RT Journal Article
SR Electronic
T1 Acidity promotes tumor progression by altering macrophage phenotype in prostate cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 478420
DO 10.1101/478420
A1 Asmaa El-Kenawi
A1 Chandler Gatenbee
A1 Mark Robertson-Tessi
A1 Rafael Bravo
A1 Jasreman Dhillon
A1 Yoganand Balagurunathan
A1 Anders Berglund
A1 Naveen Visvakarma
A1 Arig Ibrahim-Hashim
A1 Jung Choi
A1 Kimberly Luddy
A1 Robert Gatenby
A1 Shari Pilon-Thomas
A1 Alexander Anderson
A1 Brian Ruffell
A1 Robert Gillies
YR 2018
UL http://biorxiv.org/content/early/2018/11/26/478420.1.abstract
AB 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.