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.

  • Opinion
  • Published:

The tumour microenvironment as a target for chemoprevention

Abstract

New data indicate that primary dysfunction in the tumour microenvironment, in addition to epithelial dysfunction, can be crucial for carcinogenesis. These recent findings make a compelling case for targeting the microenvironment for cancer chemoprevention. We review new insights into the pathophysiology of the microenvironment and new approaches to control it with chemopreventive agents. The microenvironment of a cancer is an integral part of its anatomy and physiology, and functionally, one cannot totally dissociate this microenvironment from what have traditionally been called 'cancer cells'. Finally, we make suggestions for more effective clinical implementation of this knowledge in preventive strategies.

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

Access options

Buy this article

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

Figure 1: Correlations and contrasts between acute inflammation and carcinogenesis.
Figure 2: Angioprevention as a strategy for chemoprevention.
Figure 3: Molecular targets for chemoprevention of angiogenesis (angioprevention).

Similar content being viewed by others

References

  1. Farber, E. & Rubin, H. Cellular adaptation in the origin and development of cancer. Cancer Res. 51, 2751–2761 (1991).

    CAS  PubMed  Google Scholar 

  2. Clark, W. H. Jr. The nature of cancer: morphogenesis and progressive (self)-disorganization in neoplastic development and progression. Acta Oncol. 34, 3–21 (1995).

    Article  PubMed  Google Scholar 

  3. Sporn, M. B. The war on cancer. Lancet 347, 1377–1381 (1996).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Joyce, J. A. Therapeutic targeting of the tumor microenvironment. Cancer Cell 7, 513–520 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Bissell, M. J. & Labarge, M. A. Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment? Cancer Cell 7, 17–23 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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, 1–14 (2005).

    Article  Google Scholar 

  9. Huang, S. & Ingber, D. E. A non-genetic basis for tumorigenesis and metastatic progression: self-organizing attractors in cell regulatory networks. Breast Dis. (in the press).

  10. Kumar, V., Abbas, A. K. & Fausto, N. Robbins and Cotran Pathologic Basis of Disease, 7th Edition 47–118 (Elsevier Saunders, Philadelphia, 2005).

    Google Scholar 

  11. Dvorak, H. F. Angiogenesis: update 2005. J. Thromb. Haemost. 3, 1835–1842 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Albini, A., Tosetti, F., Benelli, R. & Noonan, D. M. Tumor inflammatory angiogenesis and its chemoprevention. Cancer Res. 65, 10637–10641 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Maruotti, N., Cantatore, F. P., Crivellato, E., Vacca, A. & Ribatti, D. Angiogenesis in rheumatoid arthritis. Histol. Histopathol. 21, 557–566 (2006).

    CAS  PubMed  Google Scholar 

  14. Karin, M. Inflammation and cancer: the long reach of Ras. Nature Med. 11, 20–21 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Sparmann, A. & Bar-Sagi, D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6, 447–458 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Balkwill, F., Charles, K. A. & Mantovani, A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7, 211–217 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Lewis, C. E. & Pollard, J. W. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 66, 605–612 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Zhu, P. et al. Macrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway. Cell 124, 615–629 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Benelli, R., Albini, A. & Noonan, D. in The neutrophil: An emerging regulator of inflammatory and immune response (ed. M. A. Cassatella) 167–181 (Karger, Basel, 2003).

    Book  Google Scholar 

  20. Benelli, R. et al. Neutrophils as a key cellular target for angiostatin: implications for regulation of angiogenesis and inflammation. FASEB J. 16, 267–269 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Scapini, P. et al. CXCL1/macrophage inflammatory protein-2-induced angiogenesis in vivo is mediated by neutrophil-derived vascular endothelial growth factor-A1. J. Immunol. 172, 5034–5040 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. 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).

    Article  CAS  PubMed  Google Scholar 

  24. Powell, D. W. et al. Myofibroblasts. I. Paracrine cells important in health and disease. Am. J. Physiol. 277, C1–C9 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Shao, J., Sheng, G. G., Mifflin, R. C., Powell, D. W. & Sheng, H. Roles of myofibroblasts in prostaglandin E2-stimulated intestinal epithelial proliferation and angiogenesis. Cancer Res. 66, 846–855 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Calle, E. E., Rodriguez, C., Walker-Thurmond, K. & Thun, M. J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U. S. adults. N. Engl. J. Med. 348, 1625–1638 (2003).

    Article  PubMed  Google Scholar 

  27. Calle, E. E. & Thun, M. J. Obesity and cancer. Oncogene 23, 6365–6378 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Wellen, K. E. & Hotamisligil, G. S. Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111–1119 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Comoglio, P. M. & Trusolino, L. Cancer: the matrix is now in control. Nature Med. 11, 1156–1159 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Grobstein, C. Inductive tissue interaction in development. Adv. Cancer Res. 4, 187–236 (1956).

