Skip to main content

Advertisement

SpringerLink
Log in

The Colon Cancer Stem Cell Microenvironment Holds Keys to Future Cancer Therapy

  • Review Article
  • Published:
Journal of Gastrointestinal Surgery Aims and scope

Abstract

Background

Colorectal cancer remains the most common gastrointestinal cancer. While screening combined with effective surgical treatment has reduced its mortality, we still do not have effective means to prevent recurrence nor to treat metastatic disease. What we know about cancer biology has gone through revolutionary changes in recent decades. The advent of the cancer stem cell theory has accelerated our understanding of the cancer cell. However, there is increasing evidence that cancer cells are influenced by their surrounding microenvironment.

Purpose

This review divides the tumor microenvironment into four functional components—the stem cell niche, cancer stroma, immune cells, and vascular endothelia—and examines their individual and collective influence on the growth and metastasis of the colon cancer stem cell. The discussion will highlight the need to fully exploit the tumor microenvironment when designing future prognostic tools and therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Cancer facts & Figures 2013, 2013, American Cancer Society: Atlanta.

  2. Reya T and Clevers H. Wnt signalling in stem cells and cancer. Nature 2005;434:843-850.

    Article  CAS  PubMed  Google Scholar 

  3. Clevers H. The cancer stem cell: Premises, promises and challenges. Nature medicine 2011;17:313-319.

    Article  CAS  PubMed  Google Scholar 

  4. Kelly P, Dakic A, Adams J, Nutt S, and Strasser A. Tumor growth need not be driven by rare cancer stem cells. Science (New York, N.Y.) 2007;317:337.

  5. Gerlinger M, Rowan A, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald N, Butler A, Jones D, Raine K, Latimer C, Santos C, Nohadani M, Eklund A, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal P, and Swanton C. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The New England journal of medicine 2012;366:883-892.

    Article  CAS  PubMed  Google Scholar 

  6. Paget S. The distribution of secondary growths in cancer of the breast. The Lancet 1889;133:571-573.

    Article  Google Scholar 

  7. Fidler I. The pathogenesis of cancer metastasis: The 'seed and soil' hypothesis revisited. Nature reviews. Cancer 2003;3:453-458.

    Article  CAS  PubMed  Google Scholar 

  8. Egeblad M, Nakasone E, and Werb Z. Tumors as organs: Complex tissues that interface with the entire organism. Developmental cell 2010;18:884-901.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Sato T, van Es J, Snippert H, Stange D, Vries R, van den Born M, Barker N, Shroyer N, van de Wetering M, and Clevers H. Paneth cells constitute the niche for lgr5 stem cells in intestinal crypts. Nature 2011;469:415-418.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Clevers H and Bevins C. Paneth cells: Maestros of the small intestinal crypts. Annual review of physiology 2013;75:289-311.

    Article  CAS  PubMed  Google Scholar 

  11. Krishnamurthy S, Dong Z, Vodopyanov D, Imai A, Helman J, Prince M, Wicha M, and Nör J. Endothelial cell-initiated signaling promotes the survival and self-renewal of cancer stem cells. Cancer research 2010;70:9969-9978.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Jia L, Xiangcang Y, Fan F, Ling X, Rajat B, Seth B, Federico T, Eric S, Yunfei Z, Isamu T, Dipen MM, David HH, Janusz R, Sendurai AM, Patrick Z-M, and Lee ME. Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of jagged-1. Cancer cell 2013;23:171-185.

    Article  Google Scholar 

  13. Rønnov-Jessen L, Petersen O, and Bissell M. Cellular changes involved in conversion of normal to malignant breast: Importance of the stromal reaction. Physiological reviews 1996;76:69-125.

    PubMed  Google Scholar 

  14. Tlsty T and Hein P. Know thy neighbor: Stromal cells can contribute oncogenic signals. Current opinion in genetics & development 2001;11:54-59.

    Article  CAS  Google Scholar 

  15. Jotzu C, Alt E, Welte G, Li J, Hennessy B, Devarajan E, Krishnappa S, Pinilla S, Droll L, and Song Y-H. Adipose tissue-derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor-derived factors. Analytical cellular pathology (Amsterdam) 2010;33:61-79.

