Abstract
Inhibiting angiogenesis is a promising strategy for treatment of cancer and several other disorders, including age-related macular degeneration. Major progress towards a treatment has been achieved over the past few years, and the first antiangiogenic agents have been recently approved for use in several countries. Therapeutic angiogenesis (promoting new vessel growth to treat ischaemic disorders) is an exciting frontier of cardiovascular medicine, but further understanding of the mechanisms of vascular morphogenesis is needed first.
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References
Ferrara, N. VEGF and the quest for tumour angiogenesis factors. Nature Rev. Cancer 2, 795–803 (2002).
Ide, A. G., Baker, N. H. & Warren, S. L. Vascularization of the Brown Pearce rabbit epithelioma transplant as seen in the transparent ear chamber. Am. J. Roentgenol. 42, 891–899 (1939).
Algire, G. H., Chalkley, H. W., Legallais, F. Y. & Park, H. D. Vascular reactions of normal and malignant tissues in vivo. I. Vascular reactions of mice to wounds and to normal and neoplastic transplants. J. Natl Cancer Inst. 6, 73–85 (1945).
Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).
Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).
Gragoudas, E. S., Adamis, A. P., Cunningham, E. T. Jr, Feinsod, M. & Guyer, D. R. Pegaptanib for neovascular age-related macular degeneration. N. Engl. J. Med. 351, 2805–2816 (2004).
Kerbel, R. & Folkman, J. Clinical translation of angiogenesis inhibitors. Nature Rev. Cancer 2, 727–739 (2002).
Ferrara, N., Gerber, H. P. & LeCouter, J. The biology of VEGF and its receptors. Nature Med. 9, 669–676 (2003).
Yancopoulos, G. D. et al. Vascular-specific growth factors and blood vessel formation. Nature 407, 242–248 (2000).
Ferrara, N. Vascular endothelial growth factor: basic science and clinical progress. Endocr. Rev. 25, 581–611 (2004).
Hattori, K. et al. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone-marrow microenvironment. Nature Med. 8, 841–849 (2002).
Gerber, H. -P. et al. Vascular endothelial growth factor regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 417, 954–958 (2002).
Luttun, A. et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nature Med. 8, 831–840 (2002).
Hiratsuka, S. et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2, 289–300 (2002).
LeCouter, J. et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 299, 890–893 (2003).
Wey, J. S. et al. Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer 104, 427–438 (2005).
Safran, M. & Kaelin, W. J. Jr. HIF hydroxylation and the mammalian oxygen-sensing pathway. J. Clin. Invest. 111, 779–783 (2003).
Dvorak, H. F. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J. Clin. Oncol. 20, 4368–4380 (2002).
Lonser, R. R. et al. von Hippel–Lindau disease. Lancet 361, 2059–2067 (2003).
Yang, J. C. et al. A randomized trial of bevacizumab, an anti-VEGF antibody, for metastatic renal cancer. N. Engl. J. Med. 349, 427–434 (2003).
Rak, J. et al. Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res. 55, 4575–4580 (1995).
Brugarolas, J. & Kaelin, W. G. Jr. Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell 6, 7–10 (2004).
Kim, K. J. et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature 362, 841–844 (1993).
Gerber, H. P. & Ferrara, N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res. 65, 671–680 (2005).
Millauer, B., Shawver, L. K., Plate, K. H., Risau, W. & Ullrich, A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367, 576–579 (1994).
Prewett, M. et al. Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis. Cancer Res. 59, 5209–5218 (1999).
Wood, J. M. et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 60, 2178–2189 (2000).
Gerber, H. P., Kowalski, J., Sherman, D., Eberhard, D. A. & Ferrara, N. Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res. 60, 6253–6258 (2000).
Holash, J. et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc. Natl Acad. Sci. USA 99, 11393–11398 (2002).
Inoue, M., Hager, J. H., Ferrara, N., Gerber, H. P. & Hanahan, D. VEGF-A has a critical, non redundant role in angiogenic switching and pancreatic β cell carcinogenesis. Cancer Cell 1, 193–202 (2002).
Lindhal, P., Johansson, B. E., Leveen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242–245 (1997).
Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E. & Hanahan, D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J. Clin. Invest. 111, 1287–1295 (2003).
Dong, J. et al. VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis. EMBO J. 23, 2800–2810 (2004).
Maisonpierre, P. C. et al. Angiopoietin-2, a natural antagonist for Tie-2 that disrupts in vivo angiogenesis. Science 277, 55–60 (1997).
Oliner, J. et al. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6, 507–516 (2004).
Carmeliet, P. & Tessier-Lavigne, M. Common mechanisms of nerve and blood vessel wiring. Nature 436, 193–200 (2005).
