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:

Cancer prevention by targeting angiogenesis

Nature Reviews Clinical Oncology volume 9, pages 498–509 (2012)Cite this article

Subjects

Abstract

Healthy individuals can harbour microscopic tumours and dysplastic foci in different organs in an undetectable and asymptomatic state for many years. These lesions do not progress in the absence of angiogenesis or inflammation. Targeting both processes before clinical manifestation can prevent tumour growth and progression. Angioprevention is a chemoprevention approach that interrupts the formation of new blood vessels when tumour cell foci are in an indolent state. Many efficacious chemopreventive drugs function by preventing angiogenesis in the tumour microenvironment. Blocking the vascularization of incipient tumours should maintain a dormancy state such that neoplasia or cancer exist without disease. The current limitations of antiangiogenic cancer therapy may well be related to the use of antiangiogenic agents too late in the disease course. In this Review, we suggest mechanisms and strategies for using antiangiogenesis agents in a safe, preventive clinical angioprevention setting, proposing different levels of clinical angioprevention according to risk, and indicate potential drugs to be employed at these levels. Finally, angioprevention may go well beyond cancer in the prevention of a range of chronic disorders where angiogenesis is crucial, including different forms of inflammatory or autoimmune diseases, ocular disorders, and neurodegeneration.

Key Points

  • Angiogenesis and inflammation are host-dependent hallmarks of cancer that can be targeted using prevention approaches long before tumours initiate and progress

  • Several prescription and non-prescription drugs are already available for use in angioprevention, as well as a growing array of nutraceuticals

  • We propose four levels of angioprevention: I for the 'healthy' population; II for patients with increased risk of cancer; III for preneoplastic lesions; and IV for prevention of cancer recurrence

  • There are several successes in cancer prevention that demonstrate clinical feasibility and levels of intervention, from no to little to intense physician involvement

  • To avoid toxicity while maintaining efficacy, angioprevention needs to achieve a degree of angiogenesis control that is not excessively suppressive, such that healthy vascular function is maintained

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Timing of angioprevention.
Figure 2: Angiogenesis is controlled by a balance of endogenous stimulators and inhibitors; in homeostasis, the sum of these effects is null.
Figure 3: Selected key signalling pathways that are targets for angioprevention.
Figure 4: Four levels of angioprevention.

Similar content being viewed by others

References

  1. Bloom, D. E. et al. The Global Economic Burden of Non-communicable Diseases [online], (2011).

    Google Scholar 

  2. Mariotto, A. B., Yabroff, K. R., Shao, Y., Feuer, E. J. & Brown, M. L. Projections of the cost of cancer care in the United States: 2010–2020. J. Natl Cancer Inst. 103, 117–128 (2011).

    PubMed  PubMed Central  Google Scholar 

  3. Albini, A. & Sporn, M. B. The tumour microenvironment as a target for chemoprevention. Nat. Rev. Cancer 7, 139–147 (2007).

    CAS  PubMed  Google Scholar 

  4. Qaseem, A. et al. Screening for colorectal cancer: a guidance statement from the American College of Physicians. Ann. Intern. Med. 156, 378–386 (2012).

    PubMed  Google Scholar 

  5. Nishizawa, S. et al. Prospective evaluation of whole-body cancer screening with multiple modalities including [18F]fluorodeoxyglucose positron emission tomography in a healthy population: a preliminary report. J. Clin. Oncol. 27, 1767–1773 (2009).

    PubMed  Google Scholar 

  6. Shih, Y. C. et al. Economic burden of renal cell carcinoma: part I--an updated review. Pharmacoeconomics 29, 315–329 (2011).

    PubMed  Google Scholar 

  7. Whyte, S., Pandor, A., Stevenson, M. & Rees, A. Bevacizumab in combination with fluoropyrimidine-based chemotherapy for the first-line treatment of metastatic colorectal cancer. Health Technol. Assess. 14, 47–53 (2010).

    CAS  PubMed  Google Scholar 

  8. Lippman, S. M. & Hawk, E. T. Cancer prevention: from 1727 to milestones of the past 100 years. Cancer Res. 69, 5269–5284 (2009).

    CAS  PubMed  Google Scholar 

  9. Willyard, C. Lifestyle: Breaking the cancer habit. Nature 471, S16–S17 (2011).

    CAS  PubMed  Google Scholar 

  10. [No authors listed] Stat bite: Lifetime risk of being diagnosed with cancer. J. Natl Cancer Inst. 95, 1745 (2003).

