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.
Highlights
Current treatment options for colonic adenocarcinoma include surgery, radiation, and chemotherapy depending on the stage of disease but mortality rates remain considerable, for patients with disseminated cancer.Insufficient blood supply, elevated metabolism, and a shift from oxidative phosphorylation towards fermentative glycolysis acid-loads the intracellular compartment of cancer cells [1]
Most existing data regarding acid-base regulation in cancer cells derive from cultured cell lines and only few have looked at freshly isolated tissue
We evaluated pHi regulation in freshly isolated crypts from human colon cancer and matched normal colon tissue in an attempt to reveal the mechanisms of acid-base transport in colonic adenocarcinomas and the adaptations taking place during colon carcinogenesis
Summary
Insufficient blood supply, elevated metabolism, and a shift from oxidative phosphorylation towards fermentative glycolysis acid-loads the intracellular compartment of cancer cells [1]. Despite the increased production of acidic waste in solid cancer tissue, intracellular pH (pHi) of cancer cells is typically maintained equal to or above that of normal cells [2, 3]. Most existing data regarding acid-base regulation in cancer cells derive from cultured cell lines and only few have looked at freshly isolated tissue. We evaluated pHi regulation in freshly isolated crypts from human colon cancer and matched normal colon tissue in an attempt to reveal the mechanisms of acid-base transport in colonic adenocarcinomas and the adaptations taking place during colon carcinogenesis
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