Abstract 6156: High-fat diet-induced gut dysbiosis promotes prostate cancer growth through mast cells and histamine 1 receptor

Abstract

Abstract Introduction and Objective High-fat diet (HFD) induce prostate inflammation and promote cancer growth. However, the mechanism of this inflammation has not been entirely clear. We provide the evidence of new histamine-mediated mechanism and the crucial role of the gut microbiota on HFD-induced prostate cancer (PCa) growth. Methods We compared between HFD-fed and control diet (CD)-fed prostate-specific Pten KO mice at 22 weeks of age as PCa models. HFD-fed mice were given histamine receptor antagonist. Tumor growth was evaluated by prostate weight and Ki67 staining. Gut microbiota compositions were analyzed by 16S rRNA gene sequencing. Histamine signaling in PCa was assessed at gene and protein level. Results HFD significantly increased prostate weight (0.25 vs. 0.46g, P = 0.01) and Ki67-positive cancer cell ratio (0.15 vs. 0.36, P = 0.01). cDNA microarray of PCa showed that expression of Hdc encoding histidine decarboxylase (HDC), which is responsible for histamine production, was upregulated in HFD-fed mice (Fold change = 2.71). The elevated expression of Hdc was also confirmed by quantitative PCR (P < 0.01). Infiltrating mast cells highly produced HDC protein, and mast cell counts around cancer foci were significantly increased in HFD-fed mice. Fexofenadine (Fexo), an H1 blocker, inhibited HFD-induced PCa growth, while ranitidine, an H2 blocker, had no inhibitory effect. Fexo reduced MDSC counts and suppressed IL6-STAT3 signaling in PCa of HFD-fed mice. In vitro, both histamine and Fexo did not affect the proliferation of DU145. HFD altered the composition of gut microbiota, and Shannon index suggesting diversity of gut microbiota was reduced in HFD-fed mice. Serum lipopolysaccharide (LPS) levels were elevated in 11-week-old HFD-fed mice, and LPS injection resulted in upregulation of Hdc in PCa. Conclusions We found that HFD caused gut microbiota dysbiosis and elevated systemic LPS level, which could promote inflammatory PCa progression through mast cells and histamine H1 receptor signaling. These results suggest the existence of “Gut-Prostate Axis.” Citation Format: Kazutoshi Fujita, Makoto Matsushita, Daisuke Motooka, Takuaki Hase, Eri Banno, Marco De Velasco, Taigo Kato, Atsunari Kawashima, Motohide Uemura, Shota Nakamura, Kazutake Tsujikawa, Eiichi Morii, Kazuhiro Yoshimura, Hirotsugu Uemura. High-fat diet-induced gut dysbiosis promotes prostate cancer growth through mast cells and histamine 1 receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6156.