Hypoxia-Inducible Factor-1 Modulates Gene Expression in Solid Tumors and Influences Both Angiogenesis and Tumor Growth

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 94; no. 15; pp. 8104 - 8109
• Main Authors: Maxwell, P. H., Dachs, G. U., Gleadle, J. M., Nicholls, L. G., Harris, A. L., Stratford, I. J., Hankinson, O., Pugh, C. W., Ratcliffe, P. J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 22-07-1997; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences of the USA
• Subjects: Animals; Biological Sciences; Carcinoma, Hepatocellular - blood supply; Carcinoma, Hepatocellular - pathology; Cell culture techniques; Cell Division; Cell growth; Cell Line; Cell lines; Cells; Cultured cells; DNA-Binding Proteins - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Heterologous transplantation; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms - blood supply; Liver Neoplasms - pathology; Medical research; Messenger RNA; Mice; Mice, Nude; Necrosis; Neoplasm Transplantation; Neovascularization, Pathologic; Nuclear Proteins - metabolism; Physical growth; Transcription Factors - metabolism; Tumors; Xenobiotics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.15.8104

Recent studies of tissue culture cells have defined a widespread system of oxygen-regulated gene expression based on the activation of a heterodimeric transcription factor termed hypoxia-inducible factor-1 (HIF-1). To determine whether the HIF-1 transcriptional response is activated within solid tumors and to define the consequences, we have studied tumor xenografts of a set of hepatoma (Hepa-1) cells that are wild type (wt), deficient (c4), and revertant (Rc4) for an obligatory component of the HIF-1 heterodimer, HIF-1β . Because HIF-1β is also essential for the xenobiotic response (in which it is termed the aryl hydrocarbon receptor nuclear translocator), we also studied c31 cells, which have a different defect in the xenobiotic response and 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 induction 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 reduced vascularity and grew more slowly. These findings show that HIF-1 activation occurs in hypoxic regions of tumors and demonstrate a major influence on gene expression, tumor angiogenesis, and growth.