Angiogenesis-Independent Neovascularization is a Major Contributor to Tumor Growth

摘要

Tumors must manipulate the host vasculature to provide a blood supply adequate for their proliferation. Although tumors may arise as avascular masses. there is increasing evidence that some tumors begin to proliferate by coopting the host vasculature. By analyzing cell proliferation kinetics of endothelial cells (EC) and PC3 prostate cancer cells, we provide evidence that EC proliferation could not account for rapid tumor growth. Although PC3mm2 expressing green fluorescent protein (GFP) failed to grow in the ears, in an orthotopic GFP - expressing melanoma model we demonstrated that the tumor vasculature was generated from a preexisting red cell-deficient vascular network that continuously remodeled to accommodate the requirements of the expanding tumor mass. Topical application of vascular endothelial growth factor (VEGF) to vascular beds generated immediate and robust vascular transitions that were morphologically similar to tumor-induced vascular transitions. N(phi)- nitro-L-arginine, a nitric oxide inhibitor that prevented VEGF-mediated vascular remodeling and vasodilatation, significantly inhibited prostate tumor growth without reducing EC proliferation. These findings suggest that prostate tumor-induced remodeling of red cell-deficient vessels, and not angiogenic sprouting, contributes to tumor vascularization and concomitant proliferation.