American Association for Cancer Research
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Supplementary Figure 6 from Acidity Generated by the Tumor Microenvironment Drives Local Invasion

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journal contribution
posted on 2023-03-30, 22:05 authored by Veronica Estrella, Tingan Chen, Mark Lloyd, Jonathan Wojtkowiak, Heather H. Cornnell, Arig Ibrahim-Hashim, Kate Bailey, Yoganand Balagurunathan, Jennifer M. Rothberg, Bonnie F. Sloane, Joseph Johnson, Robert A. Gatenby, Robert J. Gillies

PDF file - 50K, Figure S6: Ex vivo comparison of vessel density in stroma vs tumor tissue. Using the Image Scope v7.1 regions of viable tumor were manually selected. 200�m micrometers were placed around the circumference of the tumor region perpendicular to the tumor edge. A second manually selected region was drawn around the perimeter of the micrometers. This effectively segments the entire tissue section into three regions of interest; the tumor, the edge within 200�m of the tumor and the distant stromal region. The Aperio (Vista, CA, USA) microvessel algorithm v1.0 was used with the following parameters (smoothing 2; dark threshold160; light threshold 210; regioning 6; completion 7) to identify the vascular density which was defined as the vessel area divided by total area (�m2).



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.

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