Acidity Generated by the Tumor Microenvironment Drives Local Invasion

TLDR

Tumor microenvironments are acidic because of increased fermentative metabolism and poor perfusion, and this acidity has been proposed to drive local invasion by remodeling adjacent tissues. The study tracked tumor invasion and peritumoral pH in real time with intravital microscopy. Acidic, heterogeneous peritumoral pH correlated with invasion hotspots, invasion did not occur in regions of normal pH, invasive cells expressed GLUT1 and NHE1, and oral sodium bicarbonate raised pH and suppressed tumor growth and invasion. Cancer Res 73(5):1524‑1535; ©2012 AACR.

Abstract

The pH of solid tumors is acidic due to increased fermentative metabolism and poor perfusion. It has been hypothesized that acid pH promotes local invasive growth and metastasis. The hypothesis that acid mediates invasion proposes that H(+) diffuses from the proximal tumor microenvironment into adjacent normal tissues where it causes tissue remodeling that permits local invasion. In the current work, tumor invasion and peritumoral pH were monitored over time using intravital microscopy. In every case, the peritumoral pH was acidic and heterogeneous and the regions of highest tumor invasion corresponded to areas of lowest pH. Tumor invasion did not occur into regions with normal or near-normal extracellular pH. Immunohistochemical analyses revealed that cells in the invasive edges expressed the glucose transporter-1 and the sodium-hydrogen exchanger-1, both of which were associated with peritumoral acidosis. In support of the functional importance of our findings, oral administration of sodium bicarbonate was sufficient to increase peritumoral pH and inhibit tumor growth and local invasion in a preclinical model, supporting the acid-mediated invasion hypothesis. Cancer Res; 73(5); 1524-35. ©2012 AACR.