Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases.

TLDR

Solid tumors adapt to hypoxia by neovascularization and increased glycolysis, processes driven by HIF‑1 activation of genes for glucose transport, glycolytic enzymes, and VEGF, with HIF‑1α expression regulating this transcriptional activity. The authors quantified HIF‑1α expression by immunohistochemistry in 179 tumor specimens. HIF‑1α was overexpressed in 13 of 19 tumor types, correlated with p53 accumulation and proliferation, was present in preneoplastic lesions but not benign tumors, appeared in 69 % of breast cancer metastases versus 29 % of primaries, and marked angiogenic areas in brain tumors, supporting a role for HIF‑1α in human cancer progression.

Abstract

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-1alpha subunit. In this study, HIF-1alpha expression was analyzed by immunohistochemistry in 179 tumor specimens. HIF-1alpha 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-1alpha expression was correlated with aberrant p53 accumulation and cell proliferation. Preneoplastic lesions in breast, colon, and prostate overexpressed HIF-1alpha, whereas benign tumors in breast and uterus did not. HIF-1alpha overexpression was detected in only 29% of primary breast cancers but in 69% of breast cancer metastases. In brain tumors, HIF-1alpha immunohistochemistry demarcated areas of angiogenesis. These results provide the first clinical data indicating that HIF-1alpha may play an important role in human cancer progression.