JP, et al. Cancer stem cell tumor model reveals invasive morphology and increased phenotypical heterogeneity. Cancer Res. 2010;70:46–56.CrossRefPubMed Sottoriva A, Verhoeff JJC, Borovski T, McWeeney SK, Naumov L, Medema JP, et al. Cancer stem cell tumor model reveals invasive morphology and increased phenotypical heterogeneity. Cancer Res. 2010;70:46–56.CrossRefPubMed
9.
go back to reference Waclaw B, Bozic I, Pittman ME, Hruban RH, Vogelstein B, Nowak M a. Spatial model predicts dispersal and cell turnover cause reduced intra-tumor heterogeneity. Nature. 2015;525:261–7.CrossRefPubMedPubMedCentral Waclaw B, Bozic I, Pittman ME, Hruban RH, Vogelstein B, Nowak M a. Spatial model predicts dispersal and cell turnover cause reduced intra-tumor heterogeneity. Nature. 2015;525:261–7.CrossRefPubMedPubMedCentral
16.
go back to reference Visvader JE, Lindeman GJ. Cancer stem cells. Current status and evolving complexities. Cell Stem Cell. 2012;10: 717–28. Visvader JE, Lindeman GJ. Cancer stem cells. Current status and evolving complexities. Cell Stem Cell. 2012;10: 717–28.
20.
go back to reference Junttila MR, Mao W, Wang X, Wang BE, Pham T, Flygare J, et al. Targeting LGR5 + cells with an antibody-drug conjugate for the treatment of colon cancer. Sci Translational Med. 2015;7;314:14ra186-314ra186. Junttila MR, Mao W, Wang X, Wang BE, Pham T, Flygare J, et al. Targeting LGR5 + cells with an antibody-drug conjugate for the treatment of colon cancer. Sci Translational Med. 2015;7;314:14ra186-314ra186.
21.
go back to reference Colak S, Medema JP. Cancer stem cells - important players in tumor therapy resistance. FEBS J. 2014;281:4779–91.CrossRefPubMed Colak S, Medema JP. Cancer stem cells - important players in tumor therapy resistance. FEBS J. 2014;281:4779–91.CrossRefPubMed
23.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
24.
go back to reference Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci. 2003;100:3983–8.CrossRefPubMedPubMedCentral Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci. 2003;100:3983–8.CrossRefPubMedPubMedCentral
25.
go back to reference Meyer MJ, Fleming JM, Lin AF, Hussnain SA, Ginsburg E, Vonderhaar BK. CD44posCD49fhiCD133/2hi defines xenograft-initiating cells in estrogen receptor-negative breast cancer. Cancer Res. 2010;70:4624–33.CrossRefPubMedPubMedCentral Meyer MJ, Fleming JM, Lin AF, Hussnain SA, Ginsburg E, Vonderhaar BK. CD44posCD49fhiCD133/2hi defines xenograft-initiating cells in estrogen receptor-negative breast cancer. Cancer Res. 2010;70:4624–33.CrossRefPubMedPubMedCentral
26.
go back to reference Shmelkov SV, Butler JM, Hooper AT, Adilia H, Jared K, Till M, Clair RS, Muhamed B, Ian W, Jin DK, Amy C, Murphy AJ, Valenzuela DM, Gale NW, Gavin T, George DYSR. CD133 expression is not restricted to metastatic colon cancer cells initiate tumors. J Clin Invest. 2008;118:2111–20. Available from: www.jci.org/articles/view/34401.PubMedPubMedCentral Shmelkov SV, Butler JM, Hooper AT, Adilia H, Jared K, Till M, Clair RS, Muhamed B, Ian W, Jin DK, Amy C, Murphy AJ, Valenzuela DM, Gale NW, Gavin T, George DYSR. CD133 expression is not restricted to metastatic colon cancer cells initiate tumors. J Clin Invest. 2008;118:2111–20. Available from: www.​jci.​org/​articles/​view/​34401.PubMedPubMedCentral
27.