Klagsbrun, M. & Eichmann, A. A role for axon guidance receptors and ligands in blood vessel development and tumor angiogenesis. Cytokine Growth Factor Rev. 16, 535–548 (2005).
Soker, S., Takashima, S., Miao, H. Q., Neufeld, G. & Klagsbrun, M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92, 735–745 (1998).
Pasquale, E. B. Eph receptor signalling casts a wide net on cell behaviour. Nature Rev. Mol. Cell. Biol. 6, 462–475 (2005).
Pandey, A., Shao, H., Marks, R. M., Polverini, P. J. & Dixit, V. M. Role of B61, the ligand for the Eck receptor tyrosine kinase, in TNF-alpha-induced angiogenesis. Science 268, 567–569 (1995).
Martiny-Baron, G. et al. Inhibition of tumor growth and angiogenesis by soluble EphB4. Neoplasia 6, 248–257 (2004).
Dobrzanski, P. et al. Antiangiogenic and antitumor efficacy of EphA2 receptor antagonist. Cancer Res. 64, 910–919 (2004).
Wang, B. et al. Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity. Cancer Cell 4, 19–29 (2003).
DiPietro, L. A. Thrombospondin as a regulator of angiogenesis. In Regulation of Angiogenesis (eds Rosen, E. & Goldberg, I. D.) 295–314 (Springer, Berlin, 1997).
O'Reilly, M. S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285 (1997).
Sund, M. et al. Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors. Proc. Natl Acad. Sci. USA 102, 2934–2939 (2005).
Pike, S. E. et al. Vasostatin, a calreticulin fragment, inhibits angiogenesis and suppresses tumor growth. J. Exp. Med. 188, 2349–2356 (1998).
Watanabe, K. et al. Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis. J. Clin. Invest. 114, 898–907 (2004).
Nyberg, P., Xie, L. & Kalluri, R. Endogenous inhibitors of angiogenesis. Cancer Res. 65, 3967–3979 (2005).
Asahara, T. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964–967 (1997).
Takahashi, T. et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nature Med. 5, 434–438 (1999).
Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 7, 1194–1201 (2001).
Heissig, B. et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109, 625–637 (2002).
Ruzinova, M. B. et al. Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrow-derived endothelial cells in spontaneous murine tumors. Cancer Cell 4, 277–289 (2003).
De Palma, M., Venneri, M. A., Roca, C. & Naldini, L. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nature Med. 9, 789–795 (2003).
Peters, B. A. et al. Contribution of bone marrow-derived endothelial cells to human tumor vasculature. Nature Med. 11, 261–262 (2005).
Shaked, Y. et al. Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 7, 101–111 (2005).
Gasparini, G., Longo, R., Fanelli, M. & Teicher, B. A. Combination of antiangiogenic therapy with other anticancer therapies: results, challenges, and open questions. J. Clin. Oncol. 23, 1295–1311 (2005).
Browder, T. et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 60 1878–1886 (2000).
Klement, G. et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Invest. 105, R15–R24 (2000).
Sweeney, C. J. et al. The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors. Cancer Res. 61, 3369–3372 (2001).
Bertolini, F. et al. Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res. 63, 4342–4346 (2003).
Kerbel, R. S. & Kamen, B. A. The anti-angiogenic basis of metronomic chemotherapy. Nature Rev. Cancer 4, 423–436 (2004).
Kim, J. J. & Tannock, I. F. Repopulation of cancer cells during therapy: an important cause of treatment failure. Nature Rev. Cancer 5, 516–525 (2005).
Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).
Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004).
Willett, C. G. et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nature Med. 10, 145–147 (2004).
Siemann, D. W., Chaplin, D. J. & Horsman, M. R. Vascular-targeting therapies for treatment of malignant disease. Cancer 100, 2491–2499 (2004).
Ferrara, N., Hillan, K. J., Gerber, H. P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature Rev. Drug Discov. 3, 391–400 (2004).
Miller, K. D. et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J. Clin. Oncol. 23, 792–799 (2005).
Johnson, D. H. et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J. Clin. Oncol. 22, 2184–2191 (2004).
Smith, J. K., Mamoon, N. M. & Duhe, R. J. Emerging roles of targeted small molecule protein-tyrosine kinase inhibitors in cancer therapy. Oncol. Res. 14 175–225 (2004).
Herbst, R. S. et al. Phase I study of recombinant human endostatin in patients with advanced solid tumors. J. Clin. Oncol. 20, 3792–3803 (2002).
Garner, A. Vascular diseases. In Pathobiology of Ocular Disease (eds Garner, A. & Klintworth, G. K.) 1625–1710 (Marcel Dekker, New York, 1994).