    Article  CAS  PubMed  Google Scholar 

  31. Wiseman, B. S. & Werb, Z. Stromal effects on mammary gland development and breast cancer. Science 296, 1046–1049 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Allinen, M. et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6, 17–32 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Ishiguro, K., Yoshida, T., Yagishita, H., Numata, Y. & Okayasu, T. Epithelial and stromal genetic instability contributes to genesis of colorectal adenomas. Gut 55, 695–702 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Weber, F. et al. Total-genome analysis of BRCA1/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. Am. J. Hum. Genet. 78, 961–972 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Streubel, B. et al. Lymphoma-specific genetic aberrations in microvascular endothelial cells in B-cell lymphomas. N. Engl. J. Med. 351, 250–259 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Hida, K. & Klagsbrun, M. A new perspective on tumor endothelial cells: unexpected chromosome and centrosome abnormalities. Cancer Res. 65, 2507–2510 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Kim, B. G. et al. Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 441, 1015–1019 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Bindra, R. S. & Glazer, P. M. Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis. Mutat. Res. 569, 75–85 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Kelloff, G. J., Hawk, E. T. & Sigman, C. C., eds. Cancer chemoprevention: strategies for cancer chemoprevention (Humana Press, Totowa, NJ, 2005).

    Book  Google Scholar 

  40. Lippman, S. M. & Lee, J. J. Reducing the 'risk' of chemoprevention: defining and targeting high risk —2005 AACR Cancer Research and Prevention Foundation Award Lecture. Cancer Res. 66, 2893–2903 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. De Flora, S. & Ferguson, L. R. Overview of mechanisms of cancer chemopreventive agents. Mutat. Res. 591, 8–15 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Sporn, M. B. & Liby, K. T. Cancer chemoprevention: scientific promise, clinical uncertainty. Nature Clin. Pract. Oncol. 2, 518–525 (2005).

    Article  CAS  Google Scholar 

  43. Kelloff, G. J. et al. Progress in chemoprevention drug development: the promise of molecular biomarkers for prevention of intraepithelial neoplasia and cancer — a plan to move forward. Clin. Cancer Res. 12, 3661–3697 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Balkwill, F. Cancer and the chemokine network. Nature Rev. Cancer 4, 540–550 (2004).

    Article  CAS  Google Scholar 

  46. Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Karin, M. & Greten, F. R. NFκB: linking inflammation and immunity to cancer development and progression. Nature Rev. Immunol. 5, 749–759 (2005).

    Article  CAS  Google Scholar 

  48. Mann, J. R., Backlund, M. G. & DuBois, R. N. Mechanisms of disease: inflammatory mediators and cancer prevention. Nature Clin. Pract. Oncol. 2, 202–210 (2005).

    Article  CAS  Google Scholar 

  49. Suh, N. et al. Synthetic triterpenoids enhance transforming growth factor β/Smad signaling. Cancer Res. 63, 1371–1376 (2003).

    CAS  PubMed  Google Scholar 

  50. Yu, H. & Jove, R. The STATs of cancer--new molecular targets come of age. Nature Rev. Cancer 4, 97–105 (2004).

    Article  CAS  Google Scholar 

  51. Liby, K. et al. The synthetic triterpenoid CDDO-Imidazolide suppresses STAT phosphorylation and induces apoptosis in myeloma and lung cancer cells. Clin. Cancer Res. 12, 4288–4293 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Dauer, D. J. et al. Stat3 regulates genes common to both wound healing and cancer. Oncogene 24, 3397–3408 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Palumbo, J. S. et al. Spontaneous hematogenous and lymphatic metastasis, but not primary tumor growth or angiogenesis, is diminished in fibrinogen-deficient mice. Cancer Res. 62, 6966–6972 (2002).

    CAS  PubMed  Google Scholar 

  54. Karin, M. NFκB and cancer: mechanisms and targets. Mol. Carcinog. 45, 355–361 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Aggarwal, S. et al. Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IκBα kinase and Akt activation. Mol. Pharmacol. 69, 195–206 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Pfeffer, U. et al. Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression analyses. Mutat. Res. 591, 198–211 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Singh, R. P., Dhanalakshmi, S., Agarwal, C. & Agarwal, R. Silibinin strongly inhibits growth and survival of human endothelial cells via cell cycle arrest and downregulation of survivin, Akt and NFκB: implications for angioprevention and antiangiogenic therapy. Oncogene 24, 1188–1202 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Albini, A. et al. Mechanisms of the antiangiogenic activity by the hop flavonoid xanthohumol: NFκB and Akt as targets. FASEB J. 20, 527–529 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Dell'eva, R. et al. The Akt inhibitor deguelin, is an angiopreventive agent also acting on the NFκB pathway. Carcinogenesis 4 September 2006 [epub ahead of print].