    Google Scholar 

  16. Mink S, Vashistha S, Zhang W, Hodge A, Agus D, and Jain A. Cancer-associated fibroblasts derived from egfr-tki-resistant tumors reverse egfr pathway inhibition by egfr-tkis. Molecular cancer research : MCR 2010;8:809-820.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Zeisberg E, Potenta S, Xie L, Zeisberg M, and Kalluri R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer research 2007;67:10123-10128.

    Article  CAS  PubMed  Google Scholar 

  18. Bhowmick N, Chytil A, Plieth D, Gorska A, Dumont N, Shappell S, Washington M, Neilson E, and Moses H. Tgf-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science (New York, N.Y.) 2004;303:848-851

    Article  CAS  Google Scholar 

  19. Kuperwasser C, Chavarria T, Wu M, Magrane G, Gray J, Carey L, Richardson A, and Weinberg R. Reconstruction of functionally normal and malignant human breast tissues in mice. Proceedings of the National Academy of Sciences of the United States of America 2004;101:4966-4971.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Bhowmick N, Neilson E, and Moses H. Stromal fibroblasts in cancer initiation and progression. Nature 2004;432:332-337.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Bierie B and Moses H. Tumour microenvironment: Tgfbeta: The molecular jekyll and hyde of cancer. Nature reviews. Cancer 2006;6:506-520.

    Article  CAS  PubMed  Google Scholar 

  22. Mishra L, Derynck R, and Mishra B. Transforming growth factor-beta signaling in stem cells and cancer. Science (New York, N.Y.) 2005;310:68-71

    Article  CAS  Google Scholar 

  23. Siegel P and Massagué J. Cytostatic and apoptotic actions of tgf-beta in homeostasis and cancer. Nature reviews. Cancer 2003;3:807-821.

    Article  CAS  PubMed  Google Scholar 

  24. Zeisberg M, Strutz F, and Müller G. Role of fibroblast activation in inducing interstitial fibrosis. Journal of nephrology 2000;13 Suppl 3:S111-120.

    PubMed  Google Scholar 

  25. Becker C, Fantini M, Schramm C, Lehr H, Wirtz S, Nikolaev A, Burg J, Strand S, Kiesslich R, Huber S, Ito H, Nishimoto N, Yoshizaki K, Kishimoto T, Galle P, Blessing M, Rose-John S, and Neurath M. Tgf-beta suppresses tumor progression in colon cancer by inhibition of il-6 trans-signaling. Immunity 2004;21:491-501.

    Article  CAS  PubMed  Google Scholar 

  26. Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan R, Zborowska E, Kinzler K, and Vogelstein B. Inactivation of the type ii tgf-beta receptor in colon cancer cells with microsatellite instability. Science (New York, N.Y.) 1995;268:1336-1338

    Article  CAS  Google Scholar 

  27. Biswas S, Trobridge P, Romero-Gallo J, Billheimer D, Myeroff L, Willson J, Markowitz S, and Grady W. Mutational inactivation of tgfbr2 in microsatellite unstable colon cancer arises from the cooperation of genomic instability and the clonal outgrowth of transforming growth factor beta resistant cells. Genes, chromosomes & cancer 2008;47:95-106.

    Article  CAS  Google Scholar 

  28. Biswas S, Chytil A, Washington K, Romero-Gallo J, Gorska A, Wirth P, Gautam S, Moses H, and Grady W. Transforming growth factor beta receptor type ii inactivation promotes the establishment and progression of colon cancer. Cancer research 2004;64:4687-4692.

    Article  CAS  PubMed  Google Scholar 

  29. Vermeulen L, De Sousa E Melo F, van der Heijden M, Cameron K, de Jong J, Borovski T, Tuynman J, Todaro M, Merz C, Rodermond H, Sprick M, Kemper K, Richel D, Stassi G, and Medema J. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nature cell biology 2010;12:468-476.

    Article  CAS  PubMed  Google Scholar 

  30. Cheng N, Bhowmick N, Chytil A, Gorksa A, Brown K, Muraoka R, Arteaga C, Neilson E, Hayward S, and Moses H. Loss of tgf-beta type ii receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of tgf-alpha-, msp- and hgf-mediated signaling networks. Oncogene 2005;24:5053-5068.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Waldner M, Foersch S, and Neurath M. Interleukin-6--a key regulator of colorectal cancer development. International journal of biological sciences 2012;8:1248-1253.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Waugh DJ and Wilson C. The interleukin-8 pathway in cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2008;14:6735-6741.

