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

We have previously demonstrated abnormal gut microbial composition in castration-resistant prostate cancer (CRPC) patients, here we revealed the mechanism of gut microbiota-derived short-chain fatty acids (SCFAs) as a mediator linking CRPC microbiota dysbiosis and prostate cancer (PCa) progression. By using transgenic TRAMP mouse model, PCa patient samples, in vitro PCa cell transwell and macrophage recruitment assays, we examined the effects of CRPC fecal microbiota transplantation (FMT) and SCFAs on PCa progression. Our results showed that FMT with CRPC patients' fecal suspension increased SCFAs-producing gut microbiotas such as Ruminococcus, Alistipes, Phascolarctobaterium in TRAMP mice, and correspondingly raised their gut SCFAs (acetate and butyrate) levels. CRPC FMT or SCFAs supplementation significantly accelerated mice's PCa progression. In vitro, SCFAs enhanced PCa cells migration and invasion by inducing TLR3-triggered autophagy that further activated NF-κB and MAPK signalings. Meanwhile, autophagy of PCa cells released higher level of chemokine CCL20 that could reprogramme the tumor microenvironment by recruiting more macrophage infiltration and simultaneously polarizing them into M2 type, which in turn further strengthened PCa cells invasiveness. Finally in a cohort of 362 PCa patients, we demonstrated that CCL20 expression in prostate tissue was positively correlated with Gleason grade, pre-operative PSA, neural/seminal vesical invasion, and was negatively correlated with post-operative biochemical recurrence-free survival. Collectively, CRPC gut microbiota-derived SCFAs promoted PCa progression via inducing cancer cell autophagy and M2 macrophage polarization. CCL20 could become a biomarker for prediction of prognosis in PCa patients. Intervention of SCFAs-producing microbiotas may be a useful strategy in manipulation of CRPC.

Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis.

The microbiota comprises the microorganisms that live in close contact with the host, with mutual benefit for both counterparts. The contribution of the gut microbiota to the emergence of castration-resistant prostate cancer (CRPC) has not yet been addressed. We found that androgen deprivation in mice and humans promotes the expansion of defined commensal microbiota that contributes to the onset of castration resistance in mice. Specifically, the intestinal microbial community in mice and patients with CRPC was enriched for species capable of converting androgen precursors into active androgens. Ablation of the gut microbiota by antibiotic therapy delayed the emergence of castration resistance even in immunodeficient mice. Fecal microbiota transplantation (FMT) from CRPC mice and patients rendered mice harboring prostate cancer resistant to castration. In contrast, tumor growth was controlled by FMT from hormone-sensitive prostate cancer patients and Prevotella stercorea administration. These results reveal that the commensal gut microbiota contributes to endocrine resistance in CRPC by providing an alternative source of androgens.

Prednisone reduction for metastatic castration-resistant prostate cancer with recurrent pulmonary tuberculosis: Case report.

INTRODUCTION: Prednisone (10 mg/d) is often used in combination with docetaxel or abiraterone in the treatment of advanced prostate cancer. LATITUDE studies have confirmed that the combination of abiraterone and prednisone (5 mg/d) can be used for the treatment of newly diagnosed high-risk metastatic castration-sensitive prostate cancer, and have achieved satisfactory results. However, it has not been reported that abiraterone combined with prednisone (5 mg/d) in the treatment of metastatic castration-resistant prostate cancer (mCRPC). PATIENT CONCERNS: Here, we present a case of high-risk advanced prostate cancer with old pulmonary tuberculosis (PTB). The patient developed a relapse of old tuberculosis in both lungs that were discovered following 14 months of continuous application of prednisone (10 mg/d). DIAGNOSIS: The histopathological findings showed prostate adenocarcinoma carcinoma with a Gleason score of 10 (5+5). Further laboratory investigations were suggestive of positive mycobacterium tuberculosis complex DNA in pleural effusion and sputum. INTERVENTIONS: The patient underwent endocrine therapy, chemotherapy of docetaxel plus prednisone, radiotherapy, and abiraterone combined with prednisone treatment, but he eventually developed into the mCRPC stage. Then, prednisone was reduced to 5 mg/d plus abiraterone, and combined with anti-tuberculosis treatment according to multi-disciplinary diagnosis and treatment. OUTCOME: Two months later, pleural effusion and atelectasis were relieved, and PSA was remained stable at a low level. The patient achieved complete remission. CONCLUSION: We cannot, with complete certainty, say that this patient, or any patient, developed old PTB recurrence due to the use of prednisone. Based on the current evidence, endocrine therapy is the foundation, radiotherapy can reduce the tumor load, and early application of abiraterone is beneficial to survival for the high-risk mCRPC. The long-term use of prednisone can be appropriately reduced in mCRPC with old PTB, and a satisfactory curative effect can be achieved. More prospective trials are warranted before a definite recommendation could be drawn.

Preclinical Development of a WT1 Oral Cancer Vaccine Using a Bacterial Vector to Treat Castration-Resistant Prostate Cancer.

Previously, we constructed a recombinant Bifidobacterium longum displaying a partial mouse Wilms' tumor 1 (WT1) protein (B. longum 420) as an oral cancer vaccine using a bacterial vector and demonstrated that oral administration of B. longum 420 significantly inhibited tumor growth compared with the Db126 WT1 peptide vaccine in the TRAMP-C2, mouse castration-resistant prostate cancer (CRPC) syngeneic tumor model. The present study demonstrated that oral administration of 1.0×109 colony-forming units of B. longum 420 induced significantly higher cytotoxicity against TRAMP-C2 cells than intraperitoneal injection of 100 µg of Db126, and the in vivo antitumor activity of B. longum 420 in the TRAMP-C2 tumor model could be augmented by intraperitoneal injections of 250 µg of anti-PD-1 antibody. For the clinical development, we produced the B440 pharmaceutical formulation, which is lyophilized powder of inactivated B. longum 440 displaying the partially modified human WT1 protein. We confirmed that B. longum 440 could induce cellular immunity specific to multiple WT1 epitopes. In a preclinical dosage study, B440 significantly inhibited growth of the TRAMP-C2 tumors compared with that of the control groups (PBS and B. longum not expressing WT1) at all dosages (1, 5, and 10 mg/body of B440). These mouse doses were considered to correspond with practical oral administration doses of 0.2, 1, and 2 g/body for humans. Taken together, these results suggest that the B440 WT1 oral cancer vaccine can be developed as a novel oral immuno-oncology drug to treat CRPC as a monotherapy or as an adjunct to immune checkpoint inhibitors.