Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression

Abstract

Tumors are like new organs and are made of multiple cell types and components. The tumor competes with the normal microenvironment to overcome antitumorigenic pressures. Before that battle is won, the tumor may exist within the organ unnoticed by the host, referred to as 'occult cancer'. We review how normal tissue homeostasis and architecture inhibit progression of cancer and how changes in the microenvironment can shift the balance of these signals to the procancerous state. We also include a discussion of how this information is being tailored for clinical use.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The normal tissue microenvironment acts as a barrier to tumorigenesis.

Marina Corral

Similar content being viewed by others

References

  1. Berenblum, I. Carcinogenesis as a Biological Problem (North-Holland, 1974).

    Google Scholar 

  2. Alberts, B. et al. Molecular Biology of the Cell 4th edn. (Garland Science, New York, 2002).

    Google Scholar 

  3. Folkman, J. & Kalluri, R. Cancer without disease. Nature 427, 787 (2004).

    Google Scholar 

  4. Rich, A.R. On the frequency of occurrence of occult carcinoma of the prostate. J. Urol. 33, 215–223 (1935).

    Google Scholar 

  5. Rich, A.R. On the frequency of occurrence of occult carcinoma of the prostrate. 1934. Int. J. Epidemiol. 36, 274–277 (2007).

    Google Scholar 

  6. Sakr, W.A., Haas, G.P., Cassin, B.F., Pontes, J.E. & Crissman, J.D. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J. Urol. 150, 379–385 (1993).

    Google Scholar 

  7. Nielsen, M., Thomsen, J.L., Primdahl, S., Dyreborg, U. & Andersen, J.A. Breast cancer and atypia among young and middle-aged women: a study of 110 medicolegal autopsies. Br. J. Cancer 56, 814–819 (1987).

    Google Scholar 

  8. Harach, H.R., Franssila, K.O. & Wasenius, V.M. Occult papillary carcinoma of the thyroid. A “normal” finding in Finland. A systematic autopsy study. Cancer 56, 531–538 (1985).

    Google Scholar 

  9. Manser, R.L., Dodd, M., Byrnes, G., Irving, L.B. & Campbell, D.A. Incidental lung cancers identified at coronial autopsy: implications for overdiagnosis of lung cancer by screening. Respir. Med. 99, 501–507 (2005).

    Google Scholar 

  10. Biernaux, C., Sels, A., Huez, G. & Stryckmans, P. Very low level of major BCR-ABL expression in blood of some healthy individuals. Bone Marrow Transplant. 3, S45–S47 (1996).

    Google Scholar 

  11. Hruban, R., Brune, K., Fukushima, N. & Maitra, A. Pancreatic intraepithelial neoplasia. in Pancreatic Cancer (eds. Lowy, A.M., Leach, S.D. and Philip, P.A.) (Springer, New York, New York, 2008).

    Google Scholar 

  12. Bose, S., Deininger, M., Gora-Tybor, J., Goldman, J.M. & Melo, J.V. The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease. Blood 92, 3362–3367 (1998).

    Google Scholar 

  13. Patel, J., Nemoto, T., Rosner, D., Dao, T.L. & Pickren, J.W. Axillary lymph node metastasis from an occult breast cancer. Cancer 47, 2923–2927 (1981).

    Google Scholar 

  14. Potter, J.D. Morphogens, morphostats, microarchitecture and malignancy. Nat. Rev. Cancer 7, 464–474 (2007).

    Google Scholar 

  15. Wessels, N.K. Extracellular materials and tissue interactions. in Tissue Interaction and Development (ed. Benjamin, W.A.) (Benjamin/Cummings Publishing, Menlo Park, California, 1977).

    Google Scholar 

  16. Ashkenas, J., Muschler, J. & Bissell, M. The extracellular matrix in epithelial biology: shared molecules and common themes in distant phyla. Dev. Biol. 180, 433 (1996).