  11. Sporn, M. B. & Newton, D. L. Chemoprevention of cancer with retinoids. Fed. Proc. 38, 2528–2534 (1979).

    CAS  PubMed  Google Scholar 

  12. Bissell, M. J. & Hines, W. C. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 17, 320–329 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  14. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. Ebos, J. M. & Kerbel, R. S. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat. Rev. Clin. Oncol. 8, 210–221 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Jayson, G. C., Hicklin, D. J. & Ellis, L. M. Antiangiogenic therapy—evolving view based on clinical trial results. Nat. Rev. Clin. Oncol. 9, 297–303 (2012).

    CAS  PubMed  Google Scholar 

  18. Ferrara, N. Role of myeloid cells in vascular endothelial growth factor-independent tumor angiogenesis. Curr. Opin. Hematol. 17, 219–224 (2010).

    CAS  PubMed  Google Scholar 

  19. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Sanchez-Chapado, M., Olmedilla, G., Cabeza, M., Donat, E. & Ruiz, A. Prevalence of prostate cancer and prostatic intraepithelial neoplasia in Caucasian Mediterranean males: an autopsy study. Prostate 54, 238–247 (2003).

    PubMed  Google Scholar 

  21. Black, W. C. & Welch, H. G. Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. N. Engl. J. Med. 328, 1237–1243 (1993).

    CAS  PubMed  Google Scholar 

  22. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. de Visser, K. E., Eichten, A. & Coussens, L. M. Paradoxical roles of the immune system during cancer development. Nat. Rev. Cancer 6, 24–37 (2006).

    CAS  PubMed  Google Scholar 

  26. Noonan, D. M., De Lerma Barbaro, A., Vannini, N., Mortara, L. & Albini, A. Inflammation, inflammatory cells and angiogenesis: decisions and indecisions. Cancer Metastasis Rev. 27, 31–40 (2008).

    PubMed  Google Scholar 

  27. Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 4, 71–78 (2004).

    CAS  PubMed  Google Scholar 

  28. Mantovani, A. & Sica, A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr. Opin. Immunol. 22, 231–237 (2010).

    CAS  PubMed  Google Scholar 

  29. Coffelt, S. B. et al. Elusive identities and overlapping phenotypes of proangiogenic myeloid cells in tumors. Am. J. Pathol. 176, 1564–1576 (2010).

    PubMed  PubMed Central  Google Scholar 

  30. Fridlender, Z. G. & Albelda, S. M. Tumor-associated neutrophils: friend or foe? Carcinogenesis 33, 949–955 (2012).

    CAS  PubMed  Google Scholar 

  31. DeNardo, D. G., Andreu, P. & Coussens, L. M. Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev. 29, 309–316 (2010).

    PubMed  PubMed Central  Google Scholar 

  32. Mason, S. D. & Joyce, J. A. Proteolytic networks in cancer. Trends Cell Biol. 21, 228–237 (2011).

    CAS  PubMed  Google Scholar 

  33. Cao, Y. & Cao, R. Angiogenesis inhibited by drinking tea. Nature 398, 381 (1999).

    CAS  PubMed  Google Scholar 

  34. Garbisa, S. et al. Tumor invasion: molecular shears blunted by green tea. Nat. Med. 5, 1216 (1999).

    CAS  PubMed  Google Scholar 

  35. Noonan, D. M., Sogno, I. & Albini, A. in Herbal Medicines: Development and Validation of Plant-derived Medicines for Human Health (eds Bagetta, G., Cosentino, M., Corasaniti, M. T. & Sakurada, S.) 285–306 (CRC Press, Boca Raton, FL, 2011).

    Google Scholar 

  36. Albini, A., Indraccolo, S., Noonan, D. M. & Pfeffer, U. Functional genomics of endothelial cells treated with anti-angiogenic or angiopreventive drugs. Clin. Exp. Metastasis 27, 419–439 (2010).

    CAS  PubMed  Google Scholar 

  37. Araldi, E. M. et al. Natural and synthetic agents targeting inflammation and angiogenesis for chemoprevention of prostate cancer. Curr. Cancer Drug Targets 8, 146–155 (2008).

    CAS  PubMed  Google Scholar 

  38. Tahanian, E., Sanchez, L. A., Shiao, T. C., Roy, R. & Annabi, B. Flavonoids targeting of IκB phosphorylation abrogates carcinogen-induced MMP-9 and COX-2 expression in human brain endothelial cells. Drug Des. Devel. Ther. 5, 299–309 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Yang, M. D. et al. Phenethyl isothiocyanate inhibits migration and invasion of human gastric cancer AGS cells through suppressing MAPK and NF-kappaB signal pathways. Anticancer Res. 30, 2135–2143 (2010).

