1. Acidity promotes tumor progression by altering macrophage phenotype in prostate cancer
- Author
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Rafael R. Bravo, Mark Robertson-Tessi, Arig Ibrahim-Hashim, Alexander R. A. Anderson, Brian Ruffell, Robert J. Gillies, Shari.Pilon Thomas, Asmaa El-Kenawi, Robert A. Gatenby, Jasreman Dhillon, Jung Choi, Chandler Gatenbee, Yoganand Balagurunathan, Anders Berglund, Naveen Visvakarma, and Kimberly Luddy
- Subjects
0303 health sciences ,Chemistry ,medicine.disease ,Phenotype ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,In vivo ,Tumor progression ,030220 oncology & carcinogenesis ,Gene expression ,Cancer research ,medicine ,Macrophage ,Glycolysis ,030304 developmental biology ,Tramp - Abstract
Tumors rapidly ferment glucose to lactic acid even in the presence of oxygen, and coupling high glycolysis with poor perfusion leads to extracellular acidification. Here we demonstrate that acidity, independent from lactate, augments the pro-tumor phenotype of macrophages. We used zwitterionic buffers to show that activating macrophages at pH 6.8 in vitro enhanced an IL-4-driven phenotype as measured by gene expression, cytokine profiling, and functional assays. These results were recapitulated in vivo wherein neutralizing intratumoral acidity reduced the pro-tumor phenotype of macrophages, while also decreasing tumor incidence and invasion in the TRAMP model of prostate cancer. These results were recapitulated using an in silico mathematical model that simulate macrophage responses to environmental signals. By turning off acid-induced cellular responses, our in silico mathematical modeling shows that acid-resistant macrophages can limit tumor progression. In summary, this study suggests that tumor acidity contributes to prostate carcinogenesis by altering the state of macrophage activation.
- Published
- 2018