    Google Scholar 

  17. Johnson, M.S., Lu, N., Denessiouk, K., Heino, J. & Gullberg, D. Integrins during evolution: evolutionary trees and model organisms. Biochim. Biophys. Acta 1788, 779–789 (2009).

    Google Scholar 

  18. Pott, P. Chirurgical observations relative to the cataract. Polypus of the Nose, the Cancer of the Scrotum, the Different Kinds of Ruptures and Mortification of the Toes and Feet. (L. Hawes, W. Clarke and R. Collins, London, 1775).

    Google Scholar 

  19. Berenblum, I. The cocarcinogenic action of croton resin. Cancer Res. 1, 44–48 (1941).

    Google Scholar 

  20. Berenblum, I. & Shubik, P. An experimental study of the initiating state of carcinogenesis and a re-examination of the somatic cell mutation theory of cancer. Br. J. Cancer 3, 109–118 (1949).

    Google Scholar 

  21. Slaga, T.J. Overview of tumor promotion in animals. Environ. Health Perspect. 50, 3–14 (1983).

    Google Scholar 

  22. Deelman, H.T. The part played by injury and repair in the development of cancer, with some remarks on the growth of experimental cancers. Proc. R. Soc. Med. 20, 1157–1158 (1927).

    Google Scholar 

  23. Friedewald, W.F. & Rous, P. The initiating and promoting elements in tumor production: an analysis of the effects of tar, benzpyrene and methylcholanthrene on rabbit skin. J. Exp. Med. 80, 101–126 (1944).

    Google Scholar 

  24. Berenblum, I. A speculative review; the probable nature of promoting action and its significance in the understanding of the mechanism of carcinogenesis. Cancer Res. 14, 471–477 (1954).

    Google Scholar 

  25. Dolberg, D.S., Hollingsworth, R., Hertle, M. & Bissell, M.J. Wounding and its role in RSV-mediated tumor formation. Science 230, 676–678 (1985).

    Google Scholar 

  26. Sieweke, M.H. & Bissell, M.J. The tumor-promoting effect of wounding: a possible role for TGF-β–induced stromal alterations. Crit. Rev. Oncog. 5, 297–311 (1994).

    Google Scholar 

  27. Martin, G.S. Rous sarcoma virus: a function required for the maintenance of the transformed state. Nature 227, 1021–1023 (1970).

    Google Scholar 

  28. Bissell, M.J., Hatie, C. & Calvin, M. Is the product of the src gene a promoter? Proc. Natl. Acad. Sci. USA 76, 348–352 (1979).

    Google Scholar 

  29. Duran-Reynals, F. A hemorrhagic disease occurring in chicks inoculated with the Rous and Fuginami viruses. Yale J. Biol. Med. 13, 77–98 (1940).

    Google Scholar 

  30. Rous, P. A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J. Exp. Med. 13, 397–411 (1911).

    Google Scholar 

  31. Dolberg, D.S. & Bissell, M.J. Inability of Rous sarcoma virus to cause sarcomas in the avian embryo. Nature 309, 552–556 (1984).

    Google Scholar 

  32. Stoker, A.W., Hatier, C. & Bissell, M.J. The embryonic environment strongly attenuates v-src oncogenesis in mesenchymal and epithelial tissues, but not in endothelia. J. Cell Biol. 111, 217–228 (1990).

    Google Scholar 

  33. Sieweke, M.H., Thompson, N.L., Sporn, M.B. & Bissell, M.J. Mediation of wound-related Rous sarcoma virus tumorigenesis by TGF-β. Science 248, 1656–1660 (1990).

    Google Scholar 

  34. Pierce, G.B., Stevens, L.C. & Nakane, P.K. Ultrastructural analysis of the early development of teratocarcinomas. J. Natl. Cancer Inst. 39, 755–773 (1967).

