Main problem in anti-angio approach to cancer is microenvironmental (inside and near-by tumor mass) control of the vegf activity.
jci.org
J. Clin. Invest. 113:516-527 (2004). doi:10.1172/JCI200418420.
Copyright ©2004 by the American Society for Clinical Investigation
Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis
Clare R. Ozawa1, Andrea Banfi1, Nicole L. Glazer2, Gavin Thurston3, Matthew L. Springer1, Peggy E. Kraft1, Donald M. McDonald2 and Helen M. Blau1
1Baxter Laboratory in Genetic Pharmacology, Stanford University School of Medicine, Stanford, California, USA
2Cardiovascular Research Institute, Comprehensive Cancer Center, and Department of Anatomy, University of California, San Francisco, California, USA
3Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA
Address correspondence to: Helen M. Blau, Baxter Laboratory in Genetic Pharmacology, Stanford University School of Medicine, Stanford, California 94305-5175, USA. Phone: (650) 723-6209; Fax: (650) 736-0080; E-mail: hblau@stanford.edu.
Received for publication March 21, 2003, and accepted in revised form December 16, 2003.
Use of long-term constitutive expression of VEGF for therapeutic angiogenesis may be limited by the growth of abnormal blood vessels and hemangiomas. We investigated the relationship between VEGF dosage and the morphology and function of newly formed blood vessels by implanting retrovirally transduced myoblasts that constitutively express VEGF164 into muscles of adult mice. Reducing VEGF dosage by decreasing the total number of VEGF myoblasts implanted did not prevent vascular abnormalities. However, when clonal populations of myoblasts homogeneously expressing different levels of VEGF were implanted, a threshold between normal and aberrant angiogenesis was found. Clonal myoblasts that expressed low to medium levels of VEGF induced growth of stable, pericyte-coated capillaries of uniform size that were not leaky and became VEGF independent, as shown by treatment with the potent VEGF blocker VEGF-TrapR1R2. In contrast, clones that expressed high levels of VEGF induced hemangiomas. Remarkably, when different clonal populations were mixed, even a small proportion of cells with high production of VEGF was sufficient to cause hemangioma growth. These results show for the first time to our knowledge that the key determinant of whether VEGF-induced angiogenesis is normal or aberrant is the microenvironmental amount of growth factor secreted, rather than the overall dose. Long-term continuous delivery of VEGF, when maintained below a threshold microenvironmental level, can lead to normal angiogenesis without other exogenous growth factors. |