    Article  CAS  Google Scholar 

  33. Korkaya H, Liu S, and Wicha M. Regulation of cancer stem cells by cytokine networks: Attacking cancer's inflammatory roots. Clinical cancer research : an official journal of the American Association for Cancer Research 2011;17:6125-6129.

    Article  CAS  Google Scholar 

  34. Carpentino J, Hynes M, Appelman H, Zheng T, Steindler D, Scott E, and Huang E. Aldehyde dehydrogenase-expressing colon stem cells contribute to tumorigenesis in the transition from colitis to cancer. Cancer research 2009;69:8208-8215.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Guo Y, Xu F, Lu T, Duan Z, and Zhang Z. Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer treatment reviews 2012;38:904-910.

    Article  CAS  PubMed  Google Scholar 

  36. Varney M, Singh S, Li A, Mayer-Ezell R, Bond R, and Singh R. Small molecule antagonists for cxcr2 and cxcr1 inhibit human colon cancer liver metastases. Cancer letters 2011;300:180-188.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Ginestier C, Liu S, Diebel M, Korkaya H, Luo M, Brown M, Wicinski J, Cabaud O, Charafe-Jauffret E, Birnbaum D, Guan J-L, Dontu G, and Wicha M. Cxcr1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. The Journal of clinical investigation 2010;120:485-497.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Otranto M, Sarrazy V, Bonté F, Hinz B, Gabbiani G, and Desmoulière A. The role of the myofibroblast in tumor stroma remodeling. Cell adhesion & migration 2012;6:203-219.

    Article  Google Scholar 

  39. De Wever O, Demetter P, Mareel M, and Bracke M. Stromal myofibroblasts are drivers of invasive cancer growth. International journal of cancer. Journal international du cancer 2008;123:2229-2238.

    Article  PubMed  Google Scholar 

  40. Tse J, Cheng G, Tyrrell J, Wilcox-Adelman S, Boucher Y, Jain R, and Munn L. Mechanical compression drives cancer cells toward invasive phenotype. Proceedings of the National Academy of Sciences of the United States of America 2012;109:911-916.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Tsujino T, Seshimo I, Yamamoto H, Ngan C, Ezumi K, Takemasa I, Ikeda M, Sekimoto M, Matsuura N, and Monden M. Stromal myofibroblasts predict disease recurrence for colorectal cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2007;13:2082-2090.

    Article  CAS  Google Scholar 

  42. Koukourakis M, Giatromanolaki A, Harris A, and Sivridis E. Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: A metabolic survival role for tumor-associated stroma. Cancer research 2006;66:632-637.

    Article  CAS  PubMed  Google Scholar 

  43. Balkwill F and Mantovani A. Inflammation and cancer: Back to virchow? Lancet 2001;357:539-545.

    Article  CAS  PubMed  Google Scholar 

  44. Coussens L and Werb Z. Inflammation and cancer. Nature 2002;420:860-867.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Houghton A, Rzymkiewicz D, Ji H, Gregory A, Egea E, Metz H, Stolz D, Land S, Marconcini L, Kliment C, Jenkins K, Beaulieu K, Mouded M, Frank S, Wong K, and Shapiro S. Neutrophil elastase-mediated degradation of irs-1 accelerates lung tumor growth. Nature medicine 2010;16:219-223.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Nozawa H, Chiu C, and Hanahan D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America 2006;103:12493-12498.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Ong S-M, Tan Y-C, Beretta O, Jiang D, Yeap W-H, Tai J, Wong W-C, Yang H, Schwarz H, Lim K-H, Koh P-K, Ling K-L, and Wong S-C. Macrophages in human colorectal cancer are pro-inflammatory and prime t cells towards an anti-tumour type-1 inflammatory response. European journal of immunology 2012;42:89-100.

    Article  CAS  PubMed  Google Scholar 

  48. Edin S, Wikberg M, Rutegård J, and Oldenborg… P. Phenotypic skewing of macrophages in vitro by secreted factors from colorectal cancer cells. PloS one 2013;8:e74982

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Erreni M, Mantovani A, and Allavena P. Tumor-associated macrophages (tam) and inflammation in colorectal cancer. Cancer microenvironment : official journal of the International Cancer Microenvironment Society 2011;4:141-154.

