Cellular source and amount of vascular endothelial growth factor and platelet-derived growth factor in tumors determine response to angiogenesis inhibitors.
Vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and their receptors are important targets in cancer therapy based on angiogenesis inhibition. However, it is unclear whether inhibition of VEGF and PDGF together is more effective than inhibition of either one alone. Here, we used two contrasting tumor models to compare the effects of inhibiting VEGF or PDGF alone, by adenovirally generated soluble receptors, to the effects of inhibiting both together. In RIP-Tag2 tumors, VEGF and PDGF inhibition together reduced tumor vascularity and abundance of pericytes. However, VEGF inhibition reduced tumor vascularity without decreasing pericyte density, and PDGF inhibition reduced pericytes without reducing tumor vascularity. By contrast, in Lewis lung carcinomas (LLC), inhibition of VEGF or PDGF reduced blood vessels and pericytes to the same extent as did inhibition of both together. Similar results were obtained using tyrosine kinase inhibitors AG-013736 and imatinib. In LLC, VEGF expression was largely restricted to pericytes and PDGF was largely restricted to endothelial cells, but, in RIP-Tag2 tumors, expression of both growth factors was more widespread and significantly greater than in LLC. These findings suggest that inhibition of PDGF in LLC reduced pericytes, and then tumor vessels regressed because pericytes were the main source of VEGF. The vasculature of RIP-Tag2 tumors, in which most VEGF is from tumor cells, was more resistant to PDGF inhibition. The findings emphasize the interdependence of pericytes and endothelial cells in tumors and the importance of tumor phenotype in determining the cellular effects of VEGF and PDGF inhibitors on tumor vessels.
Sennino
Barbara
B
Cardiovascular Research Institute, Comprehensive Cancer Center, and Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA. barbara.sennino@ucsf.edu
Kuhnert
Frank
F
Tabruyn
Sebastien P
SP
Mancuso
Michael R
MR
Hu-Lowe
Dana D
DD
Kuo
Calvin J
CJ
McDonald
Donald M
DM
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000077784:Axitinib; D001549:Benzamides; D006801:Humans; D000068877:Imatinib Mesylate; D007093:Imidazoles / Q000627:therapeutic use; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007191:Indazoles / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010879:Piperazines / Q000627:therapeutic use; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D011743:Pyrimidines / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000187:drug effects / Q000235:genetics
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001549:Benzamides; D007093:Imidazoles; D007141:Immunoglobulin Fc Fragments; D007191:Indazoles; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; D042461:Vascular Endothelial Growth Factor A; D000068877:Imatinib Mesylate; D000077784:Axitinib; D040281:Vascular Endothelial Growth Factor Receptor-1