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Cancer Metastasis Rev (2007) 26:291298
DOI 10.1007/s10555-007-9060-4
Effects of hypoxia on tumor metabolism
Jung-whan Kim & Ping Gao & Chi V. Dang
Published online: 6 April 2007 # Springer Science + Business Media, LLC 2007
Abstract Rapidly growing tumors invariably contain hypoxic regions. Adaptive response to hypoxia through angio-genesis, enhanced glucose metabolism and diminished but optimized mitochondrial respiration confers survival and growth advantage to hypoxic tumor cells. In this review, the roles of hypoxia, the hypoxia inducible factors, oncogenes and tumor suppressors in metabolic adaptation of tumors are discussed. These new insights into hypoxic metabolic alterations in tumors will hopefully lead us to target tumor bioenergetics for the treatment of cancers.
Keywords Tumor . Hypoxia . Hypoxia-inducible factor . Metabolism . Tumor bioenergetic
1 Introduction
Ever since the build up of earths atmospheric oxygen, organisms have adapted and utilize oxygen for the efficient generation of energy through mitochondrial oxidative phosphorylation. It is intriguing that multicellular organisms have
also preserved an ability to adapt to low oxygen conditions or hypoxia, which existed in earths infancy [1]. Low oxygen supply is frequently inevitable under physiological as well as pathological conditions. The dependence of mammals on oxygen for cellular energy production necessitates an efficient, adaptive cellular response to hypoxia including metabolic alteration, angiogenesis and erythropoiesis. A number of studies have verified that hypoxia-inducible factors (HIFs) mediate this critical adaptation [2]. In addition, hypoxic cells also activate non-HIF-mediated mechanisms for adaptation to hypoxic microenvironment (Fig. 1).
The vascular system develops in an organism to deliver and distribute oxygen and nutrients to normal tissues. Solid tumors arise without an existing vascular system, and hence could only exist by recruiting new blood vessels that are invariably inadequate and dysfunctional, leaving most tumor beds hypoxic. A number of studies have demonstrated a link between hypoxia, tumor progression and clinical outcomes [3, 4]. In this review, recent advances in delineating molecular mechanisms underlying tumor metabolic alterations including hypoxic HIF-dependent and independent pathways as well as non-hypoxic cell autonomous pathways will be discussed.
2 Hypoxia-inducible factor-1 (HIF-1) and tumor metabolism
2.1 Hypoxia and HIF-1
The tumor hypoxic microenvironment, resulting from inadequate and disordered neo-vasculature, selects for tumor cells that could respond and adapt to oxygen deficiency. The hypoxia-inducible factor-1 (HIF-1) permits tumor cells to...