HYPOXIA-INDUCIBLE FACTOR-I MODULATES GENE-EXPRESSION IN SOLID TUMORS AND INFLUENCES BOTH ANGIOGENESIS AND TUMOR-GROWTH

Recent studies of tissue culture cells have defined a widespread syste m of oxygen-regulated gene expression based on the activation of a het erodimeric transcription factor termed hypoxia-inducible factor-1 (HIF -1). To determine whether the HIF-1 transcriptional response is activa ted within solid tumors and to define the consequences, we have studie d tumor xenografts of a set of hepatoma (Hepa-1) cells that are wild t ype (wt), deficient (c4), and revertant (Rc4) for an obligator compone nt of the HIF-1 heterodimer, HIF-1 beta. Because HIF-1 beta is also Es sential for the xenobiotic response (in which it is termed the aryl hy drocarbon receptor nuclear translocator), we also studied c31 cells, w hich have a different defect in the xenobiotic response anti form the HIF-1 complex normally, Two genes that show different degrees of HIF-1 -dependent hypoxia-inducible expression in cell culture were selected for analysis-the glucose transporter, GLUT3, and vascular endothelial growth factor (VEGF). In Situ hybridization showed intense focal induc tion of gene expression in tumors derived from wt, Rc4, and c31 cells, which was reduced (VEGF) or not seen (GLUT3) in those derived from c4 cells, In association with these changes, tumors of c4 cells had redu ced vascularity and grew more slowly. These findings show that HIF-1 a ctivation occurs in hypoxic regions of tumors and demonstrate a major influence on gene expression, tumor angiogenesis, and growth.