go back to reference Wang J, Sakariassen P, Tsinkalovsky O, Immervoll H, Bøe SO, Svendsen A, et al. CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int J Cancer. 2008;122:761–8.CrossRefPubMed Wang J, Sakariassen P, Tsinkalovsky O, Immervoll H, Bøe SO, Svendsen A, et al. CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int J Cancer. 2008;122:761–8.CrossRefPubMed
28.
go back to reference Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, et al. CD133+ and CD133- glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 2007;67:4010–5.CrossRefPubMed Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, et al. CD133+ and CD133- glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 2007;67:4010–5.CrossRefPubMed
30.
go back to reference Kemper K, Versloot M, Cameron K, Colak S, MeloF DSE, De Jong JH, et al. Mutations in the Ras-Raf axis underlie the prognostic value of CD133 in colorectal cancer. Clin Cancer Res. 2012;18:3132–41.CrossRefPubMed Kemper K, Versloot M, Cameron K, Colak S, MeloF DSE, De Jong JH, et al. Mutations in the Ras-Raf axis underlie the prognostic value of CD133 in colorectal cancer. Clin Cancer Res. 2012;18:3132–41.CrossRefPubMed
31.
go back to reference Jeon YK, Kim SH, Choi SH, Kim KH, Yoo BC, Ku JL, et al. Promoter hypermethylation and loss of CD133 gene expression in colorectal cancers. World J Gastroenterol. 2010;16:3153–60. Jeon YK, Kim SH, Choi SH, Kim KH, Yoo BC, Ku JL, et al. Promoter hypermethylation and loss of CD133 gene expression in colorectal cancers. World J Gastroenterol. 2010;16:3153–60.
32.
go back to reference Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–67. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–67.
34.
go back to reference Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011. p. 646–74. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011. p. 646–74.
36.
go back to reference Tomasetti C, Vogelstein B. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science. 2014;347(6217):78-81. Tomasetti C, Vogelstein B. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science. 2014;347(6217):78-81.
37.
go back to reference Zhu L, Finkelstein D, Gao C, Shi L, Wang Y, Lόpez-Terrada D, et al. Multi-organ mapping of cancer risk. Cell. 2016;166:1132–1146:e7.CrossRefPubMed Zhu L, Finkelstein D, Gao C, Shi L, Wang Y, Lόpez-Terrada D, et al. Multi-organ mapping of cancer risk. Cell. 2016;166:1132–1146:e7.CrossRefPubMed
41.
go back to reference Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Göktuna SI, Ziegler PK, et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell. 2013;152:25–38.CrossRefPubMed Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Göktuna SI, Ziegler PK, et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell. 2013;152:25–38.CrossRefPubMed
42.
go back to reference Dawson MA, Kouzarides T. Cancer epigenetics: From mechanism to therapy. Cell. 2012. p. 12–27. Dawson MA, Kouzarides T. Cancer epigenetics: From mechanism to therapy. Cell. 2012. p. 12–27.
43.
go back to reference Hitchins MP, Rapkins RW, Kwok CT, Srivastava S, Wong JJL, Khachigian LM, et al. Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5’UTR. Cancer Cell. 2011;20:200–13.CrossRefPubMed Hitchins MP, Rapkins RW, Kwok CT, Srivastava S, Wong JJL, Khachigian LM, et al. Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5’UTR. Cancer Cell. 2011;20:200–13.CrossRefPubMed
44.
go back to reference Muñoz P, Iliou MS, Esteller M. Epigenetic alterations involved in cancer stem cell reprogramming. Mol. Oncol. 2012. p. 620–36. Muñoz P, Iliou MS, Esteller M. Epigenetic alterations involved in cancer stem cell reprogramming. Mol. Oncol. 2012. p. 620–36.
