Hypoxia and tumour metabolism: approach towards new anti-cancer targets


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Jacques Pouyssegur

Institute of Signaling, Developmental Biology and Cancer Research, Nice, France

Abstract

Nutrient sensing is a fundamental process for life. In its absence, fast growing cells of the developing embryo and of expanding tumors would rapidly die. In fact cells sense and respond to variations in the concentration of key nutrients. However, early on in evolution, oxygen sensing has emerged, as a central control mechanism of energy metabolism and vasculogenesis. At the heart of this regulatory system is the Hypoxia-Inducible Factor, HIF, which controls, among other gene products, the expression of VEGF-A and Angiopoetin-2, two key angiogenic factors in vertebrates. This finding has placed the hypoxia-signaling pathway at the forefront of nutritional control.

HIF can induce a vast array of gene products controlling glycolysis, intracellular pH (pHi), angiogenesis, cell migration and invasion, and so has become recognized as a strong promoter of tumor growth. The pro-invasion feature of HIF, measured by stimulation of Epithelial-Mesenchyme-Transition, could be seen as an integrated program designed for migration-induced nutrient-search, as in microorganisms. It is therefore not surprising that HIF also promotes access to another source of nutrients by inducing macro-autophagy.

In this presentation, we will highlight some of the HIF-induced gene products that participate in tumor adaptation, resistance and progression in a nutrient-depleted and acidic microenvironment.