    Google Scholar 

  35. Pierce, G.B. Teratocarcinoma: model for a developmental concept of cancer. Curr. Top. Dev. Biol. 2, 223–246 (1967).

    Google Scholar 

  36. Stevens, L.C. The development of transplantable teratocarcinomas from intratesticular grafts of pre- and postimplantation mouse embryos. Dev. Biol. 21, 364–382 (1970).

    Google Scholar 

  37. Stevens, L.C. The biology of teratomas. Adv. Morphog. 6, 1–31 (1967).

    Google Scholar 

  38. Brinster, R.L. The effect of cells transferred into the mouse blastocyst on subsequent development. J. Exp. Med. 140, 1049–1056 (1974).

    Google Scholar 

  39. Mintz, B. & Illmensee, K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc. Natl. Acad. Sci. USA 72, 3585–3589 (1975).

    Google Scholar 

  40. Illmensee, K. & Mintz, B. Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts. Proc. Natl. Acad. Sci. USA 73, 549–553 (1976).

    Google Scholar 

  41. Hochedlinger, K. et al. Reprogramming of a melanoma genome by nuclear transplantation. Genes Dev. 18, 1875–1885 (2004).

    Google Scholar 

  42. Fujii, H., Cunha, G.R. & Norman, J.T. The induction of adenocarcinomatous differentiation in neoplastic bladder epithelium by an embryonic prostatic inductor. J. Urol. 128, 858–861 (1982).

    Google Scholar 

  43. Hayashi, N., Cunha, G.R. & Wong, Y.C. Influence of male genital tract mesenchymes on differentiation of Dunning prostatic adenocarcinoma. Cancer Res. 50, 4747–4754 (1990).

    Google Scholar 

  44. Petersen, O.W., Ronnov-Jessen, L., Howlett, A.R. & Bissell, M.J. Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. Proc. Natl. Acad. Sci. USA 89, 9064–9068 (1992).

    Google Scholar 

  45. Howlett, A.R., Petersen, O.W., Steeg, P.S. & Bissell, M.J. A novel function for the nm23–H1 gene: overexpression in human breast carcinoma cells leads to the formation of basement membrane and growth arrest. J. Natl. Cancer Inst. 86, 1838–1844 (1994).

    Google Scholar 

  46. Weaver, V.M. et al. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J. Cell Biol. 137, 231–245 (1997).

    Google Scholar 

  47. Weaver, V.M., Howlett, A.R., Langton-Webster, B., Petersen, O.W. & Bissell, M.J. The development of a functionally relevant cell culture model of progressive human breast cancer. Semin. Cancer Biol. 6, 175–184 (1995).

    Google Scholar 

  48. Rizki, A. et al. A human breast cell model of preinvasive to invasive transition. Cancer Res. 68, 1378–1387 (2008).

    Google Scholar 

  49. Hendrix, M.J. et al. Reprogramming metastatic tumour cells with embryonic microenvironments. Nat. Rev. Cancer 7, 246–255 (2007).

    Google Scholar 

  50. Postovit, L.M., Seftor, E.A., Seftor, R.E. & Hendrix, M.J. A three-dimensional model to study the epigenetic effects induced by the microenvironment of human embryonic stem cells. Stem Cells 24, 501–505 (2006).

    Google Scholar 

  51. Bussard, K.M., Boulanger, C.A., Booth, B.W., Bruno, R.D. & Smith, G.H. Reprogramming human cancer cells in the mouse mammary gland. Cancer Res. 70, 6336–6343 (2010).

    Google Scholar 

  52. Maher, J.J. & Bissell, D.M. Cell-matrix interactions in liver. Semin. Cell Biol. 4, 189–201 (1993).

    Google Scholar 

  53. Wolfe, J.N. Risk for breast cancer development determined by mammographic parenchymal pattern. Cancer 37, 2486–2492 (1976).

    Google Scholar 

  54. Boyd, N.F. et al. Mammographic density and the risk and detection of breast cancer. N. Engl. J. Med. 356, 227–236 (2007).

