Solid tumors above a critical size become hypoxic at their core. The upregulation of the angiogenic factor VEGF under these conditions is widely thought to explain tumor vascularization and continued proliferation, but Vajkoczy and coworkers point out that some metastatic tumor cells express low levels of bio-active VEGF in a constitutive manner and appear to require VEGF signaling even at a very early stage. These authors used intravital microsopy to show that glioma cells interact with the host vasculature and begin to induce angiogenesis at times well before the tumor mass has reached this limit. Small cell clusters or individual glioma cells, implanted in a vascularized tissue, spread along existing vessels. The resulting tumors did not appear to grow around the existing vessels, as would have been predicted by the so-called "cooptation" model. Rather, infiltrating cells that broke from a tumor mass appeared to migrate along these vessels and induce the sprouting of new ones, which could be distinguished from normal vessels by their disorganized structure and their leakiness. Evidently, at least for this VEGF+ tumor cell type, vascular outgrowth does not begin with hypoxia, but occurs as a continuing process of growth and remodeling, starting early in tumor progression.
Journal of Clinical Investigation