Normoxic and hypoxic regulation of vascular endothelial growth Factor (VEGF) by astrocytoma cells is mediated by Ras

Vascular endothelial growth Factor (VEGF) has been identified as a key angi ogenic factor involved in the growth and malignant progression of tumours. Glioblastoma multiforme (GBM) are the most common primary human brain tumou rs, histo-pathologically characterized by intense tumour angiogenesis. GBMs do not harbour oncogenic Ros mutations, but: there is a functional up-regu lation of Ras signaling through activation of receptor tyrosine kinases ove rexpressed by these tumours. We demonstrate that pas pathway activation reg ulates VEGF secretion in astrocytoma cell Lines. pas pathway inhibition was carried out using generic and pharmacologic techniques. Astrocytoma cells that were transfected to express the dominant inhibitory mutant H-Ras(N17) demonstrated a reduction in VEGF secretion under both normoxic and hypoxic conditions. Cells treated with the farnesyl transferase inhibitor L-744,832 demonstrated similar reductions in VEGF secretion, Furthermore, astrocytom a cells expressing a constitutively phosphorylated and truncated EGF-R comm on in GBMs (ECFRvIII or p140(EGF-R)) demonstrate further elevations in pas activation, resulting in a further increase in VEGF secretion. We have prev iously demonstrated that activation of pas plays a vital role In transducin g mitogenic signals in human malignant astrocytoma cells. Our present resul ts further extend the role of Ras activation in modulating tumour angiogene sis in these tumours. We propose that: pas may contribute to the angiogenic switch in astrocytomas. (C) 1999 Wilet-Liss, Inc.