The influence of pH and hypoxia on tumor metastasis

Abstract

Rapid malignant proliferation, prior to effective tumor neoangiogenesis, creates a microenvironment around solid cancers, which is predominantly hypoxic and characterized by a high interstitial fluid pressure. Presumably as an adaptive response, tumor cells favor metabolic activity with apparently inefficient energy output, and production of intermediates that promote cellular replication, preferentially through anaerobic glycolysis, a phenomenon that persists even in re-established normoxic conditions (anomalously referred to as ‘aerobic glycolysis’). Extrusion of the consequently excessive accumulation of lactate and protons decreases extracellular pH, leading to a microenvironment considered conducive to promotion of tumor motility, invasion and metastasis, and one that will invariably influence response to drug treatment. This review will critically assess the evidence forming the basis of current understanding of the precise pH conditions in the extracellular tumor matrix, its regulation by cancer cells and relationship with hypoxia, its relevance to malignant progression and its exploitation for therapeutic advantage.

Keywords::

• aerobic glycolysis
• cancer
• hypoxia
• metastasis
• pH
• Warburg effect

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Rapid proliferation, without adequate blood supply, creates a microenvironment around solid cancers that is predominantly hypoxic and characterized by a high IFP.

• • Cancers, unlike normal cells, derive metabolic energy preferentially from anaerobic glycolysis, even under a normoxic environment (Warburg phenomenon); however, reduced dependence on oxidative phosphorylation may only be a feature of some not all cells within a heterogeneous tumor.

• • The excessive accumulation of lactate and protons derived from glycolysis necessitates efficient redistribution of these and other molecules from and within the cell in order to maintain an appropriate intracellular pH.

• • Several key regulators of this process include V-ATPases, the NHE, bicarbonate transporters, MCTs and CA, whose activity is considered to be responsible for generating extracellular acidity.

• • Tumor cells are able to adapt and survive under their hostile microenvironment in part by oncogenic activation of glycolytic enzymes, upregulating the expression of HIF-1α and by activating autophagy and cannibalism for efficient recycling of degraded cytoplasmic constituents, reducing dependence on vascular supply of external substrates.

• • The peculiar features of the tumor microenvironment are key factors in promoting tumor progression, invasion and metastasis and of course response to therapeutic intervention.

• • Reversal or manipulation of pH may be a strategy to modify the extracellular environment such that it impedes the movement of cancer cells into it and thereby blocks access to the vascular system.

• • Manipulation of extracellular and/or intracellular pH of tumors could facilitate drug delivery by tailoring molecular structures for maximal uptake under prevailing ionic conditions.

• • Several studies have suggested the potential advantages of targeting selected pH-dependent channel transporters as a new strategy in cancer treatment as these can influence the ability of cells to metastasize. Particular targets may be those channels involved in the movement of protons and lactate across the plasma membrane.

Notes