Recent experimental studies have implicated tumor micro-environment in the selection of particular genetic mutations during tumorigenesis. In response to low oxygen conditions in the growing tumor mass, certain oncogenic mutations appear to predispose cells to apoptotic cell death. This leads to selection for anti-apoptotic mutations and for a genetic switch to a pro-angiogenesis phenotype. This switch to the angiogenic phenotype is associated with a coordinated increase in expression of angiogenic-promoting cytokines such as TNFalpha, bFGF, PDGF, and VEGF. Based on data that shows that oncogenic forms of Ha-Ras can increase the expression of VEGF, the hypothesis is put forth that oncogenic transformation primes cells for VEGF expression and that tumor hypoxia would then provide the necessary signal to increase or maintain the state of angiogenic growth factor production. Experiments are proposed which will: 1) Investigate whether cells which express oncogenic forms of Ras utilize PI-3 kinase in signaling the induction of pro-angiogenic cytokines and mitogens and whether this induction is regulated through HIF-1 and CACACAG/C; 2) To determine how Ras interacts with PDGF receptor and PI-3K signaling in the induction of VEGF; and 3) To investigate the relationship between the Ras and myc oncogenes and promoting cell death or survival at the unicellular and multicellular stages.
