Acidity Generated by the Tumor Microenvironment Drives Local Invasion

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 pHe. Immunohistochemical analyses revealed that cells in the invasive edges expressed the glucose transporter GLUT-1 and the sodium-hydrogen exchanger NHE-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.

The chemistry, physiology and pathology of pH in cancer

“…Unlike interventions that alter intracellular pH by targeting one (or more) of many membrane-bound transporter proteins, extracellular pH could be manipulated by altering H þ diffusivity or buffering capacity. Raising mobile buffering capacity with systemic bicarbonate offers an attractive means of changing the course of acid-driven somatic evolution by ablating the underlying selection pressure [88]. The steady flow of new data in support for the prominent role played by H þ ions in cancer will keep pH in the spotlight for novel therapeutic approaches for years to come.…”

Phenotypic changes of acid-adapted cancer cells push them toward aggressiveness in their evolution in the tumor microenvironment

“…8 Using dorsal window chambers, we have demonstrated that acidic environments promote tumor invasion and growth by degrading adjacent extracellular matrix]. 9,10 Thus, we view the intratumoral environment as "niche engineering" wherein cancer cells, in response to Darwinian dynamics, generate an environment that promotes their own growth and invasion 11 at the expense of the stromal cells into which they invade. Acidosis also inhibits anti-tumor immunity and promotes immune editing.…”

PEGylation of paclitaxel largely improves its safety and anti-tumor efficacy following pulmonary delivery in a mouse model of lung carcinoma

“…It is anticipated that the slightly acidic microenvironment of the tumor would lead to accelerated cleavage of PTX from the conjugate backbone compared with the non-tumor area [32,33]. Therefore, the hydrolysis of PEG-PTX could possibly take place prior to the internalization of the conjugates, which possibly resulted in a high proportion of PTX in the interstitial tumor area within the lungs.…”