Opposing effects of hypoxia on expression of the angiogenic inhibitor thrombospondin 1 and the angiogenic inducer vascular endothelial growth factor

Tumor angiogenesis, the development of new blood vessels during malignant p rogression, is a regulated process that has both genetic and physiological controls. Physiologically, angiogenesis is stimulated by decreases in tissu e oxygenation (i.e., hypoxia), We investigated the effect of hypoxia on the expression of two angiogenic factors reported to be genetically regulated by the p53 tumor suppressor gene: (a) the angiogenic inhibitor thrombospond in 1 (TSP-1); and (b) the angiogenic inducer vascular endothelial growth fa ctor (VEGF). Analysis of rodent cells that differ in their p53 genotype (p5 3(+/+) or p53(-/-)) indicated that in vitro exposure to hypoxia simultaneou sly suppressed TSP-1 and induced VEGF expression, regardless of the p53 gen otype, On transformation of these cells with E1A and oncogenic H-ras, the b asal level of TSP-I expression was strongly diminished, whereas that of VEG F could still be induced by hypoxia, Consistent with these in vitro finding s, sections of tumors derived from the transformed p53(+/+) and p53(-/-) ce lls showed that VEGF protein overlapped with regions of hypoxia, whereas TS P-I protein was below the limits of detection in tumor tissue. Using a pane l of normal/immortalized and transformed human cells, it was found that the ability of hypoxia to inhibit TSP-1 expression depends on the cell type an d/or the degree of transformation. In contrast, VEGF expression was induced by hypoxia in all of the human cell types examined. Together, these findin gs suggest that hypoxic and oncogenic signals could interact in the tumor m icroenvironment to inhibit TSP-1 and induce VEGF expression, promoting the switch to the angiogenic phenotype.