Review
HIF-1 and tumor progression: pathophysiology and therapeutics

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Abstract

Hypoxia-inducible factor 1 (HIF-1) controls oxygen delivery (via angiogenesis) and metabolic adaptation to hypoxia (via glycolysis). HIF-1 consists of a constitutively expressed HIF-1β subunit and an oxygen- and growth-factor-regulated HIF-1α subunit. In xenografts, tumor growth and angiogenesis are correlated with HIF-1 expression. In human cancers, HIF-1α is overexpressed as a result of intratumoral hypoxia and genetic alterations affecting key oncogenes and tumor suppressor genes. HIF-1α overexpression in biopsies of brain, breast, cervical, esophageal, oropharyngeal and ovarian cancers is correlated with treatment failure and mortality. Increased HIF-1 activity promotes tumor progression, and inhibition of HIF-1 could represent a novel approach to cancer therapy.

Section snippets

Molecular and cellular biology of HIF-1

HIF-1 is a heterodimer composed of HIF-1α and HIF-1β subunits, which are basic helix–loop–helix–PAS domain proteins. HIF-1β is constitutively expressed, whereas the expression of HIF-1α is maintained at low levels in most cells under normoxic conditions (Fig. 1). The negative regulation of HIF-1α expression results from the activity of oxygen-dependent prolyl hydroxylases that modify residues 564 and 402 [7]. This enzymatic modification of HIF-1α is required for the binding of the von

Mechanisms and consequences of HIF-1α overexpression in human cancers

Immunohistochemical analysis of human tumor biopsies revealed dramatic overexpression of HIF-1α in common cancers 16., 17.; this is a consequence of both intra-tumoral hypoxia and genetic alterations (Table 1). Whereas hypoxia is a universal stimulus for HIF-1α expression, the effect of genetic alterations (other than VHL loss-of-function) appears to depend on the signal transduction pathways that are active in a particular tumor cell. These data provide a molecular mechanism linking oncogene

Therapeutic implications

The recent data regarding the role of HIF-1 in tumor progression have important clinical implications. First, as described above, immunohistochemical analysis of tumor biopsies for HIF-1α expression might provide prognostic information and identify subsets of patients requiring aggressive therapy that would not be offered to the general patient population because the increased side-effects seen in all patients would offset the survival benefits seen in the high-risk subgroup. This scenario

Concluding remarks

Anti-angiogenic therapy is a promising new approach (Box 1), although concerns have been raised that it will select for highly aggressive, hypoxia-adapted tumor cells [36]. The assumption that selection for endothelial cells that are resistant to the therapy is unlikely to occur has been called into question by the identification of mutations affecting proteins in apoptotic pathways in endothelial cells of patients with primary pulmonary hypertension [37]. The combination of an anti-angiogenic

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