Overexpression of Hypoxia-inducible Factor 1a in Common Human Cancers and Their Metastases

Neovascularization and increased glycolysis, two universal characteristics of solid tumors, represent adaptations to a hypoxic microenvironment that are correlated with tumor invasion, metastasis, and lethality. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. HIF-1 transcriptional activity is determined by regulated expression of the HIF-1a subunit. In this study, HIF-1a expression was analyzed by immunohistochemistry in 179 tumor specimens. HIF-1a was overexpressed in 13 of 19 tumor types compared with the respective normal tissues, including colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas. HIF-1a expression was correlated with aberrant p53 accumulation and cell proliferation. Preneoplastic lesions in breast, colon, and prostate overexpressed HIF-1a, whereas benign tumors in breast and uterus did not. HIF-1a overexpression was detected in only 29% of primary breast cancers but in 69% of breast cancer metastases. In brain tumors, HIF-1a immunohistochemistry demarcated areas of angiogenesis. These results provide the first clinical data indicating that HIF-1a may play an important role in human cancer progression.