Title: The role of VEGF pathways in human physiologic and pathologic angiogenesis. Authors
|Lyons, John - LSU HEALTH SCIENCE CTR|
|Schwimer, Joshua - LSU HEALTH SCIENCE CTR|
|Anthony, Cathy - LSU HEALTH SCIENCE CTR|
|Cundiff, Jason - LSU HEALTH SCIENCE CTR|
|Casey, Douglas - LSU HEALTH SCIENCE CTR|
|Maccini, Cynthia - PROVIDENCE CANCER CTR|
|Kucera, Paul - PROVIDENCE CANCE CTR|
|Wang, Yi-Zarn - LSU HEALTH SCIENCE CTR|
Submitted to: Journal of Surgical Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 15, 2008
Publication Date: March 1, 2010
Citation: Lyons, J., Schwimer, J.E., Anthony, C.T., Thomson, J.L., Cundiff, J.D., Casey, D.T., Maccini, C., Kucera, P., Wang, Y. 2010. The role of VEGF pathways in human physiologic and pathologic angiogenesis. Journal of Surgical Research. 159(1):517-527. Interpretive Summary: The human body's abilitiy to grow new blood vessels occurs in normal (wound healing and menustration) as well as diseased (cancer) processes. Of the many compounds believed to affect this ability, the vascular endothelial growth factor (VEGF) is one of the most significant. However, while VEGF's ability to stimulate new blood vessel growth has been shown to occur in many animal models, it has not been directly shown in humans. We tested VEGF's ability to stimulate new blood vessel growth in both normal (human placental veins) and diseased (tumors) human tissue. Additionally, we tested the ability of anti-VEGF compounds to stop new blood vessel growth in normal and diseased human tissue. We found that VEGF did not stimulate new blood vessel growth in either normal or diseased human tissue. Additionally, anti-VEGF compounds that targeted only VEGF mechanisms did not consistently stop growth while one compound that targeted both VEGF and non-VEGF mechanisms was very effective in stopping growth. These results suggest that targeting VEGF in combination with other growth factors may be a more effective method of stopping angiogenesis than targeting VEGF alone. Hence, the use of chemotherapy drugs that target multiple growth factors including VEGF may prove to be a more effective treatment of cancers.
Technical Abstract: In pre-clinical models VEGF is a potent stimulant of both physiologic and pathologic angiogenesis. Conversely, anti-VEGF regimens have successfully inhibited angiogenesis both in vitro and in vivo. We hypothesized that VEGF would stimulate both physiologic and pathologic angiogenesis in a human-based fibrin-thrombin clot angiogenesis assay. We further speculated that anti-VEGF regimens would inhibit angiogenesis in this assay. To test these hypotheses, discs of human placental veins (physiologic model) and fragments of human tumors (pathologic model) were embedded in fibrin-thrombin clots, and treated with either VEGF-A165 (VEGF) or anti-VEGF pathway reagents, including bevacizumab, IMC-18F1, IMC-1121, and PTK787 (n=30 wells per treatment group, multiple concentrations tested in each specimen). Angiogenic responses were assessed visually using a previously validated grading scheme. The percent of tissue explants that developed angiogenic invasion into the clot (%I), as well as the extent of angiogenic growth (AI) via a semi-quantitative scale, was assessed at set intervals. VEGF failed to stimulate angiogenesis in both the physiologic and the pathologic model. While anti-VEGF reagents that targeted only one element of the VEGF pathway failed to consistently inhibit angiogenesis, PTK787, a receptor tyrosine kinase inhibitor that targets multiple VEGF and non-VEGF receptors, profoundly inhibited both physiologic and pathologic angiogenesis. These results suggest that VEGF-related pathways may not be solely responsible for stimulating angiogenesis in humans. Targeting the VEGF pathway in combination with elements of other growth factor pathways may provide a more effective means of inhibiting angiogenesis than targeting VEGF alone.