46.
go back to reference Lu R, Wang P, Parton T, Zhou Y, Chrysovergis K, Rockowitz S, et al. Epigenetic perturbations by Arg882-mutated DNMT3A potentiate aberrant stem cell gene-expression program and acute leukemia development. Cancer Cell. 2016;30:92–107.CrossRefPubMed Lu R, Wang P, Parton T, Zhou Y, Chrysovergis K, Rockowitz S, et al. Epigenetic perturbations by Arg882-mutated DNMT3A potentiate aberrant stem cell gene-expression program and acute leukemia development. Cancer Cell. 2016;30:92–107.CrossRefPubMed
47.
go back to reference Zhang J, Wang J, Liu Y, Sidik H, Young KH, Lodish HF, et al. Oncogenic Kras-induced leukemogeneis: Hematopoietic stem cells as the initial target and lineage-specific progenitors as the potential targets for final leukemic transformation. Blood. 2009;113:1304–14.CrossRefPubMedPubMedCentral Zhang J, Wang J, Liu Y, Sidik H, Young KH, Lodish HF, et al. Oncogenic Kras-induced leukemogeneis: Hematopoietic stem cells as the initial target and lineage-specific progenitors as the potential targets for final leukemic transformation. Blood. 2009;113:1304–14.CrossRefPubMedPubMedCentral
48.
go back to reference Jolly MK, Jia D, Boareto M, Mani S a, Pienta KJ, Ben-Jacob E, et al. Coupling the modules of EMT and stemness : a tunable “stemness window” model. Oncotarget. 2015;6:1–14.CrossRef Jolly MK, Jia D, Boareto M, Mani S a, Pienta KJ, Ben-Jacob E, et al. Coupling the modules of EMT and stemness : a tunable “stemness window” model. Oncotarget. 2015;6:1–14.CrossRef
49.
go back to reference Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.CrossRefPubMedPubMedCentral Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.CrossRefPubMedPubMedCentral
50.
go back to reference Ye X, Leong Tam W, Shibue T, Kaygusuz Y, Reinhardt F, Ng Eaton E, et al. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Ye X, Leong Tam W, Shibue T, Kaygusuz Y, Reinhardt F, Ng Eaton E, et al. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells.
51.
go back to reference Chaffer CL, Marjanovic ND, Lee T, Bell G, Kleer CG, Reinhardt F, et al. XPoised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell. 2013. Chaffer CL, Marjanovic ND, Lee T, Bell G, Kleer CG, Reinhardt F, et al. XPoised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell. 2013.
53.
go back to reference Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, et al. A bivalent chromatin structure marks Key developmental genes in embryonic stem cells. Cell. 2006;125:315–26.CrossRefPubMed Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, et al. A bivalent chromatin structure marks Key developmental genes in embryonic stem cells. Cell. 2006;125:315–26.CrossRefPubMed
54.
go back to reference Sachs M, Onodera C, Blaschke K, Ebata K, Song J, Ramalho-Santos M. Bivalent chromatin marks developmental regulatory genes in the mouse embryonic germline InVivo. Cell Rep. 2013;3:1777–84.CrossRefPubMedPubMedCentral Sachs M, Onodera C, Blaschke K, Ebata K, Song J, Ramalho-Santos M. Bivalent chromatin marks developmental regulatory genes in the mouse embryonic germline InVivo. Cell Rep. 2013;3:1777–84.CrossRefPubMedPubMedCentral
57.
go back to reference Almendro V, Cheng YK, Randles A, Itzkovitz S, Marusyk A, Ametller E, et al. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity. Cell Rep. 2014;6:514–27.CrossRefPubMedPubMedCentral Almendro V, Cheng YK, Randles A, Itzkovitz S, Marusyk A, Ametller E, et al. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity. Cell Rep. 2014;6:514–27.CrossRefPubMedPubMedCentral
60.
go back to reference Balkwill F, Mantovani A. Inflammation and cancer: Back to Virchow? Lancet. 2001. p. 539–45. Balkwill F, Mantovani A. Inflammation and cancer: Back to Virchow? Lancet. 2001. p. 539–45.