Ruckman, J. et al. 2′-Fluoropyrimidine RNA-based aptamers to the 165-amino acid form of vascular endothelial growth factor (VEGF165). Inhibition of receptor binding and VEGF-induced vascular permeability through interactions requiring the exon 7-encoded domain. J. Biol. Chem. 273, 20556–20567 (1998).
Chen, Y. et al. Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured Fab in complex with antigen. J. Mol. Biol. 293, 865–881 (1999).
Kerbel, R. S. et al. Possible mechanisms of acquired resistance to anti-angiogenic drugs: implications for the use of combination therapy approaches. Cancer Metastasis Rev. 20, 79–86 (2001).
Sweeney, C. J., Miller, K. D. & Sledge, G. W. Jr. Resistance in the anti-angiogenic era: nay-saying or a word of caution? Trends Mol. Med. 9, 24–29 (2003).
Yu, J. L., Rak, J. W., Coomber, B. L., Hicklin, D. J. & Kerbel, R. S. Effect of p53 status on tumor response to antiangiogenic therapy. Science 295, 1526–1528 (2002).
Glade Bender, J., Cooney, E. M., Kandel, J. J. & Yamashiro, D. J. Vascular remodeling and clinical resistance to antiangiogenic cancer therapy. Drug Resist. Updat. 7, 289–300 (2004).
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).
Lewis, C. & Murdoch, C. Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am. J. Pathol. 167, 627–635 (2005).
Guo, W. & Giancotti, F. G. Integrin signalling during tumour progression. Nature Rev. Mol. Cell. Biol. 5, 816–826 (2004).
Hida, K. et al. Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res. 64, 8249–8255 (2004).
Streubel, B. et al. Lymphoma-specific genetic aberrations in microvascular endothelial cells in B-cell lymphomas. N. Engl. J. Med. 351, 250–259 (2004).
Ferrara, N. & Alitalo, K. Clinical applications of angiogenic growth factors and their inhibitors. Nature Med. 5, 1359–1364 (1999).
Simons, M. Angiogenesis: where do we stand now? Circulation 111, 1556–1566 (2005).
Lederman, R. J. et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 359, 2053–2058 (2002).
Henry, T. D. et al. The VIVA trial: Vascular endothelial growth factor in ischemia for vascular angiogenesis. Circulation 107, 1359–1365 (2003).
Heinl-Green, A. et al. The efficacy of a ‘master switch gene’ HIF-1α in a porcine model of chronic myocardial ischaemia. Eur. Heart J. 26, 1327–1332 (2005).
Rafii, S. & Lyden, D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nature Med. 9, 702–712 (2003).
Tateishi-Yuyama, E. et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 360, 427–435 (2002).
Romond, E. H. et al. Trastuzumab plus adjuvant chemotherapy for operable HER-2-positive breast cancer. N. Engl. J. Med. 353, 1673–1684 (2005).
Morgan, B. et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J. Clin. Oncol. 21, 3955–3964 (2003).
LeCouter, J. et al. Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature 412, 877–884 (2001).
Samson, M. et al. Human endocrine gland-derived vascular endothelial growth factor: expression early in development and in Leydig cell tumors suggests roles in normal and pathological testis angiogenesis. J. Clin. Endocrinol. Metab. 89, 4078–4088 (2004).
Webb, T. Work on breast cancer stem cells raises questions about treatment strategies. J. Natl. Cancer Inst. 95, 774–775 (2003).
Jones, R. J., Matsui, W. H. & Smith, B. D. Cancer stem cells: are we missing the target? J. Natl. Cancer Inst. 96, 583–585 (2004).
Ponti, D. et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 65, 5506–5511 (2005).
Acknowledgements
R.S.K. was supported by grants from the Canadian Institutes for Health Research and the National Institute of Health.
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The authors declare competing financial interests: Dr Kerbel has received ad hoc consulting fees from Genentech, Novartis, Amgen and Centocor. He is a paid consultant for Inclone Systems and receives research funds from Inclone Systems. Dr Kerbel is also a member of the Scientific Advisory Board of Oxigene Inc., Compound Therapeutics and Attenuon, and receives consultant fees as well as stock options. All of the aforementioned companies are involved in the late-stage anti-angiogenic drug development.
Editor’s note: The Dr Ferrara has declared interests in Genentech, who have co-sponsored this Nature Insight. However, all the editorial content was commissioned entirely independently of this partnership.
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Ferrara, N., Kerbel, R. Angiogenesis as a therapeutic target. Nature 438, 967–974 (2005). https://doi.org/10.1038/nature04483
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DOI: https://doi.org/10.1038/nature04483