Gut microbiota-derived short-chain fatty acids promote prostate cancer progression through inducing cancer cell autophagy and M2 macrophage polarization

Abstract

Objective: Emerging research have reported the regulative role of gut microbiota-derived short-chain fatty acids (SCFAs) within tumor microenvironment. In previous study we have demonstrated abnormal gut microbial composition in castration-resistant prostate cancer (CRPC) patients, here we sought to reveal the mechanism of SCFAs as a mediator linking microbiota dysbiosis and prostate cancer (PCa) progression. Methods:By using transgenic TRAMP mouse model, PCa patient samples, in vitro PCa cell transwell assay, and macrophage recruitment assay, we examined the effects of fecal microbiota transplantation (FMT) and SCFAs on PCa progression. Results: FMT using CRPC patients’ fecal suspension increased the abundance of SCFAs-producing gut microbiotas in TRAMP mice including Ruminococcus, Alistipes, Phascolarctobaterium, and correspondingly raised mice’s gut acetate and butyrate levels. CRPC FMT or SCFAs supplementation accelerated TRAMP mice’s cancer progression. In vitro, SCFAs enhanced PCa cells migration and invasion by inducing TLR3-triggered autophagy that further activated NF-κB and MAPK signalings. Also, PCa cell-derived CCL20 activated by SCFAs reprogrammed the tumor microenvironment by recruiting more macrophage infiltration and simultaneously inducing M2 macrophage polarization, which in turn further strengthened PCa cells invasiveness. Finally in a large cohort of 362 PCa patients from our department, we demonstrated that CCL20 expression in prostate was positively correlated with Gleason grade, pre-operative PSA, neural invasion, seminal vesical invasion, and was negatively correlated with post-operative biochemical recurrence-free survival. Gut microbiota dysbiosis-related CCL20 could be a biomarker for predicting prognosis in PCa patients. Conclusion: Collectively, gut microbiota dysbiosis-derived SCFAs promoted PCa progression through inducing cancer cell autophagy and M2 macrophage polarization. Intervention of SCFAs-producing microbiotas may be a useful strategy in the manipulation of CRPC.

Role of microbiome and its metabolite, short chain fatty acid in prostate cancer

“…Recently, Liu et al [ 78 ] have observed the effect after transplantation of a fecal suspension from a patient with castration refractory prostate cancer (CRPC) into a transgenic TRAMP mouse model (unpublished). Fecal material transplantation from CRPC patients accelerated cancer progression in TRAMP mice.…”

Dissecting Microbiome-Derived SCFAs in Prostate Cancer: Analyzing Gut Microbiota, Racial Disparities, and Epigenetic Mechanisms

“…These findings suggest that SCFAs may play a role in PCa progression [ 67 ]. Liu et al [ 108 ] recently transplanted fecal suspension from a castration-refractory prostate cancer (CRPCa) patient into a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model. This transplantation resulted in the acceleration of cancer progression in the TRAMP mouse.…”

“…This transplantation resulted in the acceleration of cancer progression in the TRAMP mouse. In this study, SCFAs increased in vitro migration and invasion of PCa cells [ 108 ].…”

Multidimensional progressive single‐cell sequencing reveals cell microenvironment composition and cancer heterogeneity in lung cancer

“…[7][8][9] The development of tumors and the effectiveness of cancer treatments strongly correlate with this genetic heterogeneity. 10,11 Furthermore, detecting genetic variations using bulk mRNA sequencing is challenging due to the significant intertumoral heterogeneity. The limits of several analytical approaches that capture intertumoral heterogeneity continue to be a key obstacle to this strategy, despite the fact that discovering oncogenic drivers using it has led to significant therapeutic advancements for some tumor types, such as melanoma.…”

“…Individual tumor cells develop cell‐specific genomic alterations due to mutation and clonal‐selection dynamics during tumor formation 7–9 . The development of tumors and the effectiveness of cancer treatments strongly correlate with this genetic heterogeneity 10,11 …”