Clinical Significance of VEGFA

Patients with large tumor burdens and widespread metastatic disease have increased levels of circulating

VEGF-A, often multiples of those found in normal individuals. Although not useful as a screening tool, increasing serum VEGF-A levels may signify increased tumor growth, recurrence, or metastatic spread in individual patients. There is debate about whether plasma or serum levels are more meaningful because platelets sequester VEGF-A and because plasma a2 macroglobulin binds it and makes it unavailable to at least some antibodies. Also, both megakaryocytes and leukocytes synthesize VEGF-A. Therefore, serum levels reflect not only VEGF-A of tumor origin but also that released from platelets and leukocytes, making it difficult to establish a range of normal values. VEGF-A levels are also elevated in malignant effusions and in the urine of patients with bladder cancer.

Treatments that reduce VEGF-A expression or inhibit its action have been advanced as an antiangiogenesis approach to cancer therapy. Antibodies that neutralize VEGF-A strikingly inhibit tumor growth in mice and have recently shown success in prolonging the life of colon cancer patients when used in combination with chemotherapy. Conversely, VEGF-A has been used in attempts to induce the growth of new blood vessels in ischemic tissues (e.g., myocardial infarctions, peripheral vascular disease), but there are many reasons for caution. Very recently, reduced VEGF-A has been implicated in amyotrophic lateral sclerosis and in certain neurovascular disorders.

Glossary

Angiogenesis: The development of new blood vessels from preexisting blood vessels.

Vasculogenesis: The development of blood vessels from angioblasts as in development.

Vesiculo-vacuolar organelles (VVOs): Interconnected chains of uncoated cytoplasmic vesicles and vacuoles that span the entire thickness of venule endothelial cell cytoplasm from lumen to albumen. VVOs serve as a pathway for macromolecular extravasation and as an intracellular store of plasma membrane that can be transferred to the cell surface to allow rapid plasma membrane expansion and vessel enlargement.

Further Reading

Carmeliet, P. (2003). Blood vessels and nerves: Common signals, pathways and diseases. Nat. Rev. Genet. 4, 710-720. VEGF-A biological activities.

Cross, M. J., Dixelius, J., Matsumoto, T., and Claesson-Welsh, L. (2003). VEGF-receptor signal transduction. Trends Biochem. Sci. 28, 488-494. VEGF-A receptors and signaling. Dvorak, H. F. (2002). 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. VEGF-A structure, receptors and signaling, biological activities, expression, regulation of expression, clinical significance. Dvorak, H. F. (2003). Rous-Whipple Award Lecture. How tumors make bad blood vessels and stroma. Am. J. Pathol. 162, 1747-1757. New blood vessels induced by VEGF-A. Dvorak, H. F., Nagy, J. A., Feng, D., Brown, L. F., and Dvorak, A. M. (1999). Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis. Curr. Top. Microbiol. Immunol. 237, 97-132. VEGF-A biological activities, expression. Feng, D., Nagy, J. A., Pyne, K., Hammel, I., Dvorak, H. F., and Dvorak, A. M. (1999). Pathways of macromolecular extravasation across microvascular endothelium in response to VPF/VEGF and other vasoactive mediators. Microcirculation 6, 23-44. VEGF-A biological activities (vascular permeability mechanisms). Ferrara, N., Gerber, H. P., and LeCouter, J. (2003). The biology of VEGF and its receptors. Nat. Med. 9, 669-676. VEGF-A structure, biological activities, expression clinical significance. Melder, R. J., Koenig, G. C., Witwer, B. P., Safabakhsh, N., Munn, L. L., and Jain, R. K. (1996). During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat. Med. 2, 992-997. VEGF-A biological activities.

Mukhopadhyay, D., and Zeng, H. (2002). Involvement of G proteins in vascular permeability factor/vascular endothelial growth factor signaling. Cold Spring Harbor Symp. Quant. Biol. 67, 275-283. VEGF-A receptors and signaling.

Nagy, J. A., Dvorak, A. M., and Dvorak, H. F. (2003). VEGF-A(164/165) and PlGF: Roles in angiogenesis and arteriogenesis. Trends Cardio-vasc. Med. 13, 169-175. New blood vessels induced by VEGF-A.

Nagy, J. A., Vasile, E., Feng, D., Sundberg, C., Brown, L. F., Manseau, E. J., Dvorak, A. M., and Dvorak, H. F. (2002). VEGF-A induces angio-genesis, arteriogenesis, lymphangiogenesis, and vascular malformations. Cold Spring Harbor Symp. Quant. Biol. 67, 227-237. New blood vessels induced by VEGF-A.

Rafii, S., Lyden, D., Benezra, R., Hattori, K., and Heissig, B. (2002). Vascular and haematopoietic stem cells: Novel targets for anti-angiogene-sis therapy? Nat. Rev. Cancer 2, 826-835. Biological activities of VEGF-A.

Rak, J., Filmus, J., Finkenzeller, G., Grugel, S., Marme, D., and Kerbel, R. S. (1995). Oncogenes as inducers of tumor angiogenesis. Cancer Metastasis Rev. 14, 263-277. Regulation of VEGF-A expression by oncogenes and tumor suppressor genes.

Stalmans, I., Ng, Y. S., Rohan, R., Fruttiger, M., Bouche, A., Yuce, A., Fujisawa, H. Hermans, B., Shani, M., Jansen, S., Hicklin, D., Anderson, D. J., Gardiner, T., Hammes, H. P., Moons, L., Dewerchin, M., Collen, D., Carmeliet, P., and D'Amore, P. A. (2002). Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J. Clin. Invest. 109, 327-336. VEGF-A structure.

Capsule Biography

Dr. Dvorak has served as chair of the Department of Pathology at Beth Israel Deaconess Medical Center and as Mallinckrodt Professor of Pathology at the Harvard Medical School since 1979. The recipient of the 2002 Rous-Whipple Award from the American Society for Investigative Pathology, his laboratory focuses primarily on the angiogenic response in health and disease. His work is supported by grants from the NIH and the National Foundation for Cancer Research.

Endothelial Progenitor Cells, Vasculogenesis, and Their Contribution to New Blood Vessel Formation in the Adult

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