Abstract
BackgroundTumours rapidly ferment glucose to lactic acid even in the presence of oxygen, and coupling high glycolysis with poor perfusion leads to extracellular acidification. We hypothesise that acidity, independent from lactate, can augment the pro-tumour phenotype of macrophages.MethodsWe analysed publicly available data of human prostate cancer for linear correlation between macrophage markers and glycolysis genes. We used zwitterionic buffers to adjust the pH in series of in vitro experiments. We then utilised subcutaneous and transgenic tumour models developed in C57BL/6 mice as well as computer simulations to correlate tumour progression with macrophage infiltration and to delineate role of acidity.ResultsActivating 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 neutralising intratumoural acidity reduced the pro-tumour phenotype of macrophages, while also decreasing tumour 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 modelling shows that acid-resistant macrophages can limit tumour progression.ConclusionsThis study suggests that tumour acidity contributes to prostate carcinogenesis by altering the state of macrophage activation.
Highlights
Tumours rapidly ferment glucose to lactic acid even in the presence of oxygen, and coupling high glycolysis with poor perfusion leads to extracellular acidification
Macrophage infiltration correlates with MCT4 expression Advanced stages of prostate cancer adopt a high glycolytic phenotype that correlated with poor prognosis.[36]
We questioned whether highly glycolytic phenotype correlates with macrophage infiltration or phenotype in late-stage prostate cancer
Summary
Tumours rapidly ferment glucose to lactic acid even in the presence of oxygen, and coupling high glycolysis with poor perfusion leads to extracellular acidification. RESULTS: 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 neutralising intratumoural acidity reduced the protumour phenotype of macrophages, while decreasing tumour incidence and invasion in the TRAMP model of prostate cancer. Metabolic by-products, nutrients and hormones modulate these cellular interactions that, in turn, can regulate tumour progression.[1] One important property of malignant cells is that they preferentially metabolise glucose into lactate even in the presence of oxygen—known as aerobic glycolysis or the “Warburg Effect”—which confers on them a growth advantage.[2] Coupling elevated glycolysis with poor tumour perfusion leads to increased pericellular accumulation of organic acids (e.g. lactic acid) and reduced pH in extracellular spaces.[3] Low pH induces the activity of proteolytic enzymes and can be toxic to surrounding stromal cells, leading to tissue remodelling and local invasion.[4,5] It is known to inhibit T cell-mediated immune surveillance,[6] but the effect of tumour acidosis on the myeloid compartment within tumour is less well studied. Hypoxia augments the immunosuppressive ability of TAMs,[14] while lactic acid induces tissue remodelling though expression of vascular endothelial growth factor (VEGF) and arginase I.15 Whether acidic pH, as an independent entity from lactate,[16] alters macrophage polarisation within tumours is not clear, we sought to investigate the impact of tumour acidosis on the phenotypic characteristics of macrophages in vitro using zwitterionic organic
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