Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth

Abstract

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-1␤. Because HIF-1␤ 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 inf luence on gene expression, tumor angiogenesis, and growth.

Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival

“…Since HIF1 and HIF2 stabilization up-regulates the expression of angiogenic and glycolytic pathways to restore oxygen homeostasis, HIFs may have an important role for the survival and growth of cancer. Indeed, recent experimental studies confirm that HIFs modulate gene expression resulting in increased angiogenesis and tumoural growth (Jiang et al, 1997;Maxwell et al, 1997).…”

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

“…Mouse Hepa-1 hepatomas from HIF-1b-deficient cells exhibited reduced hypoxia-mediated gene expression, vascularity and growth rate, compared with the wild type tumors (Maxwell et al, 1997). Analogously, HIF-1b À/À knockout embryonic stem (ES) cells failed to activate hypoxiaresponsive genes and to respond to a decrease in glucose concentration (Maltepe et al, 1997).…”

Levels of hypoxia‐inducible factor‐1α independently predict prognosis in patients with lymph node negative breast carcinoma

“…Direct correlations between HIF-1, VEGF, and tumor angiogenesis have been demonstrated. 8,10,12 HIF-1 expression may have prognostic and therapeutic consequences because angiogenesis is a prognostic indicator. 13,14 Although the precise mechanism, and especially the initiation, of tumor angiogenesis is not understood fully, antiangiogenic therapies are under rapid development and clinical evaluation.…”