Cancer Microenvironment

, 4:181 | Cite as

The Colorectal Tumor Microenvironment: The Next Decade



Colorectal cancer cells establish a crosstalk with the tumor microenvironment, such that implantation and development of the tumor is generally favoured. CRC progression depends on mutations in the tumor’s oncogenic pathways as well as metastasis suppressor genes, but is also influenced by the inflammatory components in the microenvironment. Inflammation results from the dietary intakes and is either compounded or counterbalanced by our lifestyles. Whether driven by intrinsic pathways or infection, inflammation produces a massive influx of cytokines and chemokines. Currently, in colorectal cancer, the best approach to counter this inflammatory wave in the microenvironment appears to be CCL2 cytokine targeting. A fairly new avenue of discovery has identified microRNAs regulating colorectal cancer-mediated inflammation, and in particular the IL-6 pro-inflammatory pathway that induces pro-apoptotic genes and HIF1α-elicited VEGF secretion. miRNAs also play a significant role in controlling metabolic genes such as the upregulation of the fatty acid synthase gene with the concomitant down-regulation of the carnitine palmitoyl transferase 1 gene. Within the metastatic environment, the Discoidin domain receptor-2 (DDR2) gene encodes a tyrosine kinase receptor for fibrillar collagen that contributes to colorectal cancer metastasis by increasing myofibroblasts, neoangiogenic vessels and proliferating cancer cells. Ongoing identification of gene signatures differentiating between primary tumor cells and their metastatic counterparts promises a wealth of new targets to be exploited for further therapeutic use within the next decade.


Colorectal cancer Microenvironment Inflammation Cytokines Chemokines CCL2 miRNA DDR2 



Work in Dr. Beauchemin’s laboratory is funded through the Canadian Institutes of Health Research and the Cancer Research Society Inc.


