Acidosis and cancer: from mechanism to neutralization

Abstract

The extracellular pH of solid tumors is unequivocally acidic due to a combination of high rates of lactic acid production (a consequence of fermentative glycolytic metabolism) and poor perfusion. This has been documented by us and others in a wide variety of solid tumor models, primarily using magnetic resonance spectroscopic imaging (MRSI). This acidity contributes to tumor progression by inducing genome instability, promoting local invasion and metastases, inhibiting anti-tumor immunity, and conferring resistance to chemo- and radio-therapies. Systemic buffer therapies can neutralize tumor acidity and has been shown to inhibit local invasion and metastasis and improve immune surveillance in a variety of cancer model systems. This review will revisit the causes and consequences of acidosis by summarizing strategies used by cancer cells to adapt to acidosis, and how this acidity associated with carcinogenesis, metastasis, and immune function. Finally, this review will discuss how neutralization of acidity can be used to inhibit carcinogenesis and metastasis and improve anti-cancer immunotherapy.

Keywords: Acidosis; Carcinogenesis; Immunotherapy; Metastasis; Neutralization.

Figure 1.. Schematic diagram of tumor acidosis.

Acidosis generated by tumor cells enhnces adaptive mechanisms that canbe inhibited by neutralization.

Figure 2.. The effect of NaHCO3 treatment on tumor pH.

A, ratiometric images from SNARF-1 analysis were used to measure and compare the pH of control tumors to those tumors that were treated with 200 mmol/L of Bicarbonate. The image shown here is of a bicarbonate treated tumor. In vitro pH calibration was applied to the ratiometric image. pHe profiles that originated from the center of the tumor, were obtained using a radial graph. pHe values were obtained along the radial lines and the edge of the tumors were defined using GFP images of the tumor. B, pHe values corresponding to radial lines were plotted. “0” indicates the centroid of tumor and the green, dotted line indicates tumor edge.