    CAS  PubMed  Google Scholar 

  40. Manikandan, P., Murugan, R. S., Priyadarsini, R. V., Vinothini, G. & Nagini, S. Eugenol induces apoptosis and inhibits invasion and angiogenesis in a rat model of gastric carcinogenesis induced by MNNG. Life Sci. 86, 936–941 (2010).

    CAS  PubMed  Google Scholar 

  41. Cao, Y., Cao, R. & Brakenhielm, E. Antiangiogenic mechanisms of diet-derived polyphenols. J. Nutr. Biochem. 13, 380–390 (2002).

    CAS  PubMed  Google Scholar 

  42. Ferrari, N. et al. Diet-derived phytochemicals: from cancer chemoprevention to cardio-oncological prevention. Curr. Drug Targets 12, 1909–1924 (2011).

    CAS  PubMed  Google Scholar 

  43. Li, W. W., Li, V. W., Hutnik, M. & Chiou, A. S. Tumor angiogenesis as a target for dietary cancer prevention. J. Oncol. 2012, 879623 (2012).

    PubMed  Google Scholar 

  44. Sidky, Y. A. & Borden, E. C. Inhibition of angiogenesis by interferons: effects on tumor- and lymphocyte-induced vascular responses. Cancer Res. 47, 5155–5161 (1987).

    CAS  PubMed  Google Scholar 

  45. Li, V. W. & Li, W. W. Antiangiogenesis in the treatment of skin cancer. J. Drugs Dermatol. 7 (Suppl. 1), s17–s24 (2008).

    PubMed  Google Scholar 

  46. Li, V. W., Li, W. W., Talcott, K. E. & Zhai, A. W. Imiquimod as an antiangiogenic agent. J. Drugs Dermatol. 4, 708–717 (2005).

    PubMed  Google Scholar 

  47. Sidbury, R. et al. Topically applied imiquimod inhibits vascular tumor growth in vivo. J. Invest. Dermatol. 121, 1205–1209 (2003).

    CAS  PubMed  Google Scholar 

  48. Fisher, B. et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl Cancer Inst. 90, 1371–1388 (1998).

    CAS  PubMed  Google Scholar 

  49. Bendrik, C., Karlsson, L. & Dabrosin, C. Increased endostatin generation and decreased angiogenesis via MMP-9 by tamoxifen in hormone dependent ovarian cancer. Cancer Lett. 292, 32–40 (2010).

    CAS  PubMed  Google Scholar 

  50. Aberg, U. W. et al. Tamoxifen and flaxseed alter angiogenesis regulators in normal human breast tissue in vivo. PLoS ONE 6, e25720 (2011).

    PubMed  Google Scholar 

  51. Blackwell, K. L. et al. Tamoxifen inhibits angiogenesis in estrogen receptor-negative animal models. Clin. Cancer Res. 6, 4359–4364 (2000).

    CAS  PubMed  Google Scholar 

  52. Lindahl, G., Saarinen, N., Abrahamsson, A. & Dabrosin, C. Tamoxifen, flaxseed, and the lignan enterolactone increase stroma- and cancer cell-derived IL-1Ra and decrease tumor angiogenesis in estrogen-dependent breast cancer. Cancer Res. 71, 51–60 (2011).

    CAS  PubMed  Google Scholar 

  53. Bachmeier, B. E. et al. Reference profile correlation reveals estrogen-like trancriptional activity of Curcumin. Cell. Physiol. Biochem. 26, 471–482 (2010).

    CAS  PubMed  Google Scholar 

  54. William, W. N. Jr, Heymach, J. V., Kim, E. S. & Lippman, S. M. Molecular targets for cancer chemoprevention. Nat. Rev. Drug Discov. 8, 213–225 (2009).

    CAS  PubMed  Google Scholar 

  55. Rothwell, P. M. et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 377, 31–41 (2011).

    CAS  PubMed  Google Scholar 

  56. Harris, R. E. Cyclooxygenase-2 (cox-2) blockade in the chemoprevention of cancers of the colon, breast, prostate, and lung. Inflammopharmacology 17, 55–67 (2009).