  1. 1.
    Smith SC, Theodorescu D (2009) Learning therapeutic lessons from metastasis suppressor proteins. Nat Rev Cancer 9(4):253–264PubMedCrossRefGoogle Scholar
  2. 2.
    Nash GM, Gimbel M, Shia J, Nathanson DR, Ndubuisi MI, Zeng ZS, Kemeny N, Paty PB (2010) KRAS mutation correlates with accelerated metastatic progression in patients with colorectal liver metastases. Ann Surg Oncol 17(2):572–578PubMedCrossRefGoogle Scholar
  3. 3.
    Yokota T, Ura T, Shibata N, Takahari D, Shitara K, Nomura M, Kondo C, Mizota A, Utsunomiya S, Muro K, Yatabe Y (2011) BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br J Cancer 104(5):856–862PubMedCrossRefGoogle Scholar
  4. 4.
    Park JH, Han SW, Oh DY, Im SA, Jeong SY, Park KJ, Kim TY, Bang YJ, Park JG (2011) Analysis of KRAS, BRAF, PTEN, IGF1R, EGFR intron 1 CA status in both primary tumors and paired metastases in determining benefit from cetuximab therapy in colon cancer. Cancer Chemother Pharmacol (Feb 22):[Epub ahead of print]Google Scholar
  5. 5.
    Ju HX, An B, Okamoto Y, Shinjo K, Kanemitsu Y, Komori K, Hirai T, Shimizu Y, Sano T, Sawaki A, Tajika M, Yamao K, Fujii M, Murakami H, Osada H, Ito H, Takeuchi I, Sekido Y, Kondo Y (2011) Distinct profiles of epigenetic evolution between colorectal cancers with and without metastasis. Am J Pathol 178(4):1835–1846PubMedCrossRefGoogle Scholar
  6. 6.
    Bandres E, Agirre X, Bitarte N, Ramirez N, Zarate R, Roman-Gomez J, Prosper F, Garcia-Foncillas J (2009) Epigenetic regulation of microRNA expression in colorectal cancer. Int J Cancer 125(11):2737–2743PubMedCrossRefGoogle Scholar
  7. 7.
    Fuchs CS, Giovannucci EL, Colditz GA, Hunter DJ, Stampfer MJ, Rosner B, Speizer FE, Willett WC (1999) Dietary fiber and the risk of colorectal cancer and adenoma in women. N Engl J Med 340(3):169–176PubMedCrossRefGoogle Scholar
  8. 8.
    Koushik A, Hunter DJ, Spiegelman D et al (2007) Fruits, vegetables, and colon cancer risk in a pooled analysis of 14 cohort studies. J Natl Cancer Inst 99(19):1471–1483PubMedCrossRefGoogle Scholar
  9. 9.
    Yanovski SZ, Yanovski JA (2011) Obesity prevalence in the United States–up, down, or sideways? N Engl J Med 364(11):987–989PubMedCrossRefGoogle Scholar
  10. 10.
    Chan AT, Ogino S, Fuchs CS (2007) Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 356:2131–2142PubMedCrossRefGoogle Scholar
  11. 11.
    Flossmann E, Rothwell PM (2007) Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 369:1603–1613PubMedCrossRefGoogle Scholar
  12. 12.
    Sparmann A, Bar-Sagi D (2004) Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6:447–458PubMedCrossRefGoogle Scholar
  13. 13.
    Shchors K, Shchors E, Rostker F, Lawlor ER, Brown-Swigart L, Evan GI (2006) The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1beta. Genes Dev 20:1651–1656CrossRefGoogle Scholar
  14. 14.
    Bierie B, Chung CH, Parker JS, Stover DG, Cheng N, Chytil A, Aakre M, Shyr Y, Moses HL (2009) Abrogation of TGF-beta signaling enhances chemokine production and correlates with prognosis in human breast cancer. J Clin Invest 119(6):1571–1582PubMedCrossRefGoogle Scholar
  15. 15.
    Popivanova BK, Kostadinova FI, Furuichi K, Shamekh MM, Kondo T, Wada T, Egashira K, Mukaida N (2009) Blockade of a chemokine, CCL2, reduces chronic colitis-associated carcinogenesis in mice. Cancer Res 69(19):7884–7892PubMedCrossRefGoogle Scholar
  16. 16.
    Loberg RD, Ying C, Craig M, Day LL, Sargent E, Neeley C, Wojno K, Snyder LA, Yan L, Pienta KJ (2007) Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo. Cancer Res 67(19):9417–9424PubMedCrossRefGoogle Scholar
  17. 17.
    Qian B-Z, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard JW (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature doi: 10.1038/nature10138
  18. 18.
    Hsu CP, Chen YL, Huang CC, Chou CC, Liu CL, Hung CH, Kao TY, Chung YC (2011) Anti-interleukin-6 receptor antibody inhibits the progression in human colon carcinoma cells. Eur J Clin Invest 41(3):277–284PubMedCrossRefGoogle Scholar
  19. 19.
    Febbraio MA, Rose-John S, Pedersen BK (2010) Is interleukin-6 receptor blockade the Holy Grail for inflammatory diseases? Clin Pharmacol Ther 87(4):396–398PubMedCrossRefGoogle Scholar
  20. 20.
    Popivanova BK, Kitamura K, Wu Y, Kondo T, Kagaya T, Kaneko S, Oshima M, Fujii C, Mukaida N (2008) Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Invest 118(2):560–570PubMedGoogle Scholar
  21. 21.
    Sakai H, Yamada Y, Shimizu M, Saito K, Moriwaki H, Hara A (2010) Genetic ablation of Tnfalpha demonstrates no detectable suppressive effect on inflammation-related mouse colon tumorigenesis. Chem Biol Interact 184(3):423–430PubMedCrossRefGoogle Scholar
  22. 22.
    Ghosh N, Chaki R, Mandal V, Mandal SC (2010) COX-2 as a target for cancer chemotherapy. Pharmacol Rep 62(2):233–244PubMedGoogle Scholar
  23. 23.
    Forssell J, Oberg A, Henriksson ML, Stenling R, Jung A, Palmqvist R (2007) High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res 13:1472–1479PubMedCrossRefGoogle Scholar
  24. 24.
    Jedinak A, Dudhgaonkar S, Sliva D (2010) Activated macrophages induce metastatic behavior of colon cancer cells. Immunobiology 215:242–249PubMedCrossRefGoogle Scholar
  25. 25.
    Mantovani A, Sica A, Allavena P, Garlanda C, Locati M (2009) Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation. Hum Immunobiol 70(5):325–330CrossRefGoogle Scholar
  26. 26.
    Arndt GM, Dossey L, Cullen LM, Lai A, Druker R, Eisbacher M, Zhang C, Tran N, Fan H, Retzlaff K, Bittner A, Raponi M (2009) Characterization of global microRNA expression reveals oncogenic potential of miR-145 in metastatic colorectal cancer. BMC Cancer 9:374PubMedCrossRefGoogle Scholar
  27. 27.
    Dumoutier L, Leemans C, Lejeune D, Kotenko SV, Renauld JC (2001) Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J Immunol 167:3545–3549PubMedGoogle Scholar
  28. 28.
    Gregory PA, Bracken CP, Bert AG, Goodall GJ (2008) MicroRNAs as regulators of epithelialmesenchymal transition. Cell Cycle 7:3112–3118PubMedCrossRefGoogle Scholar
  29. 29.
    Noonan EJ, Place RF, Pookot D, Basak S, Whitson JM, Hirata H, Giardina C, Dahiya R (2009) miR-449a targets HDAC-1 and induces growth arrest in prostate cancer. Oncogene 28:1714–1724PubMedCrossRefGoogle Scholar
  30. 30.
    Iliopoulos D, Drosatos K, Hiyama Y, Goldberg IJ, Zannis VI (2010) MicroRNA-370 controls the expression of MicroRNA-122 and Cpt1alpha and affects lipid metabolism. J Lipid Res 51(6):1513–1523PubMedCrossRefGoogle Scholar
  31. 31.
    Rego RL, Foster NR, Smyrk TC, Le M, O’Connell MJ, Sargent DJ, Windschitl H, Sinicrope FA (2010) Prognostic effect of activated EGFR expression in human colon carcinomas: comparison with EGFR status. Br J Cancer 102:165–172PubMedCrossRefGoogle Scholar
  32. 32.
    Olaso E, Badiola I, Crende O, Friedman SL et al (2011) Discoidin domain receptor 2 deficiency predisposes hepatic tissue to colon carcinoma metastasis. Gut in pressGoogle Scholar
  33. 33.
    Agrawal D, Chen T, Irby R, Quackenbush J, Chambers AF, Szabo M, Cantor A, Coppola D, Yeatman TJ (2002) Osteopontin identified as lead marker of colon cancer progression, using pooled sample expression profiling. J Natl Cancer Inst 94(7):513–521PubMedGoogle Scholar
  34. 34.
    Fritzmann J, Morkel M, Besser D, Budczies J, Kosel F, Brembeck FH, Stein U, Fichtner I, Schlag PM, Birchmeier W (2009) Colorectal cancer expression profile that includes transforming growth factor beta inhibitor BAMBI predicts metastatic potential. Gastroenterology 137:165–175PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Goodman Cancer Research CentreMcGill UniversityMontrealCanada

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