    Google Scholar 

  55. Sickles, E.A. Wolfe mammographic parenchymal patterns and breast cancer risk. AJR Am. J. Roentgenol. 188, 301–303 (2007).

    Google Scholar 

  56. Chin, K. et al. In situ analyses of genome instability in breast cancer. Nat. Genet. 36, 984–988 (2004).

    Google Scholar 

  57. Gudjonsson, T. et al. Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition. J. Cell Sci. 115, 39–50 (2002).

    Google Scholar 

  58. Beliveau, A. et al. Raf-induced MMP9 disrupts tissue architecture of human breast cells in three-dimensional culture and is necessary for tumor growth in vivo. Genes Dev. 24, 2800–2811 (2010).

    Google Scholar 

  59. Joyce, J.A. & Pollard, J.W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 9, 239–252 (2009).

    Google Scholar 

  60. Qian, B.Z. & Pollard, J.W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).

    Google Scholar 

  61. Mueller, M.M. & Fusenig, N.E. Friends or foes—bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer 4, 839–849 (2004).

    Google Scholar 

  62. Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 6, 392–401 (2006).

    Google Scholar 

  63. Bhowmick, N.A., Neilson, E.G. & Moses, H.L. Stromal fibroblasts in cancer initiation and progression. Nature 432, 332–337 (2004).

    Google Scholar 

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

    Google Scholar 

  65. Sympson, C.J., Bissell, M.J. & Werb, Z. Mammary gland tumor formation in transgenic mice overexpressing stromelysin-1. Semin. Cancer Biol. 6, 159–163 (1995).

    Google Scholar 

  66. Thomasset, N. et al. Expression of autoactivated stromelysin-1 in mammary glands of transgenic mice leads to a reactive stroma during early development. Am. J. Pathol. 153, 457–467 (1998).

    Google Scholar 

  67. Sternlicht, M.D. et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 98, 137–146 (1999).

    Google Scholar 

  68. Radisky, D.C. et al. Rac1b and reactive oxygen species mediate MMP-3–induced EMT and genomic instability. Nature 436, 123–127 (2005).

    Google Scholar 

  69. Bhowmick, N.A. et al. TGF-β signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303, 848–851 (2004).

    Google Scholar 

  70. Schor, S.L., Schor, A.M., Rushton, G. & Smith, L. Adult, foetal and transformed fibroblasts display different migratory phenotypes on collagen gels: evidence for an isoformic transition during foetal development. J. Cell Sci. 73, 221–234 (1985).

    Google Scholar 

  71. Schor, S.L., Schor, A.M., Durning, P. & Rushton, G. Skin fibroblasts obtained from cancer patients display foetal-like migratory behaviour on collagen gels. J. Cell Sci. 73, 235–244 (1985).

    Google Scholar 

  72. Schor, S.L., Schor, A.M. & Rushton, G. Fibroblasts from cancer patients display a mixture of both foetal and adult-like phenotypic characteristics. J. Cell Sci. 90, 401–407 (1988).

    Google Scholar 

  73. Schor, S.L. et al. Migration-stimulating factor: a genetically truncated onco-fetal fibronectin isoform expressed by carcinoma and tumor-associated stromal cells. Cancer Res. 63, 8827–8836 (2003).

    Google Scholar 

  74. Camps, J.L. et al. Fibroblast-mediated acceleration of human epithelial tumor growth in vivo. Proc. Natl. Acad. Sci. USA 87, 75–79 (1990).

    Google Scholar 

  75. Olumi, A.F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).

    Google Scholar 

  76. Barcellos-Hoff, M.H. & Ravani, S.A. Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res. 60, 1254–1260 (2000).

    Google Scholar 

  77. Krtolica, A., Parrinello, S., Lockett, S., Desprez, P.Y. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl. Acad. Sci. USA 98, 12072–12077 (2001).

    Google Scholar 

  78. Rønnov-Jessen, L. & Petersen, O.W. Induction of a-smooth muscle actin by transforming growth factor-β1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab. Invest. 68, 696–707 (1993).