    CAS  PubMed  Google Scholar 

  57. Cui, X. et al. Resveratrol suppresses colitis and colon cancer associated with colitis. Cancer Prev. Res. (Phila.) 3, 549–559 (2010).

    CAS  Google Scholar 

  58. Yu, H., Pardoll, D. & Jove, R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9, 798–809 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Lamy, S., Akla, N., Ouanouki, A., Lord-Dufour, S. & Beliveau, R. Diet-derived polyphenols inhibit angiogenesis by modulating the interleukin-6/STAT3 pathway. Exp. Cell Res. 318, 1586–1596 (2012).

    CAS  PubMed  Google Scholar 

  60. Aggarwal, B. B., Vijayalekshmi, R. V. & Sung, B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin. Cancer Res. 15, 425–430 (2009).

    CAS  PubMed  Google Scholar 

  61. Gupta, S. C., Kim, J. H., Prasad, S. & Aggarwal, B. B. Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metastasis Rev. 29, 405–434 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Gately, S. & Li, W. W. Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy. Semin. Oncol. 31, 2–11 (2004).

    CAS  PubMed  Google Scholar 

  63. Fosslien, E. Review: molecular pathology of cyclooxygenase-2 in cancer-induced angiogenesis. Ann. Clin. Lab. Sci. 31, 325–348 (2001).

    CAS  PubMed  Google Scholar 

  64. Greenberger, S. & Bischoff, J. Infantile Hemangioma-Mechanism(s) of Drug Action on a Vascular Tumor. Cold Spring Harb. Perspect. Med. 1, a006460 (2011).

    PubMed  PubMed Central  Google Scholar 

  65. Vannini, N., Pfeffer, U., Lorusso, G., Noonan, D. M. & Albini, A. Endothelial cell aging and apoptosis in prevention and disease: E-selectin expression and modulation as a model. Curr. Pharm. Des. 14, 221–225 (2008).

    CAS  PubMed  Google Scholar 

  66. Nishikawa, T. et al. The inhibition of autophagy potentiates anti-angiogenic effects of sulforaphane by inducing apoptosis. Angiogenesis 13, 227–238 (2010).

    CAS  PubMed  Google Scholar 

  67. Delmas, D., Solary, E. & Latruffe, N. Resveratrol, a phytochemical inducer of multiple cell death pathways: apoptosis, autophagy and mitotic catastrophe. Curr. Med. Chem. 18, 1100–1121 (2011).

    CAS  PubMed  Google Scholar 

  68. Christov, K. T., Shilkaitis, A. L., Kim, E. S., Steele, V. E. & Lubet, R. A. Chemopreventive agents induce a senescence-like phenotype in rat mammary tumours. Eur. J. Cancer 39, 230–239 (2003).

    CAS  PubMed  Google Scholar 

  69. Albini, A., Cesana, E. & Noonan, D. M. Cancer stem cells and the tumor microenvironment: soloists or choral singers. Curr. Pharm. Biotechnol. 12, 171–181 (2011).

    CAS  PubMed  Google Scholar 

  70. Hursting, S. D., Smith, S. M., Lashinger, L. M., Harvey, A. E. & Perkins, S. N. Calories and carcinogenesis: lessons learned from 30 years of calorie restriction research. Carcinogenesis 31, 83–89 (2010).

    CAS  PubMed  Google Scholar 

  71. Aljada, A., O'Connor, L., Fu, Y. Y. & Mousa, S. A. PPAR gamma ligands, rosiglitazone and pioglitazone, inhibit bFGF- and VEGF-mediated angiogenesis. Angiogenesis 11, 361–367 (2008).

    CAS  PubMed  Google Scholar 

  72. Merchan, J. R. et al. Antiangiogenic activity of 2-deoxy-D-glucose. PLoS ONE 5, e13699 (2010).

    PubMed  PubMed Central  Google Scholar 

  73. Fraisl, P., Mazzone, M., Schmidt, T. & Carmeliet, P. Regulation of angiogenesis by oxygen and metabolism. Dev. Cell 16, 167–179 (2009).

    CAS  PubMed  Google Scholar 

  74. Lee, D. F. et al. IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130, 440–455 (2007).

    CAS  PubMed  Google Scholar 

  75. Fasolo, A. & Sessa, C. Targeting mTOR pathways in human malignancies. Curr. Pharm. Des. 18, 2766–2777 (2012).

    CAS  PubMed  Google Scholar 

  76. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  77. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  78. Phoenix, K. N., Vumbaca, F. & Claffey, K. P. Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERalpha negative MDA-MB-435 breast cancer model. Breast Cancer Res. Treat. 113, 101–111 (2009).