64.
go back to reference Korkaya H, Kim G, Davis A, Malik F, Henry NL, Ithimakin S, et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell. 2012;47:570–84.CrossRefPubMedPubMedCentral Korkaya H, Kim G, Davis A, Malik F, Henry NL, Ithimakin S, et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell. 2012;47:570–84.CrossRefPubMedPubMedCentral
66.
go back to reference Hoey T, Yen WC, Axelrod F, Basi J, Donigian L, Dylla S, et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell. 2009;5:168–77.CrossRefPubMed Hoey T, Yen WC, Axelrod F, Basi J, Donigian L, Dylla S, et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell. 2009;5:168–77.CrossRefPubMed
68.
go back to reference Borovski T, Verhoeff JJC, Ten Cate R, Cameron K, De Vries NA, Van Tellingen O, et al. Tumor microvasculature supports proliferation and expansion of glioma-propagating cells. Int J Cancer. 2009;125:1222–30.CrossRefPubMed Borovski T, Verhoeff JJC, Ten Cate R, Cameron K, De Vries NA, Van Tellingen O, et al. Tumor microvasculature supports proliferation and expansion of glioma-propagating cells. Int J Cancer. 2009;125:1222–30.CrossRefPubMed
75.
go back to reference Shin Y, Kim H, Han S, Won J, Jeong HE, Lee ES, et al. Extracellular matrix heterogeneity regulates three-dimensional morphologies of breast adenocarcinoma cell invasion. Adv Healthc Mater. 2013;2:790–4.CrossRefPubMed Shin Y, Kim H, Han S, Won J, Jeong HE, Lee ES, et al. Extracellular matrix heterogeneity regulates three-dimensional morphologies of breast adenocarcinoma cell invasion. Adv Healthc Mater. 2013;2:790–4.CrossRefPubMed
78.
go back to reference Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, et al. Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005;8:241–54.CrossRefPubMed Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, et al. Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005;8:241–54.CrossRefPubMed
83.
go back to reference Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C, et al. The hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell. 2011;147:759–72.CrossRefPubMed Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C, et al. The hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell. 2011;147:759–72.CrossRefPubMed
86.
go back to reference Chan J, Ko FCF, Yeung YS, Ng IOL, Yam JWP. Integrin-linked kinase overexpression and its oncogenic role in promoting tumorigenicity of hepatocellular carcinoma. PLoS One. 2011;6. Chan J, Ko FCF, Yeung YS, Ng IOL, Yam JWP. Integrin-linked kinase overexpression and its oncogenic role in promoting tumorigenicity of hepatocellular carcinoma. PLoS One. 2011;6.
89.
go back to reference Neal JT, Kuo CJ. Organoids as models for neoplastic transformation. Annu Rev Pathol Mech Dis. 2016;11:199–220.CrossRef Neal JT, Kuo CJ. Organoids as models for neoplastic transformation. Annu Rev Pathol Mech Dis. 2016;11:199–220.CrossRef
90.
go back to reference Hickman JA, Graeser R, de Hoogt R, Vidic S, Brito C, Gutekunst M, et al. Three-dimensional models of cancer for pharmacology and cancer cell biology: Capturing tumor complexity in vitro/ex vivo. Biotechnol. J. 2014. p. 1115–28. Hickman JA, Graeser R, de Hoogt R, Vidic S, Brito C, Gutekunst M, et al. Three-dimensional models of cancer for pharmacology and cancer cell biology: Capturing tumor complexity in vitro/ex vivo. Biotechnol. J. 2014. p. 1115–28.
Metadata
Title
Intra-tumor heterogeneity from a cancer stem cell perspective
Authors
Pramudita R. Prasetyanti
Jan Paul Medema
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2017
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-017-0600-4

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