    Google Scholar 

  79. Rønnov-Jessen, L., Petersen, O.W. & Bissell, M.J. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol. Rev. 76, 69–125 (1996).

    Google Scholar 

  80. Rønnov-Jessen, L., Petersen, O.W., Koteliansky, V.E. & Bissell, M.J. The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J. Clin. Invest. 95, 859–873 (1995).

    Google Scholar 

  81. Chang, H.Y. et al. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol. 2, E7 (2004).

    Google Scholar 

  82. Chang, H.Y. et al. Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc. Natl. Acad. Sci. USA 102, 3738–3743 (2005).

    Google Scholar 

  83. Finak, G. et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat. Med. 14, 518–527 (2008).

    Google Scholar 

  84. Toullec, A. et al. Oxidative stress promotes myofibroblast differentiation and tumour spreading. EMBO Mol. Med. 2, 211–230 (2010).

    Google Scholar 

  85. Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005).

    Google Scholar 

  86. Pollard, J.W. Macrophages define the invasive microenvironment in breast cancer. J. Leukoc. Biol. 84, 623–630 (2008).

    Google Scholar 

  87. Bissell, M.J. & Radisky, D. Putting tumours in context. Nat. Rev. Cancer 1, 46–54 (2001).

    Google Scholar 

  88. Pierce, G.B. & Speers, W.C. Tumors as caricatures of the process of tissue renewal: prospects for therapy by directing differentiation. Cancer Res. 48, 1996–2004 (1988).

    Google Scholar 

  89. Pierce, G.B. Relationship between differentiation and carcinogenesis. J. Toxicol. Environ. Health 2, 1335–1342 (1977).

    Google Scholar 

  90. Kenny, P.A., Lee, G.Y. & Bissell, M.J. Targeting the tumor microenvironment. Front. Biosci. 12, 3468–3474 (2007).

    Google Scholar 

  91. Dvorak, H.F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    Google Scholar 

  92. Kraman, M. et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-a. Science 330, 827–830 (2010).

    Google Scholar 

  93. Cecchini, M.G. et al. Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. Development 120, 1357–1372 (1994).

    Google Scholar 

  94. Saadi, A. et al. Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers. Proc. Natl. Acad. Sci. USA 107, 2177–2182 (2010).

    Google Scholar 

  95. Farmer, P. et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat. Med. 15, 68–74 (2009).

    Google Scholar 

  96. Koleske, A.J., Baltimore, D. & Lisanti, M.P. Reduction of caveolin and caveolae in oncogenically transformed cells. Proc. Natl. Acad. Sci. USA 92, 1381–1385 (1995).

    Google Scholar 

  97. Williams, T.M. et al. Stromal and epithelial caveolin-1 both confer a protective effect against mammary hyperplasia and tumorigenesis: caveolin-1 antagonizes cyclin D1 function in mammary epithelial cells. Am. J. Pathol. 169, 1784–1801 (2006).

    Google Scholar 

  98. Witkiewicz, A.K. et al. An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers. Am. J. Pathol. 174, 2023–2034 (2009).

    Google Scholar 

  99. Sloan, E.K. et al. Stromal cell expression of caveolin-1 predicts outcome in breast cancer. Am. J. Pathol. 174, 2035–2043 (2009).

    Google Scholar 

  100. Paulsson, J. et al. Prognostic significance of stromal platelet-derived growth factor b receptor expression in human breast cancer. Am. J. Pathol. 175, 334–341 (2009).

    Google Scholar 

  101. Barry-Hamilton, V. et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat. Med. 16, 1009–1017 (2010).

    Google Scholar 

  102. Balis, F.M. Evolution of anticancer drug discovery and the role of cell-based screening. J. Natl. Cancer Inst. 94, 78–79 (2002).

    Google Scholar 

  103. Colozza, M. et al. Achievements in systemic therapies in the pregenomic era in metastatic breast cancer. Oncologist 12, 253–270 (2007).