    CAS  PubMed  Google Scholar 

  79. Xavier, D. O. et al. Metformin inhibits inflammatory angiogenesis in a murine sponge model. Biomed. Pharmacother. 64, 220–225 (2010).

    CAS  PubMed  Google Scholar 

  80. Esfahanian, N. et al. Effect of metformin on the proliferation, migration, and MMP-2 and -9 expression of human umbilical vein endothelial cells. Mol. Med. Report 5, 1068–1074 (2012).

    CAS  Google Scholar 

  81. Akin, S. et al. Pigment epithelium-derived factor (PEDF) increases in type 2 diabetes after treatment with metformin. Clin. Endocrinol. (Oxf.) http:dx.doi.org/10.1111/j.1365-2265.2012.04341.x.

  82. Alom-Ruiz, S. P., Anilkumar, N. & Shah, A. M. Reactive oxygen species and endothelial activation. Antioxid. Redox Signal. 10, 1089–1100 (2008).

    CAS  PubMed  Google Scholar 

  83. De Flora, S. et al. Multiple points of intervention in the prevention of cancer and other mutation-related diseases. Mutat. Res. 480–481, 9–22 (2001).

    PubMed  Google Scholar 

  84. Tosetti, F., Noonan, D. M. & Albini, A. Metabolic regulation and redox activity as mechanisms for angioprevention by dietary phytochemicals. Int. J. Cancer 125, 1997–2003 (2009).

    CAS  PubMed  Google Scholar 

  85. Aggarwal, B. B. Targeting inflammation-induced obesity and metabolic diseases by curcumin and other nutraceuticals. Annu. Rev. Nutr. 30, 173–199 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Yadav, V. R. & Aggarwal, B. B. Curcumin: a component of the golden spice, targets multiple angiogenic pathways. Cancer Biol. Ther. 11, 236–241 (2011).

    CAS  PubMed  Google Scholar 

  87. Tan, B. K. et al. Metformin decreases angiogenesis via NF-kappaB and Erk1/2/Erk5 pathways by increasing the antiangiogenic thrombospondin-1. Cardiovasc. Res. 83, 566–574 (2009).

    CAS  PubMed  Google Scholar 

  88. De Lorenzo, M. S. et al. Caloric restriction reduces growth of mammary tumors and metastases. Carcinogenesis 32, 1381–1387 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Zhou, J. R., Li, L. & Pan, W. Dietary soy and tea combinations for prevention of breast and prostate cancers by targeting metabolic syndrome elements in mice. Am. J. Clin. Nutr. 86, s882–s888 (2007).

    PubMed  Google Scholar 

  90. Cazzaniga, M., Bonanni, B., Guerrieri-Gonzaga, A. & Decensi, A. Is it time to test metformin in breast cancer clinical trials? Cancer Epidemiol. Biomarkers Prev. 18, 701–705 (2009).

    CAS  PubMed  Google Scholar 

  91. Cuzick, J. et al. Preventive therapy for breast cancer: a consensus statement. Lancet Oncol. 12, 496–503 (2011).

    CAS  PubMed  Google Scholar 

  92. Mallery, S. R. et al. Topical application of a bioadhesive black raspberry gel modulates gene expression and reduces cyclooxygenase 2 protein in human premalignant oral lesions. Cancer Res. 68, 4945–4957 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Vannini, N. et al. The synthetic oleanane triterpenoid, CDDO-methyl ester, is a potent antiangiogenic agent. Mol. Cancer Ther. 6, 3139–3146 (2007).

    CAS  PubMed  Google Scholar 

  94. Kim, E. H. et al. CDDO-methyl ester delays breast cancer development in BRCA1-mutated mice. Cancer Prev. Res. (Phila.) 5, 89–97 (2012).

    CAS  Google Scholar 

  95. Sporn, M. B. Perspective: The big C - for Chemoprevention. Nature 471, S10–S11 (2011).

    CAS  PubMed  Google Scholar 

  96. Li, W., Hutnik, M. & Li, V. in Angiogenesis: Basic Science and Clinical Applications (eds Maragoudakis, M. & Papadimitriou, E.) 377–417 (Research Signpost, Trivandrum, India, 2008).

    Google Scholar 

  97. Albini, A. et al. Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J. Natl Cancer Inst. 102, 14–25 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Comen, E., Norton, L. & Massague, J. Clinical implications of cancer self-seeding. Nat. Rev. Clin. Oncol. 8, 369–377 (2011).

