Upregulated Na⁺/H⁺-Exchange Protects Human Colon Cancer Tissue against Intracellular Acidification

Abstract

Increased metabolism accelerates local acid production in cancer tissue. The mechanisms eliminating acidic waste products from human colon cancer tissue represent promising therapeutic targets for pharmacological manipulation in order to improve prognosis for the increasing number of patients with colon cancer. We sampled biopsies of human colonic adenocarcinomas and matched normal colon tissue from patients undergoing colon cancer surgery. We measured steady-state intracellular pH and rates of net acid extrusion in freshly isolated human colonic crypts based on fluorescence microscopy. Net acid extrusion was almost entirely (>95%) Na+-dependent. The capacity for net acid extrusion was increased and steady-state intracellular pH elevated around 0.5 in crypts from colon cancer tissue compared with normal colon tissue irrespective of whether they were investigated in the presence or absence of CO2/HCO3–. The accelerated net acid extrusion from the human colon cancer tissue was sensitive to the Na+/H+-exchange inhibitor cariporide. We conclude that enhanced net acid extrusion via Na+/H+-exchange elevates intracellular pH in human colon cancer tissue.

The Acidic Tumor Microenvironment as a Driver of Cancer

“…Although there is little doubt, as detailed throughout this review, that the acidic extracellular microenvironment overall promotes cancer development and progression, it is likely that pH o in tumors can reach levels so low that even the cancer cells become restricted in their functions. Cancer cells usually have higher intracellular pH (pH i ) than normal cells when investigated under similar environmental conditions (8,20,21). Nonetheless, pH i of cancer cells drops substantiallyand to an almost similar extent as that of normal cells-when pH o declines (8,20).…”

“…When the Na + ,HCO 3 − -cotransporter NBCn1, which is responsible for the elevated net acid extrusion capacity in breast cancer tissue compared to normal breast tissue, is genetically disrupted, breast cancer development is delayed, and cell proliferation and tumor growth rate are decelerated (8,57,97). However, the dependency of pH i regulation on HCO 3 − uptake mechanisms is not universal for cancer cells as, for instance, the elevated pH i of human colon cancer tissue relies almost exclusively on accelerated Na + /H + -exchange activity (21). The different transporter dependencies in various cancer forms are in line with the notion that increased capacity for net acid extrusion in cancer cells results from selection for this phenotype rather than upregulation of specific molecular mechanisms.…”

The impact of tumour pH on cancer progression: strategies for clinical intervention

“…Its use in cancer patients is supported by early preclinical studies which demonstrated activity in leukemia and cholangiocarcinoma cells [12,[95][96][97]. Recently, preclinical activity of cariporide has been demonstrated across a broad range of cancer types [98][99][100][101][102][103]. The drug has been shown to inhibit invasion of head and neck squamous cancer [98] and EGFR driven invasion of pancreatric cancer [99].…”

Alterations in the Ca2+ toolkit in oesophageal adenocarcinoma

“…Acidic conditions, occurring during GORD, are a key stimulus for the development of BO [6]; those with BO are 40-50 times more likely to develop OAC [42]. Decreased extracellular pH has been implicated in the proliferation of some cancer-derived cell lines (prostate, colon, lung, and breast cancers; pH ranged from 6.0-6.8) [43][44][45][46][47][48]. Extracellular acid (EA) has also been implicated in cancer metastasis in other cell lines (prostate, lung, and murine melanoma cancers; pH ranged from 5.9-6.8) [49][50][51].…”

“…Whether acidic extracellular environments result in oncogenesis in OAC, via the development of BO or by other mechanisms, remains unclear. Proposed oncogenic mechanisms include the production of reactive oxygen species (ROS), increased genomic instability, increased proliferation, dysregulation of apoptosis, and increased inflammation [43][44][45][46][47][48][49][50][51][52][53][54][55][56]. Exposure to EA has been linked to ROS production in BO [56].…”