Value of pH regulators in the diagnosis, prognosis and treatment of cancer

Abstract

Altered metabolism, associated with acidification of the extracellular milieu, is one of the major features of cancer. As pH regulation is crucial for the maintenance of all biological functions, cancer cells rely on the activity of lactate exporters and proton transporters to regulate their intracellular pH. The major players in cancer pH regulation are proton pump ATPases, sodium-proton exchangers (NHEs), monocarboxylate transporters (MCTs), carbonic anhydrases (CAs) and anion exchangers (AEs), which have been shown to be upregulated in several human malignancies. Thanks to the activity of the proton pumps and transporters, tumours acidify their microenvironment, becoming more aggressive and resistant to therapy. Thus, targeting tumour pH may contribute to more effective anticancer strategies for controlling tumour progression and therapeutic resistance. In the present study, we review the role of the main pH regulators expressed in human cancer cells, including their diagnostic and prognostic value, as well as their usefulness as therapeutic targets.

Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma – MCT1 as potential target in diffuse large B cell lymphoma

“…Indeed, the vast majority of DLBCL samples was positive for MCT1 (72.0%) and MCT4 (65.6%), similar to what has been observed by Noble et al [35] with respect to MCT1 expression (but not MCT4 expression, where positivity was only observed in 27% of DLBCL cases). Due to their correlation with tumour aggressiveness and poor outcome in various neoplastic disorders (reviewed in [36,37]), these isoforms are best characterized. It has e.g.…”

Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

“…As stated above, upregulation of MCT1 and MCT4 has been described in a variety of human cancers, and inhibition of MCT activity has been showing promising results in preclinical models (41). In vitro, MCT inhibition impairs lactate transport, cell proliferation, invasion and migration, and induces cell death, while it delays tumor growth, induces necrosis and decreases invasion in vivo.…”

“…MCT1 and MCT4 isoforms are strongly associated with the hyperglycolytic phenotype of cancer cells. These transporters display distinct affinities for monocarboxylic acids that are associated with their expression patterns within tissues (41). MCT1 expression was identified in most tissues, being associated with the uptake/extrusion of lactate, while MCT4 has an important role in the export of lactate in highly glycolytic tissues.…”

“…MCT1 expression was identified in most tissues, being associated with the uptake/extrusion of lactate, while MCT4 has an important role in the export of lactate in highly glycolytic tissues. MCTs have been widely studied by our group and others, and found to be robustly expressed in a variety of solid human tumors such as colon, glioblastoma, breast, prostate, stomach and others, as depicted in Table 1 [for a comprehensive review see (41,72)]. MCT expression/cell localization can differ from cancer to cancer.…”

“…However, LDHA expression in malignant tumor tissues does not correlate consistently with serum LDH levels, which may indicate that these are independent prognostic factors in cancer (138,139). Studies on lactate transporters (MCTs/CD147) are not as solid as for LDH, but also reveal prognostic value ( Table 1) (41). In a recent meta-analysis Bovenzi et al (140) identified association between increased MCT4/CD147 expression with decreased OS and disease-free survival (DFS) across many cancer types, while there was no clear association for MCT1 expression with these parameters.…”