    PubMed  Google Scholar 

  99. Albini, A. & Noonan, D. M. Angiopoietin2 and tie2: tied to lymphangiogenesis and lung metastasis. New perspectives in antimetastatic antiangiogenic therapy. J. Natl Cancer Inst. 104, 429–431 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Albini, A. & Noonan, D. M. The 'chemoinvasion' assay, 25 years and still going strong: the use of reconstituted basement membranes to study cell invasion and angiogenesis. Curr. Opin. Cell. Biol. 22, 677–689 (2010).

    CAS  PubMed  Google Scholar 

  101. Pasquier, E., Kavallaris, M. & Andre, N. Metronomic chemotherapy: new rationale for new directions. Nat. Rev. Clin. Oncol. 7, 455–465 (2010).

    PubMed  Google Scholar 

  102. Spigel, D. R. et al. Phase II study of bevacizumab and chemoradiation in the preoperative or adjuvant treatment of patients with stage II/III rectal cancer. Clin. Colorectal Cancer 11, 45–52 (2012).

    CAS  PubMed  Google Scholar 

  103. Allegra, C. J. et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J. Clin. Oncol. 29, 11–16 (2011).

    CAS  PubMed  Google Scholar 

  104. Jonietz, E. Designing smarter cancer prevention trials. Nature 471, S20–S21 (2011).

    CAS  PubMed  Google Scholar 

  105. Sogno, I., Conti, M., Consonni, P., Noonan, D. M. & Albini, A. Surface-activated chemical ionization-electrospray ionization source improves biomarker discovery with mass spectrometry. Rapid Commun. Mass Spectrom. 26, 1213–1218 (2012).

    CAS  PubMed  Google Scholar 

  106. Cervi, D. et al. Platelet-associated PF-4 as a biomarker of early tumor growth. Blood 111, 1201–1207 (2008).

    CAS  PubMed  Google Scholar 

  107. Italiano, J. E. Jr et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 111, 1227–1233 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Peterson, J. E. et al. Normal ranges of angiogenesis regulatory proteins in human platelets. Am. J. Hematol. 85, 487–493 (2010).

    CAS  PubMed  Google Scholar 

  109. Fish, J. E. & Srivastava, D. MicroRNAs: opening a new vein in angiogenesis research. Sci. Signal. 2, pe1 (2009).

    PubMed  PubMed Central  Google Scholar 

  110. Reuter, S., Gupta, S. C., Park, B., Goel, A. & Aggarwal, B. B. Epigenetic changes induced by curcumin and other natural compounds. Genes Nutr. 6, 93–108 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Noratto, G. D., Angel-Morales, G., Talcott, S. T. & Mertens-Talcott, S. U. Polyphenolics from açai (Euterpe oleracea Mart.) and red muscadine grape (Vitis rotundifolia) protect human umbilical vascular endothelial cells (HUVEC) from glucose- and lipopolysaccharide (LPS)-induced inflammation and target microRNA-126. J. Agric. Food Chem. 59, 7999–8012 (2011).

    CAS  PubMed  Google Scholar 

  112. White, N. M. et al. Metastamirs: a stepping stone towards improved cancer management. Nat. Rev. Clin. Oncol. 8, 75–84 (2011).

    CAS  PubMed  Google Scholar 

  113. Sogno, I. et al. Angioprevention with fenretinide: targeting angiogenesis in prevention and therapeutic strategies. Crit. Rev. Oncol. Hematol. 75, 2–14 (2010).

    PubMed  Google Scholar 

  114. 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).

    CAS  PubMed  Google Scholar 

  115. US National Library of Medicine. ClinicalTrials.gov[online], (2011).

  116. [No authors listed] Standards of medical care in diabetes—2009. Diabetes Care 32 (Suppl. 1), S13–S61 (2009).

  117. Currie, C. J., Poole, C. D. & Gale, E. A. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52, 1766–1777 (2009).

    CAS  PubMed  Google Scholar 

  118. Goodwin, P. J. et al. Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents. Breast Cancer Res. Treat. 126, 215–220 (2011).

    CAS  PubMed  Google Scholar 

  119. Li, D., Yeung, S. C., Hassan, M. M., Konopleva, M. & Abbruzzese, J. L. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 137, 482–488 (2009).

    PubMed  Google Scholar 

  120. Cole, B. F. et al. Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the randomized trials. J. Natl Cancer Inst. 101, 256–266 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Rothwell, P. M. et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 376, 1741–1750 (2010).