    Google Scholar 

  104. Anders, M. et al. Disruption of three-dimensional tissue integrity facilitates adenovirus infection by deregulating the coxsackievirus and adenovirus receptor. Proc. Natl. Acad. Sci. USA 100, 1943–1948 (2003).

    Google Scholar 

  105. Whiteside, T.L. The tumor microenvironment and its role in promoting tumor growth. Oncogene 27, 5904–5912 (2008).

    Google Scholar 

  106. Coussens, L.M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    Google Scholar 

  107. Weaver, V.M. et al. β4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. Cancer Cell 2, 205–216 (2002).

    Google Scholar 

  108. Weigelt, B., Lo, A.T., Park, C.C., Gray, J.W. & Bissell, M.J. HER2 signaling pathway activation and response of breast cancer cells to HER2-targeting agents is dependent strongly on the 3D microenvironment. Breast Cancer Res. Treat. 122, 35–43 (2010).

    Google Scholar 

  109. Polo, M.L. et al. Responsiveness to PI3K and MEK inhibitors in breast cancer. Use of a 3D culture system to study pathways related to hormone independence in mice. PLoS ONE 5, e10786 (2010).

    Google Scholar 

  110. Wang, F. et al. Phenotypic reversion or death of cancer cells by altering signaling pathways in three-dimensional contexts. J. Natl. Cancer Inst. 94, 1494–1503 (2002).

    Google Scholar 

  111. Muthuswamy, S.K., Li, D., Lelievre, S., Bissell, M.J. & Brugge, J.S. ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini. Nat. Cell Biol. 3, 785–792 (2001).

    Google Scholar 

  112. Park, C.C. et al. β1 integrin inhibitory antibody induces apoptosis of breast cancer cells, inhibits growth, and distinguishes malignant from normal phenotype in three dimensional cultures and in vivo. Cancer Res. 66, 1526–1535 (2006).

    Google Scholar 

  113. Park, C.C., Zhang, H.J., Yao, E.S., Park, C.J. & Bissell, M.J. β1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts. Cancer Res. 68, 4398–4405 (2008).

    Google Scholar 

  114. Olive, K.P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).

    Google Scholar 

  115. Thompson, C.B. et al. Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical animal models. Mol. Cancer Ther. 9, 3052–3064 (2010).

    Google Scholar 

  116. Levental, K.R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

    Google Scholar 

  117. Xu, R. et al. Sustained activation of STAT5 is essential for chromatin remodeling and maintenance of mammary-specific function. J. Cell Biol. 184, 57–66 (2009).

    Google Scholar 

  118. Bissell, M.J., Kenny, P.A. & Radisky, D.C. Microenvironmental regulators of tissue structure and function also regulate tumor induction and progression: the role of extracellular matrix and its degrading enzymes. Cold Spring Harb. Symp. Quant. Biol. 70, 343–356 (2005).

    Google Scholar 

  119. McMillin, D.W. et al. Tumor cell–specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity. Nat. Med. 16, 483–489 (2010).

    Google Scholar 

  120. Chen, A. et al. Endothelial cell migration and vascular endothelial growth factor expression are the result of loss of breast tissue polarity. Cancer Res. 69, 6721–6729 (2009).

    Google Scholar 

  121. Kaplan, R.N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    Google Scholar 

  122. Peinado, H., Lavothskin, S. & Lyden, D. The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin. Cancer. Biol. published online, doi:10.1016/j.semcancer.2011.01.002 (18 January 2011).

  123. Nelson, C.M. & Bissell, M.J. Of extracellular matrix, scaffolds and signaling: tissue architecture regulates development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol. 22, 287–309 (2006).

    Google Scholar 

  124. Paget, S. The distribution of secondary growths in cancer of the breast. Lancet 1, 571–573 (1889).

    Google Scholar 

  125. O'Reilly, M.S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285 (1997).

    Google Scholar 

  126. Ferrara, N., Hillan, K.J., Gerber, H.P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat. Rev. Drug Discov. 3, 391–400 (2004).

