title: Hypoxia and cellular metabolism in tumour pathophysiology.
abstract: Cancer cells are optimised for growth and survival via an ability to outcompete normal cells in their microenvironment. Many of these advantageous cellular adaptations are promoted by the pathophysiological hypoxia that arises in solid tumours due to incomplete vascularisation. Tumour cells are thus faced with the challenge of an increased need for nutrients to support the drive for proliferation in the face of a diminished extracellular supply. Among the many modifications occurring in tumour cells, hypoxia inducible factors (HIFs) act as essential drivers of key pro-survival pathways via the promotion of numerous membrane and cytosolic proteins. Here we focus our attention on two areas: the role of amino acid uptake and the handling of metabolic acid (CO2/H+) production. We provide evidence for a number of hypoxia-induced proteins that promote cellular anabolism and regulation of metabolic acid-base levels in tumour cells including amino-acid transporters (LAT1), monocarboxylate transporters, and acid-base regulating carbonic anhydrases (CAs) and bicarbonate transporters (NBCs). Emphasis is placed on current work manipulating multiple CA isoforms and NBCs, which is at an interesting crossroads of gas physiology as they are regulated by hypoxia to contribute to the cellular handling of CO2and pHiregulation. Our research combined with others indicates that targeting of HIF-regulated membrane proteins in tumour cells will provide promising future anti-cancer therapeutic approaches and we suggest strategies that could be potentially used to enhance these tactics.
authors.affiliation: Medical Biology Department, Centre Scientifique de Monaco, 8 Quai Antoine 1er, MC-98000, Monaco, Principality of Monaco.
authors.forename: Scott K
authors.identifier: 0000-0002-6558-7856
authors.initials: SK
authors.lastname: Parks
authors.affiliation: Medical Biology Department, Centre Scientifique de Monaco, 8 Quai Antoine 1er, MC-98000, Monaco, Principality of Monaco.
authors.forename: Yann
authors.initials: Y
authors.lastname: Cormerais
authors.affiliation: Medical Biology Department, Centre Scientifique de Monaco, 8 Quai Antoine 1er, MC-98000, Monaco, Principality of Monaco.|Institute for Research on Cancer and Aging (IRCAN), CNRS, INSERM, Centre A. Lacassagne, University of Nice-Sophia Antipolis, Nice, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouysségur
mesh_terms: D026905:Amino Acid Transport Systems / Q000378:metabolism; D000818:Animals; D002256:Carbonic Anhydrases / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D026905:Amino Acid Transport Systems; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D002256:Carbonic Anhydrases
keywords: amino-acid transport; cell proliferation; pH regulation; tumour hypoxia