    CAS  PubMed  Google Scholar 

  122. Burn, J. et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 378, 2081–2087 (2011).

    PubMed  PubMed Central  Google Scholar 

  123. Battinelli, E. M., Markens, B. A. & Italiano, J. E. Jr. Release of angiogenesis regulatory proteins from platelet alpha granules: modulation of physiologic and pathologic angiogenesis. Blood 118, 1359–1369 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Borthwick, G. M. et al. Therapeutic levels of aspirin and salicylate directly inhibit a model of angiogenesis through a Cox-independent mechanism. FASEB J. 20, 2009–2016 (2006).

    CAS  PubMed  Google Scholar 

  125. Hawley, S. A. et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336, 918–922 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Lynch, P. M. et al. The safety and efficacy of celecoxib in children with familial adenomatous polyposis. Am. J. Gastroenterol. 105, 1437–1443 (2010).

    CAS  PubMed  Google Scholar 

  127. Bertagnolli, M. M. et al. Five-year efficacy and safety analysis of the Adenoma Prevention with Celecoxib Trial. Cancer Prev. Res. (Phila.) 2, 310–321 (2009).

    CAS  Google Scholar 

  128. Chan, A. T. et al. C-reactive protein and risk of colorectal adenoma according to celecoxib treatment. Cancer Prev. Res. (Phila.) 4, 1172–1180 (2011).

    CAS  Google Scholar 

  129. Elmets, C. A. et al. Chemoprevention of nonmelanoma skin cancer with celecoxib: a randomized, double-blind, placebo-controlled trial. J. Natl Cancer Inst. 102, 1835–1844 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Bettuzzi, S. et al. Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res. 66, 1234–1240 (2006).

    CAS  PubMed  Google Scholar 

  131. Brausi, M., Rizzi, F. & Bettuzzi, S. Chemoprevention of human prostate cancer by green tea catechins: two years later. A follow-up update. Eur. Urol. 54, 472–473 (2008).

    PubMed  Google Scholar 

  132. Shimizu, M. et al. Green tea extracts for the prevention of metachronous colorectal adenomas: a pilot study. Cancer Epidemiol. Biomarkers Prev. 17, 3020–3025 (2008).

    CAS  PubMed  Google Scholar 

  133. Li, N., Sun, Z., Han, C. & Chen, J. The chemopreventive effects of tea on human oral precancerous mucosa lesions. Proc. Soc. Exp. Biol. Med. 220, 218–224 (1999).

    CAS  PubMed  Google Scholar 

  134. Ahn, W. S. et al. Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Eur. J. Cancer Prev. 12, 383–390 (2003).

    PubMed  Google Scholar 

  135. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  136. Cheng, A. L. et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 21, 2895–2900 (2001).

    CAS  PubMed  Google Scholar 

  137. Dhillon, N. et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin. Cancer Res. 14, 4491–4499 (2008).

    CAS  PubMed  Google Scholar 

  138. Carroll, R. E. et al. Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev. Res. (Phila.) 4, 354–364 (2011).

    CAS  Google Scholar 

  139. Cruz-Correa, M. et al. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin. Gastroenterol. Hepatol. 4, 1035–1038 (2006).

    CAS  PubMed  Google Scholar 

  140. Brown, V. A. et al. Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. Cancer Res. 70, 9003–9011 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Howells, L. M. et al. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases—safety, pharmacokinetics, and pharmacodynamics. Cancer Prev. Res. (Phila.) 4, 1419–1425 (2011).

    CAS  Google Scholar 

  142. Timmers, S. et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell. Metab. 14, 612–622 (2011).

    CAS  PubMed  Google Scholar 

  143. Siervo, M. et al. Body mass index is directly associated with biomarkers of angiogenesis and inflammation in children and adolescents. Nutrition 28, 262–266 (2012).

    CAS  PubMed  Google Scholar 

  144. Bhattacharjee, Y. Exoplanetary research. A distant glimpse of alien life? Science 333, 930–932 (2011).

    CAS  PubMed  Google Scholar 

  145. Lally, D. R., Gerstenblith, A. T. & Regillo, C. D. Preferred therapies for neovascular age-related macular degeneration. Curr. Opin. Ophthalmol. 23, 182–188 (2012).

    PubMed  Google Scholar 

  146. Breitner, J. C. et al. Extended results of the Alzheimer's disease anti-inflammatory prevention trial. Alzheimers Dement. 7, 402–411 (2011).

