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A microenvironmental model of carcinogenesis

Nature Reviews Cancer volume 8, pages 56–61 (2008)Cite this article

Abstract

We propose that carcinogenesis requires tumour populations to surmount six distinct microenvironmental proliferation barriers that arise in the adaptive landscapes of normal and premalignant populations growing from epithelial surfaces. Somatic evolution of invasive cancer can then be viewed as a sequence of phenotypical adaptations to these barriers. The genotypical and phenotypical heterogeneity of cancer populations is explained by an equivalence principle in which multiple strategies can successfully adapt to the same barrier. This model provides a theoretical framework in which the diverse cancer genotypes and phenotypes can be understood according to their roles as adaptive strategies to overcome specific microenvironmental growth constraints.

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Figure 1: Cartoons of the three distinctive adaptive landscapes during evolution of invasive cancer.
Figure 2: Proposed barriers to carcinogenesis based on the adaptive landscapes in Figure 1.

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References

  1. Garcia, S. B., Novelli, M. & Wright, N. A. The clonal origin and clonal evolution of epithelial tumors. Int. J. Exp. Path. 81, 89–116 (2000).

    Article  CAS  Google Scholar 

  2. Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976).

    Article  CAS  Google Scholar 

  3. Ilyas, M., Straub, J., Tomlinson, I. P. M. & Bodmer, W. F. Genetic pathways in colorectal and other cancers. Eur. J. Cancer 35, 335–351 (1999).

    Article  CAS  Google Scholar 

  4. Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    Article  CAS  Google Scholar 

  5. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    CAS  Google Scholar 

  6. Gatenby, R. A. & Gillies, R. J. Why do cancers have high aerobic glycolysis? Nature Rev. Cancer 4, 891–899 (2004).

    Article  CAS  Google Scholar 

  7. Gatenby, R. A. & Vincent, T. L. An evolutionary model of carcinogenesis. Cancer Res. 63, 6212–6220 (2003).

    CAS  PubMed  Google Scholar 

  8. Gatenby, R. A., Vincent, T. & Gillies, R. Evolutionary dynamics in carcinogenesis. Math. Models Methods Appl. Sci. 15, 1–20 (2005).

    Article  Google Scholar 

  9. Vincent, T. L. & Gatenby, R. A. Modeling cancer as an evolutionary game. Int. Game Theor. Rev. 7, 331–346 (2005).

    Article  Google Scholar 

  10. Gatenby, R. et al. Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer. Br. J. Cancer 97, 646–653 (2007).

    Article  CAS  Google Scholar 

  11. Isakoff, S. J. et al. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res. 65, 10992–11000 (2005).

    Article  CAS  Google Scholar 

  12. Derksen, P. W. B. et al. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell 10, 437–449 (2006).

    Article  CAS  Google Scholar 

  13. Eckert, L. B. et al. Involvement of Ras activation in human breast cancer cell signaling, invasion, and anoikis. Cancer Res. 64, 4585–4592 (2004).

    Article  CAS  Google Scholar 

  14. Ishida, H. et al. Critical role of estrogen receptor on anoikis and invasion of squamous cell carcinoma. Cancer Sci. 98, 636–643 (2007).

    Article  CAS  Google Scholar 

  15. Carroll, D. K. et al. p63 regulates an adhesion program and cell survival in epithelial cells. Nature Cell Biol. 8, 551–560 (2006).

    Article  CAS  Google Scholar 

  16. Hofmann, C. et al. Cell–cell contacts prevent anoikis in primary human colonic epithelial cells. Gastroenterology 132, 587–600 (2007).

    Article  CAS  Google Scholar 

  17. Sporn, M. B. & Roberts, A. B. Autocrine growth factors and cancer. Nature 313, 745–747 (1985).

    Article  CAS  Google Scholar 

  18. Arteag, C. L. Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist 4, 31–39 (2002).

    Article  Google Scholar 

  19. Cantley, L. C. et al. Oncogenes and signal transduction. Cell 64, 281–302 (1991).

    Article  CAS  Google Scholar 

  20. Sarkisian, C. J. et al. Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nature Cell Biol. 9, 493–505 (2007).

    Article  CAS  Google Scholar 

  21. Smallbone, K., Gatenby, R. A., Gillies, R., Maini, P. & Gavaghan, D. Metabolic changes during carcinogenesis: potential impact on invasiveness. J. Theor. Biol. 244, 703–713 (2007).

