HIF-1 alpha-mediated up-regulation of vascular endothelial growth factor, independent of basic fibroblast growth factor, is important in the switch to the angiogenic phenotype during early tumorigenesis

The switch to the angiogenic phenotype represents a critical checkpoint dur ing tumor progression. The acquisition of new capillary vessels provides ne wly vascularized tumor nodules with a distinct biological advantage over th eir avascular counterparts by conferring upon them the ability to expand an d develop both locally and metastatically. To identify the molecules and me chanisms underlying this rate-limiting step in successful tumorigenesis, we have developed an in vivo tumor model that reproducibly recapitulates the angiogenic switch. Using this model, we have analyzed vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hypoxia-in ducible factor-1 alpha (HIF-1 alpha) expression and activity in both avascu lar and vascular growth phases of the tumor. A significantly higher level o f VEGF protein was detected in avascular tumor nodules compared with vascul ar nodules. As avascular tumors became vascularized, VEGF levels decreased similar to 10-fold. In contrast, bFGF levels were not elevated in avascular nodules but rather were detected at levels similar to2 times higher in vas cular nodules compared with the avascular tumor nodules. Given that VEGF is transcriptionally regulated by HIF-1 alpha, immunohistochemical studies of chondrosarcoma nodules were conducted and revealed that the nuclear transl ocation of HIF-1 alpha was detected exclusively in avascular tumor nodules. This study implicates HIF-1 alpha -mediated up-regulation of VEGF but not bFGF in the switch to the angiogenic phenotype during tumorigenesis.