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Review
. 2017 Apr 15;595(8):2439-2450.
doi: 10.1113/JP273309. Epub 2017 Feb 19.

Hypoxia and cellular metabolism in tumour pathophysiology

Scott K Parks  1 , Yann Cormerais  1 , Jacques Pouysségur  1   2
Affiliations
Review

Hypoxia and cellular metabolism in tumour pathophysiology

Scott K Parks et al. J Physiol. .

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 CO2 and pHi regulation. 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.

Keywords: amino-acid transport; cell proliferation; pH regulation; tumour hypoxia.

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Figures

Figure 1
Figure 1. Generalised model for cellular metabolism, nutrient supply and metabolic waste handling in hypoxic tumour cells
Gene induction via the hypoxia‐inducible factor (HIF) leads to modulation of various cellular pathways that may be exploited for anti‐cancer strategies. AA, amino acids; GLUT1, glucose transporter 1; LAT1, large neutral amino acid transporter 1; MCT1/4, monocarboxylate transporter 1 and 4; mTOR, mammalian target of rapamycin; NBC, Na+–HCO3 − co‐transporter; NHE1, Na+/H+ exchanger 1.
See this image and copyright information in PMC

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