Regulation of tumor pH and the role of carbonic anhydrase 9

Abstract

The high metabolic rate required for tumor growth often leads to hypoxia in poorly-perfused regions. Hypoxia activates a complex gene expression program, mediated by hypoxia inducible factor 1 (HIF1alpha). One of the consequences of HIF1alpha activation is up-regulation of glycolysis and hence the production of lactic acid. In addition to the lactic acid-output, intracellular titration of acid with bicarbonate and the engagement of the pentose phosphate shunt release CO(2) from cells. Expression of the enzyme carbonic anhydrase 9 on the tumor cell surface catalyses the extracellular trapping of acid by hydrating cell-generated CO(2) into [see text] and H(+). These mechanisms contribute towards an acidic extracellular milieu favoring tumor growth, invasion and development. The lactic acid released by tumor cells is further metabolized by the tumor stroma. Low extracellular pH may adversely affect the intracellular milieu, possibly triggering apoptosis. Therefore, primary and secondary active transporters operate in the tumor cell membrane to protect the cytosol from acidosis. We review mechanisms regulating tumor intracellular and extracellular pH, with a focus on carbonic anhydrase 9. We also review recent evidence that may suggest a role for CA9 in coordinating pH(i) among cells of large, unvascularized cell-clusters.

Increased hyperpolarized [1‐13C] lactate production in a model of joint inflammation is not accompanied by tissue acidosis as assessed using hyperpolarized 13C‐labelled bicarbonate

“…The measured pH corresponded therefore to that of the dominant tissue observed in MR images of this volume (see Figure 4), which was mainly muscle, tendon, ligament and connective tissue in the paw. The very short half‐life of the nuclear spin polarization in hyperpolarized H 13 CO 3 and 13 CO 2 means that the ratio reflects predominantly the extracellular pH46, 50 in regions that are relatively well perfused and that would have also received the hyperpolarized [1‐ 13 C]pyruvate. The absence of a decrease in extracellular pH measured here in CFA‐inflamed paws (pH 7.32 ± 0.09 versus pH 7.23 ± 0.06 in controls) is in contrast to a study by Scholz et al,41 who used hyperpolarized [ 13 C]bicarbonate to measure pH in an acute inflammation model in the rat leg (injection of concanavalin A 2 hours prior to imaging).…”

Pyruvate kinase type M2 is upregulated in colorectal cancer and promotes proliferation and migration of colon cancer cells

“…Moreover, lactate stimulates some cytokines, such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), resulting lactate-induced angiogenesis and increased tumor metastasis (43,44). Another reason for PKM2-enhanced tumor metastasis is that, by favoring aerobic glycolysis, tumor cells generate bicarbonic and lactic acids, which render the extracellular environment more acidic, and potentially favoring tumor invasion by pH-dependent activation of cathepsins and metalloproteinases (45).…”

Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumour phenotype

“…Indeed, GST-AS shows only one half of the enzyme activity of the corresponding GST-PG þ CA protein containing the complete catalytic domain. However, it is very difficult to translate this finding directly into local cellular context, where CA IX interacts with bicarbonate transporters and contributes to pH regulation across the plasma membrane under hypoxic conditions (Svastova et al, 2004;Morgan et al, 2007;Swietach et al, 2007). First, activity measurements were performed with the proteins produced in bacteria in a setting free of any subcellular structures, protein -protein interactions, ion fluxes, and microenvironmental influences, which certainly play a role in modulating the catalytic performance of CA IX.…”

“…Moreover, CA IX also appears to play an active role in tumour biology via modulation of cell adhesion and control of pH Svastova et al, 2004;Swietach et al, 2007). CA IX participates in bicarbonate transport metabolon and contributes to acidification of extracellular microenvironment in response to hypoxia (Svastova et al, 2004;Morgan et al, 2007).…”