    PubMed  PubMed Central  Google Scholar 

  147. Desai, B. S., Schneider, J. A., Li, J. L., Carvey, P. M. & Hendey, B. Evidence of angiogenic vessels in Alzheimer's disease. J. Neural. Transm. 116, 587–597 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Zeng, S., Hernandez, J. & Mullins, R. F. Effects of antioxidant components of AREDS vitamins and zinc ions on endothelial cell activation: implications for macular degeneration. Invest. Ophthalmol. Vis. Sci. 53, 1041–1047 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Konisti, S., Kiriakidis, S. & Paleolog, E. M. Hypoxia--a key regulator of angiogenesis and inflammation in rheumatoid arthritis. Nat. Rev. Rheumatol. 8, 153–162 (2012).

    CAS  PubMed  Google Scholar 

  150. Lainer-Carr, D. & Brahn, E. Angiogenesis inhibition as a therapeutic approach for inflammatory synovitis. Nat. Clin. Pract. Rheumatol. 3, 434–442 (2007).

    CAS  PubMed  Google Scholar 

  151. Cao, Y. Angiogenesis modulates adipogenesis and obesity. J. Clin. Invest. 117, 2362–2368 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Cao, Y. Adipose tissue angiogenesis as a therapeutic target for obesity and metabolic diseases. Nat. Rev. Drug Discov. 9, 107–115 (2010).

    CAS  PubMed  Google Scholar 

  153. Daquinag, A. C., Zhang, Y. & Kolonin, M. G. Vascular targeting of adipose tissue as an anti-obesity approach. Trends Pharmacol. Sci. 32, 300–307 (2011).

    CAS  PubMed  Google Scholar 

  154. Belo, V. A. et al. Vascular endothelial growth factor haplotypes associated with childhood obesity. DNA Cell Biol. 30, 709–714 (2011).

    CAS  PubMed  Google Scholar 

  155. Zhang, Y. et al. Effects of catechin-enriched green tea beverage on visceral fat loss in adults with a high proportion of visceral fat: a double-blind, placebo-controlled, randomized trial. J. Functional Foods 4, 315–322 (2012).

    CAS  Google Scholar 

  156. Shin, S. et al. Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. Eur. J. Pharmacol. 620, 138–144 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Diana Saville (Angiogenesis Foundation) for rendering medical graphics. We thank Paola Corradino (MultiMedica IRCCS) for data management, and Alessandra Panvini Rosati (MultiMedica Onlus) and Giuseppe Bertani (IRCCS–Arcispedale Santa Maria Nuova) for administrative assistance. The authors were supported by grants from the AIRC (Associazione Italiana per la Ricerca sul Cancro; IG5968 to D. M. Noolan, IG10228 to A. Albini), the Cariplo Foundation, Progetto Finalizzato of the Ministero della Sanità and by funds from the University of Insubria (fondi di Ateneo) and MultiMedica Onlus. A. Albini is currently Director of Research and Statistics Infrastructure, IRCCS–Arcispedale Santa Maria Nuova (Reggio Emilia-Italy).

Author information

Authors and Affiliations

  1. IRCCS MultiMedica, Science and Technology Pole, Via Fantoli 16/15, Milan, 20138, Italy

    Adriana Albini

  2. Department of Translational Oncology Research, IRCCS Azienda Ospedaliera Universitaria San Martino—IST—Istituto Nazionale per la Ricerca sul Cancro, Genova, 16132, Italy

    Francesca Tosetti

  3. Institute for Advanced Studies, The Angiogenesis Foundation, One Broadway 14th Floor, Cambridge, 02142, MA, USA

    Vincent W. Li & William W. Li

  4. Department of Biotechnologies and Life Sicences, University of Insubria, Viale Ottorino Rossi 9, Varese, 21100, Italy

    Douglas M. Noonan

Authors
  1. Adriana Albini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francesca Tosetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vincent W. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Douglas M. Noonan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. William W. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors made a substantial contribution to researching and discussing data for this Review, and to writing the manuscript. All authors reviewed and edited the manuscript prior to submission. D. M. Noonan and W. W. Li contributed equally to this article.

Corresponding author

Correspondence to Adriana Albini.

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., Tosetti, F., Li, V. et al. Cancer prevention by targeting angiogenesis. Nat Rev Clin Oncol 9, 498–509 (2012). https://doi.org/10.1038/nrclinonc.2012.120

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2012.120

This article is cited by

Search

Advanced 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