Department of Urology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
Department of Clinical Pathology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
Cancer Commun (Lond). 2021 May;41(5):389-403. doi: 10.1002/cac2.12137. Epub 2021 Mar 27.
Recent studies have indicated that a high-fat diet (HFD) and/or HFD-induced obesity may influence prostate cancer (PCa) progression, but the role of HFD in PCa microenvironment is unclear. This study aimed to delineate the molecular mechanisms of PCa progression under HFD milieus and define the stromal microenvironment focusing on macrophage inhibitory cytokine-1 (MIC-1) activation.
We investigated the effects of HFD on PCa stromal microenvironment and MIC-1 signaling activation using PC-3M-luc-C6 PCa model mice fed with HFD or control diet. Further, we explored the effect of periprostatic adipocytes derived from primary PCa patients on activation and cytokine secretion of prostate stromal fibroblasts. Expression patterns and roles of MIC-1 signaling on human PCa stroma activation and progression were also investigated.
HFD stimulated PCa cell growth and invasion as a result of upregulated MIC-1 signaling and subsequently increased the secretion of interleukin (IL)-8 and IL-6 from prostate stromal fibroblasts in PC-3M-luc-C6 PCa mouse model. In addition, periprostatic adipocytes directly stimulated MIC-1 production from PC-3 cells and IL-8 secretion in prostate stromal fibroblasts through the upregulation of adipose lipolysis and free fatty acid release. The increased serum MIC-1 was significantly correlated with human PCa stroma activation, high serum IL-8, IL-6, and lipase activity, advanced PCa progression, and high body mass index of the patients. Glial-derived neurotrophic factor receptor α-like (GFRAL), a specific receptor of MIC-1, was highly expressed in both cytoplasm and membrane of PCa cells and surrounding stromal fibroblasts, and the expression level was decreased by androgen deprivation therapy and chemotherapy.
HFD-mediated activation of the PCa stromal microenvironment through metabolically upregulated MIC-1 signaling by increased available free fatty acids may be a critical mechanism of HFD and/or obesity-induced PCa progression.
最近的研究表明，高脂肪饮食（HFD）和/或 HFD 诱导的肥胖可能会影响前列腺癌（PCa）的进展，但 HFD 在 PCa 微环境中的作用尚不清楚。本研究旨在描绘 HFD 环境下 PCa 进展的分子机制，并定义以巨噬细胞抑制细胞因子-1（MIC-1）激活为重点的基质微环境。
我们使用高脂饮食或对照饮食喂养的 PC-3M-luc-C6 PCa 模型小鼠，研究 HFD 对 PCa 基质微环境和 MIC-1 信号激活的影响。此外，我们还探讨了源自原发性 PCa 患者的前列腺周脂肪细胞对前列腺基质成纤维细胞激活和细胞因子分泌的影响。我们还研究了 MIC-1 信号对人 PCa 基质激活和进展的表达模式和作用。
HFD 通过上调 MIC-1 信号刺激 PCa 细胞生长和侵袭，进而增加 PC-3M-luc-C6 PCa 小鼠模型中前列腺基质成纤维细胞分泌白细胞介素（IL）-8 和 IL-6。此外，前列腺周脂肪细胞通过上调脂肪分解和游离脂肪酸释放，直接刺激 PC-3 细胞产生 MIC-1 和前列腺基质成纤维细胞中 IL-8 的分泌。增加的血清 MIC-1 与人类 PCa 基质激活、高血清 IL-8、IL-6 和脂肪酶活性、PCa 进展的进展以及患者的高体重指数显著相关。胶质细胞衍生的神经营养因子受体 α 样（GFRAL），MIC-1 的特异性受体，在 PCa 细胞及其周围基质成纤维细胞的细胞质和膜中均高度表达，并且表达水平在去势治疗和化疗后降低。
通过增加游离脂肪酸的代谢上调 MIC-1 信号，HFD 介导的 PCa 基质微环境的激活可能是 HFD 和/或肥胖诱导的 PCa 进展的关键机制。