    Article  CAS  Google Scholar 

  22. Rubin, H. Multistage carcinogenesis in cell culture. Dev. Biol. 106, 61–66 (2001).

    CAS  Google Scholar 

  23. Burger, A. M. et al. Effect of oncogene expression on telomerase activation and telomere length in human endothelial, fibroblast and prostate epithelial cells. Int. J. Oncol. 19, 1043–1048 (1998).

    Google Scholar 

  24. Robey, I. F., Lien, A. D., Welsh, S. J., Baggett, B. K. & Gillies, R. J. Hypoxia-inducible factor-1α and the glycolytic phenotype in tumors. Neoplasia 7, 324–330 (2005).

    Article  CAS  Google Scholar 

  25. Gillies, R. J. & Gatenby, R. A. Hypoxia and adaptive landscapes in the evolution of carcinogenesis. Cancer Metastasis Rev. 26, 311–317 (2007).

    Article  CAS  Google Scholar 

  26. Park, H. J., Lyons, J. C., Ohtsubo, T. & Song, C. W. Acidic environment causes apoptosis by increasing caspase activity. Br. J. Cancer 80, 1892–1897 (1999).

    Article  CAS  Google Scholar 

  27. Gatenby, R. A. & Gawlinski, E. T. A reaction-diffuse model of acid-mediated invasion of normal tissue by neoplastic tissue. Cancer Res. 56, 5745–5753 (1996).

    CAS  PubMed  Google Scholar 

  28. Rohzin, J., Sameni, M., Ziegler, G. & Sloane, B. F. Pericellular pH affects distribution and secretion of cathepsin B in malignant cells. Cancer Res. 54, 6517–6525 (1994).

    Google Scholar 

  29. Abbey, C. K. et al. In vivo PET imaging of progression of transformation in a mouse model of mammary neoplasia. Proc. Natl Acad. Sci. USA 101, 11438–11443 (2005).

    Article  Google Scholar 

  30. Yasuda, S. et al. 18F-FDG PET detection of colonic adenomas. J. Nucl. Med. 42, 989–992 (2001).

    CAS  PubMed  Google Scholar 

  31. Younes, M., Ertan, A., Lechago, L. V., Somoano, J. & Lechago, J. Human erythrocyte glucose transporter (Glut1) is immunohistochemically detected as a late event during malignant progression in Barrett's metaplasia. Cancer Epidemiol. Biomarkers Prev. 6, 303–305 (1997).

    CAS  PubMed  Google Scholar 

  32. Folkman, J. Role of angiogenesis in tumor growth and metastasis. Semin. Oncol. 29, 15–18 (2002).

    Article  CAS  Google Scholar 

  33. Naumov, G. N. et al. A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J. Natl Cancer Inst. 98, 316–325 (2006).

    Article  Google Scholar 

  34. Giuriato, S. et al. Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch. Proc. Natl Acad. Sci. USA 103, 16266–16271 (2006).

    Article  CAS  Google Scholar 

  35. Gatenby, R. A. et al. Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res. 66, 5216–5223 (2006).

    Article  CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. Robert A. Gatenby and Robert J. Gillies are at the Department of Radiology, University of Arizona, 1501 N Campbell Avenue, Tucson, Arizona 85724, USA.,

    Robert A. Gatenby & Robert J. Gillies

  2. Robert A. Gatenby is also at the Department of Applied Mathematics, University of Arizona, 1041 East Lowell Street, Tucson, Arizona 857721, USA.,

    Robert A. Gatenby

  3. Robert J. Gillies is also at the Department of Biochemistry & Molecular Biophysics, University of Arizona, 617 N Santa Rita Avenue, Tucson, Arizona 85721, USA.,

    Robert J. Gillies

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  1. Robert A. Gatenby
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  2. Robert J. Gillies
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Correspondence to Robert A. Gatenby or Robert J. Gillies.

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Gatenby, R., Gillies, R. A microenvironmental model of carcinogenesis. Nat Rev Cancer 8, 56–61 (2008). https://doi.org/10.1038/nrc2255

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