ROLE OF THE HYPOXIA SENSING SYSTEM, ACIDITY AND REPRODUCTIVE HORMONESIN THE VARIABILITY OF VASCULAR ENDOTHELIAL GROWTH-FACTOR INDUCTION INHUMAN BREAST-CARCINOMA CELL-LINES

Vascular endothelial growth factor (VEGF) is a potent angiogenic facto r implicated in many pathological processes. We investigated the regul ation of 4 alternatively spliced isoforms (121, 165, 189 and 206 amino acids) by hypoxia, hypoglycemia, acidity, female reproductive hormone s and vitamin D in breast carcinoma cell lines representing different tumor phenotypes. There was a 17-fold difference in total VEGF mRNA ex pression across the cell lines. The isoform expression, 121 > 165 > 18 9, was unchanged by different culture conditions. Hypoxia was the most potent stimulus, and the cell lines demonstrated a 1.4- to 6.9-fold r ange of VEGF induction, maintained when other hypoxically regulated ge nes (phosphoglycerate kinase I and glucose transporter () and a HIF-1- dependent reporter gene were examined. The relative inducibility of th e genes was maintained in each cell line, but basal expression was ind ependent of -fold induction. VEGF expression decreased under acidic co nditions in 2 cell lines, but the hypoxia stimulus remained effective under acidic conditions. Hypoglycemia, female reproductive hormones an d vitamin D exerted no effect on expression, nor did inhibitors of mut ant ras. Our results show that VEGF expression varies widely between c ell lines and that capacity to respond to hypoxia is also cell specifi c, relating mostly to the hypoxic sensing of the cell and the signal t ransduction mechanism. Such characteristics, if maintained in vivo, ha ve implications for the angiogenic potential of different tumor cells under normal and hypoxic conditions. (C) 1998 Wiley-Liss, Inc.