    Google Scholar 

  127. Kupsch, P. et al. Results of a phase I trial of sorafenib (BAY 43–9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer. Clin. Colorectal Cancer 5, 188–196 (2005).

    Google Scholar 

  128. Pan, B.S. et al. MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 70, 1524–1533 (2010).

    Google Scholar 

  129. Wolf, A.M. et al. The effect of zoledronic acid on the function and differentiation of myeloid cells. Haematologica 91, 1165–1171 (2006).

    Google Scholar 

  130. Veltman, J.D. et al. Zoledronic acid impairs myeloid differentiation to tumour-associated macrophages in mesothelioma. Br. J. Cancer 103, 629–641 (2010).

    Google Scholar 

  131. Teitelbaum, S.L. Bone resorption by osteoclasts. Science 289, 1504–1508 (2000).

    Google Scholar 

  132. Theoleyre, S. et al. The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev. 15, 457–475 (2004).

    Google Scholar 

  133. Burger, J.A. & Peled, A. CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. Leukemia 23, 43–52 (2009).

    Google Scholar 

  134. Fingleton, B. MMPs as therapeutic targets—still a viable option? Semin. Cell Dev. Biol. 19, 61–68 (2008).

    Google Scholar 

  135. Palermo, C. & Joyce, J.A. Cysteine cathepsin proteases as pharmacological targets in cancer. Trends Pharmacol. Sci. 29, 22–28 (2008).

    Google Scholar 

  136. Bell-McGuinn, K.M., Garfall, A.L., Bogyo, M., Hanahan, D. & Joyce, J.A. Inhibition of cysteine cathepsin protease activity enhances chemotherapy regimens by decreasing tumor growth and invasiveness in a mouse model of multistage cancer. Cancer Res. 67, 7378–7385 (2007).

    Google Scholar 

  137. Demaria, S. et al. Cancer and inflammation: promise for biologic therapy. J. Immunother. 33, 335–351 (2010).

    Google Scholar 

  138. Qiang, Y.W., Yao, L., Tosato, G. & Rudikoff, S. Insulin-like growth factor I induces migration and invasion of human multiple myeloma cells. Blood 103, 301–308 (2004).

    Google Scholar 

  139. Hideshima, T., Mitsiades, C., Tonon, G., Richardson, P.G. & Anderson, K.C. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat. Rev. Cancer 7, 585–598 (2007).

    Google Scholar 

  140. Rajkumar, S.V., Richardson, P.G., Hideshima, T. & Anderson, K.C. Proteasome inhibition as a novel therapeutic target in human cancer. J. Clin. Oncol. 23, 630–639 (2005).

    Google Scholar 

Download references

Acknowledgements

We thank C. Ghajar for considerable help for the background materials and him, J. Mott and I. Kuhn for critical reading of the manuscript. We also thank K. Andersen, D. Lyden, S. Rafii, M. de Sousa and M.H. Barcellos-Hoff for referring us to clinically related articles qualifying as 'microenvironmental therapy'. We thank M. Bisoffi for providing the full-text versions of articles on the occult tumors in the prostate and E. Collisson for directing us to references on occult tumors of the pancreas. The work from M.J.B.'s laboratory is supported by grants from the US Department of Energy, Office of Biological and Environmental Research and Low Dose Radiation Program (contract no. DE-AC02-05CH1123), by the US National Cancer Institute (awards R37CA064786, U54CA126552, R01CA057621, U54CA112970, U01CA143233 and U54CA143836—Bay Area Physical Sciences–Oncology Center, University of California–Berkeley) and by the US Department of Defense (W81XWH0810736).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mina J Bissell.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Table 1 (PDF 184 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bissell, M., Hines, W. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med 17, 320–329 (2011). https://doi.org/10.1038/nm.2328

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2328

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer