Acidity generated by the tumor microenvironment drives local invasion

By V. Estrella, Tingan Chen, M. Lloyd, Jonathan W. Wojtkowiak, H. Cornnell, Arig Ibrahim-Hashim, K. Bailey, Y. Balagurunathan, J. Rothberg, Bonnie F. Sloane and 3 more. Cancer Research, 2013

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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.

Subfields: Biomedical Engineering, Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b75141811a9df9dc45e66e032ef54d2ed2d9e6ae

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Citations in the corpus

Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches (2019, background): “5 in tumor microenvironment is associated with metastasis, angiogenesis and therapy resistance, a characteristic phenotype of more aggressive tumors (103, 104).”
The Warburg Effect: How Does it Benefit Cancer Cells? (2016, background): “Elevated glucose metabolism decreases the pH in the microenvironment due to lactate secretion (Figure 2) [42].”
The Acidic Tumor Microenvironment as a Driver of Cancer. (2019, background): “Long-term adaptation to acidic pHo favors invasion in a wide range of cell types (95, 150, 151).”
Intratumor heterogeneity: the Rosetta stone of therapy resistance (2020, background): “For example, local acidification at the tumor edge drives mesenchymal transition, mediating tissue invasion (Estrella et al., 2013).”