    Google Scholar 

  60. Bertl, E., Bartsch, H. & Gerhauser, C. Inhibition of angiogenesis and endothelial cell functions are novel sulforaphane-mediated mechanisms in chemoprevention. Mol. Cancer Ther. 5, 575–585 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Xu, C., Shen, G., Chen, C., Gelinas, C. & Kong, A. N. Suppression of NF-κB and NF-κB-regulated gene expression by sulforaphane and PEITC through IκBα, IKK pathway in human prostate cancer PC-3 cells. Oncogene 24, 4486–4495 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Huang, S., DeGuzman, A., Bucana, C. D. & Fidler, I. J. Nuclear factor-κB activity correlates with growth, angiogenesis, and metastasis of human melanoma cells in nude mice. Clin. Cancer Res. 6, 2573–2581 (2000).

    CAS  PubMed  Google Scholar 

  63. Huang, S., Pettaway, C. A., Uehara, H., Bucana, C. D. & Fidler, I. J. Blockade of NF-κB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene 20, 4188–4197 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Reed, J. C. The Survivin saga goes in vivo. J. Clin. Invest. 108, 965–969 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Tran, J. et al. A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc. Natl Acad. Sci. USA 99, 4349–4354 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. O'Connor, D. S. et al. Control of apoptosis during angiogenesis by survivin expression in endothelial cells. Am. J. Pathol. 156, 393–398 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Xiang, R. et al. A DNA vaccine targeting survivin combines apoptosis with suppression of angiogenesis in lung tumor eradication. Cancer Res. 65, 553–561 (2005).

    CAS  PubMed  Google Scholar 

  68. Tosetti, F., Ferrari, N., De Flora, S. & Albini, A. Angioprevention: angiogenesis is a common and key target for cancer chemopreventive agents. FASEB J. 16, 2–14 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Brahimi-Horn, M. C. & Pouyssegur, J. The hypoxia-inducible factor and tumor progression along the angiogenic pathway. Int. Rev. Cytol. 242, 157–213 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Esteban, M. A. & Maxwell, P. H. HIF, a missing link between metabolism and cancer. Nature Med. 11, 1047–1048 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Semenza, G. L. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit. Rev. Biochem. Mol. Biol. 35, 71–103 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Cramer, T. et al. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 112, 645–657 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Myzak, M. C., Dashwood, W. M., Orner, G. A., Ho, E. & Dashwood, R. H. Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apc-minus mice. FASEB J. 20, 506–508 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Kopelovich, L., Crowell, J. A. & Fay, J. R. The epigenome as a target for cancer chemoprevention. J. Natl Cancer Inst. 95, 1747–1757 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Kong, X. et al. Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1alpha. Mol. Cell Biol. 26, 2019–2028 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Fath, D. M. et al. Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-α. J. Biol. Chem. 281, 13612–13619 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Zhang, Q. et al. Green tea extract and (-)- epigallocatechin-3-gallate inhibit hypoxia- and serum-induced HIF-1α protein accumulation and VEGF expression in human cervical carcinoma and hepatoma cells. Mol. Cancer Ther. 5, 1227–1238 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Zhang, Q. et al. Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1α and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells. Mol. Cancer Ther. 4, 1465–1474 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Fang, J. et al. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. FASEB J. 19, 342–353 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Semenza, G. L. Targeting HIF-1 for cancer therapy. Nature Rev. Cancer 3, 721–732 (2003).

    Article  CAS  Google Scholar 

  81. Blouw, B. et al. The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 4, 133–146 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Acker, T. et al. Genetic evidence for a tumor suppressor role of HIF-2α. Cancer Cell 8, 131–141 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Talalay, P., Dinkova-Kostova, A. T. & Holtzclaw, W. D. Importance of phase 2 gene regulation in protection against electrophile and reactive oxygen toxicity and carcinogenesis. Adv. Enzyme Regul. 43, 121–134 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Ryter, S. W., Alam, J. & Choi, A. M. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol. Rev. 86, 583–650 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Zhang, Y. & Gordon, G. B. A strategy for cancer prevention: stimulation of the Nrf2-ARE signaling pathway. Mol. Cancer Ther. 3, 885–893 (2004).

