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Acidity promotes tumor progression by altering macrophage phenotype in prostate cancer

View ORCID ProfileAsmaa El-Kenawi, Chandler Gatenbee, Mark Robertson-Tessi, Rafael Bravo, Jasreman Dhillon, Yoganand Balagurunathan, Anders Berglund, Naveen Visvakarma, Arig Ibrahim-Hashim, Jung Choi, Kimberly Luddy, View ORCID ProfileRobert Gatenby, Shari Pilon-Thomas, View ORCID ProfileAlexander Anderson, Brian Ruffell, View ORCID ProfileRobert Gillies
doi: https://doi.org/10.1101/478420
Asmaa El-Kenawi
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Egypt
2Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
5Department of Cancer Physiology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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  • For correspondence: Asmaa.Elkenawi@moffitt.org
Chandler Gatenbee
3Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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Mark Robertson-Tessi
3Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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Rafael Bravo
3Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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Jasreman Dhillon
4Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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Yoganand Balagurunathan
5Department of Cancer Physiology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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Anders Berglund
6Department of Biostatistics, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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Naveen Visvakarma
5Department of Cancer Physiology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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Arig Ibrahim-Hashim
5Department of Cancer Physiology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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Jung Choi
6Department of Biostatistics, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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Kimberly Luddy
5Department of Cancer Physiology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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Robert Gatenby
3Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
7Department of Radiology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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Shari Pilon-Thomas
2Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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Alexander Anderson
3Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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Brian Ruffell
2Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
8Department of Breast Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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Robert Gillies
5Department of Cancer Physiology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
7Department of Radiology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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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.

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Posted November 26, 2018.
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Acidity promotes tumor progression by altering macrophage phenotype in prostate cancer
Asmaa El-Kenawi, Chandler Gatenbee, Mark Robertson-Tessi, Rafael Bravo, Jasreman Dhillon, Yoganand Balagurunathan, Anders Berglund, Naveen Visvakarma, Arig Ibrahim-Hashim, Jung Choi, Kimberly Luddy, Robert Gatenby, Shari Pilon-Thomas, Alexander Anderson, Brian Ruffell, Robert Gillies
bioRxiv 478420; doi: https://doi.org/10.1101/478420
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Acidity promotes tumor progression by altering macrophage phenotype in prostate cancer
Asmaa El-Kenawi, Chandler Gatenbee, Mark Robertson-Tessi, Rafael Bravo, Jasreman Dhillon, Yoganand Balagurunathan, Anders Berglund, Naveen Visvakarma, Arig Ibrahim-Hashim, Jung Choi, Kimberly Luddy, Robert Gatenby, Shari Pilon-Thomas, Alexander Anderson, Brian Ruffell, Robert Gillies
bioRxiv 478420; doi: https://doi.org/10.1101/478420

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