    Article  CAS  Google Scholar 

  50. Nakanishi Y, Nakatsuji M, Seno H, Ishizu S, Akitake-Kawano R, Kanda K, Ueo T, Komekado H, Kawada M, Minami M, and Chiba T. Cox-2 inhibition alters the phenotype of tumor-associated macrophages from m2 to m1 in apcmin/+ mouse polyps. Carcinogenesis 2011;32:1333-1339.

    Article  CAS  PubMed  Google Scholar 

  51. Almand B, Resser JR, Lindman B, Nadaf S, Clark JI, Kwon ED, Carbone DP, and Gabrilovich DI. Clinical significance of defective dendritic cell differentiation in cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2000;6:1755-1766.

    CAS  Google Scholar 

  52. Gabrilovich D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nature reviews. Immunology 2004;4:941-952.

    Article  CAS  PubMed  Google Scholar 

  53. Novitskiy SV, Ryzhov S, Zaynagetdinov R, Goldstein AE, Huang Y, Tikhomirov OY, Blackburn MR, Biaggioni I, Carbone DP, Feoktistov I, and Dikov MM. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 2008;112:1822-1831.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Gabrilovich D, Ostrand-Rosenberg S, and Bronte V. Coordinated regulation of myeloid cells by tumours. Nature reviews. Immunology 2012;12:253-268.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Shojaei F, Wu X, Qu X, Kowanetz M, Yu L, Tan M, Meng Y, and Ferrara N. G-csf-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-vegf therapy in mouse models. Proceedings of the National Academy of Sciences of the United States of America 2009;106:6742-6747.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Pylayeva-Gupta Y, Lee K, Hajdu C, Miller G, and Bar-Sagi D. Oncogenic kras-induced gm-csf production promotes the development of pancreatic neoplasia. Cancer cell 2012;21:836-847.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Motz G and Coukos G. The parallel lives of angiogenesis and immunosuppression: Cancer and other tales. Nature reviews. Immunology 2011;11:702-711.

    Article  CAS  PubMed  Google Scholar 

  58. Pardoll D. The blockade of immune checkpoints in cancer immunotherapy. Nature reviews. Cancer 2012;12:252-264.

    Article  CAS  PubMed  Google Scholar 

  59. Di Renzo M, Olivero M, Giacomini A, Porte H, Chastre E, Mirossay L, Nordlinger B, Bretti S, Bottardi S, and Giordano S. Overexpression and amplification of the met/hgf receptor gene during the progression of colorectal cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 1995;1:147-154.

    Google Scholar 

  60. Mao Q, Zhang Y, Fu X, Xue J, Guo W, Meng M, Zhou Z, Mo X, and Lu Y. A tumor hypoxic niche protects human colon cancer stem cells from chemotherapy. Journal of cancer research and clinical oncology 2013;139:211-222.

    Article  CAS  PubMed  Google Scholar 

  61. Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, Fang X, Sloan AE, Mao Y, Lathia JD, Min W, McLendon RE, Rich JN, and Bao S. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 2013;153:139-152.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature medicine 1995;1:27-31.

    Article  CAS  PubMed  Google Scholar 

  63. Cook K and Figg W. Angiogenesis inhibitors: Current strategies and future prospects. CA: a cancer journal for clinicians 2010;60:222-243.

    Google Scholar 

  64. Shih T and Lindley C. Bevacizumab: An angiogenesis inhibitor for the treatment of solid malignancies. Clinical therapeutics 2006;28:1779-1802.

    Article  CAS  PubMed  Google Scholar 

  65. Siemann D. The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by tumor-vascular disrupting agents. Cancer treatment reviews 2011;37:63-74.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge Kristen Huang, PhD, for careful reading of the text.

Author information

Authors and Affiliations

  1. Department of Surgery, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA

    Sugong Chen

  2. Department of Surgery, Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA

    Emina H. Huang

  3. Department of Colorectal Surgery, Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH, USA

    Emina H. Huang

Authors
  1. Sugong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emina H. Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sugong Chen.

Additional information

Grant Support: Sugong Chen receives support from NIH T32 CA106493, awarded to Kevin E Behrns. Emina H. Huang is the principal investigator of NIH R01 CA142808 and R01 CA157663.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, S., Huang, E.H. The Colon Cancer Stem Cell Microenvironment Holds Keys to Future Cancer Therapy. J Gastrointest Surg 18, 1040–1048 (2014). https://doi.org/10.1007/s11605-014-2497-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11605-014-2497-1

Keywords

Search

Navigation