    CAS  PubMed  Google Scholar 

  86. Lee, J. S. & Surh, Y. J. Nrf2 as a novel molecular target for chemoprevention. Cancer Lett. 224, 171–184 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Buteau-Lozano, H., Ancelin, M., Lardeux, B., Milanini, J. & Perrot-Applanat, M. Transcriptional regulation of vascular endothelial growth factor by estradiol and tamoxifen in breast cancer cells: a complex interplay between estrogen receptors α and β. Cancer Res. 62, 4977–4984 (2002).

    CAS  PubMed  Google Scholar 

  88. Loureiro, R. M. & D'Amore, P. A. Transcriptional regulation of vascular endothelial growth factor in cancer. Cytokine Growth Factor Rev. 16, 77–89 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Yen, W. C., Prudente, R. Y., Corpuz, M. R., Negro-Vilar, A. & Lamph, W. W. A selective retinoid X receptor agonist bexarotene (LGD1069, targretin) inhibits angiogenesis and metastasis in solid tumours. Br. J. Cancer 94, 654–660 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).

    Article  CAS  PubMed  Google Scholar 

  91. Carmeliet, P. Angiogenesis in life, disease and medicine. Nature 438, 932–936 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Kerbel, R. S. Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science 312, 1171–1175 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Brown, J. R. & DuBois, R. N. COX-2: a molecular target for colorectal cancer prevention. J. Clin. Oncol. 23, 2840–2855 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Harris, R. E., Beebe-Donk, J. & Alshafie, G. A. Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors. BMC Cancer 6, 27 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Oshima, M. et al. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87, 803–809 (1996).

    Article  CAS  PubMed  Google Scholar 

  96. Masferrer, J. L. et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res. 60, 1306–1311 (2000).

    CAS  PubMed  Google Scholar 

  97. Donà, M. et al. Neutrophil restraint by green tea: inhibition of inflammation, associated angiogenesis, and pulmonary fibrosis. J. Immunol. 170, 4335–4341 (2003).

    Article  PubMed  Google Scholar 

  98. Ferrari, N. et al. The transforming growth factor-beta family members bone morphogenetic protein-2 and macrophage inhibitory cytokine-1 as mediators of the antiangiogenic activity of N-(4-hydroxyphenyl)retinamide. Clin. Cancer Res. 11, 4610–4619 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Shishodia, S., Gutierrez, A. M., Lotan, R. & Aggarwal, B. B. N-(4-hydroxyphenyl)retinamide inhibits invasion, suppresses osteoclastogenesis, and potentiates apoptosis through down-regulation of IκBα kinase and nuclear factor-κB-regulated gene products. Cancer Res. 65, 9555–9565 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Veronesi, U. et al. Fifteen-year results of a randomized phase III trial of fenretinide to prevent second breast cancer. Ann. Oncol. 17, 1065–1071 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Demierre, M. F., Higgins, P. D., Gruber, S. B., Hawk, E. & Lippman, S. M. Statins and cancer prevention. Nature Rev. Cancer 5, 930–942 (2005).

    Article  CAS  Google Scholar 

  102. Arber, N. et al. Celecoxib for the prevention of colorectal adenomatous polyps. N. Engl. J. Med. 355, 885–895 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Bertagnolli, M. M. et al. Celecoxib for the prevention of sporadic colorectal adenomas. N. Engl. J. Med. 355, 873–884 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Solomon, S. D. et al. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation 114, 1028–1035 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Gail, M. H. & Costantino, J. P. Validating and improving models for projecting the absolute risk of breast cancer. J. Natl Cancer Inst. 93, 334–335 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Freedman, A. N. et al. Estimates of the number of US women who could benefit from tamoxifen for breast cancer chemoprevention. J. Natl Cancer Inst. 95, 526–532 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Szabo, E. Selecting targets for cancer prevention: where do we go from here? Nature Rev. Cancer 6, 867–874 (2006).

    Article  CAS  Google Scholar 

  108. Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).

    Article  CAS  PubMed  Google Scholar 

  109. De Backer, G. et al. European guidelines on cardiovascular disease prevention in clinical practice: third joint task force of European and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of eight societies and by invited experts). Eur. J. Cardiovasc. Prev. Rehabil. 10, S1–S10 (2003).

    PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Padgett for expert editorial and stylistic assistance in the preparation of this manuscript. K. Liby, F. Tosetti, R. Benelli and D. Noonan have given valuable suggestions and comments. We are especially indebted to C. Leaf for comments about 'risk versus risk'. A.A. is supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) and Ministero della Salute. M.B.S. is supported by grants from the US National Cancer Institute and the National Foundation for Cancer Research.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Adriana Albini or Michael B. Sporn.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Albini, A., Sporn, M. The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 7, 139–147 (2007). https://doi.org/10.1038/nrc2067

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2067

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing