Departamento de Morfologia y Biologia Celular, Facultad de Medicina, University of Oviedo, Julian Claveria 6, 33006, Oviedo, Spain.
Instituto Universitario de Oncología del Principado de Asturias (IUOPA), 33006, Oviedo, Spain.
Cell Commun Signal. 2023 Sep 28;21(1):267. doi: 10.1186/s12964-023-01294-y.
Adipose tissue has gained attention due to its potential paracrine role. Periprostatic adipose tissue surrounds the prostate and the prostatic urethra, and it is an essential player in prostate cancer progression. Since obesity is directly related to human tumor progression, and adipose tissue depots are one of the significant components of the tumor microenvironment, the molecular mediators of the communication between adipocytes and epithelial cells are in the spotlight. Although periprostatic white adipose tissue contributes to prostate cancer progression, brown adipose tissue (BAT), which has beneficial effects in metabolic pathologies, has been scarcely investigated concerning cancer progression. Given that adipose tissue is a target of androgen signaling, the actual role of androgen removal on the periprostatic adipose tissue was the aim of this work.
Surgical castration of the transgenic adenocarcinoma of the mouse prostate (TRAMP) was employed. By histology examination and software analysis, WAT and BAT tissue was quantified. 3T3-like adipocytes were used to study the role of Casodex® in modifying adipocyte differentiation and to investigate the function of the secretome of adipocytes on the proliferation of androgen-dependent and independent prostate cancer cells. Finally, the role of cell communication was assayed by TRAMP-C1 xenograft implanted in the presence of 3T3-like adipocytes.
Androgen removal increases brown/beige adipose tissue in the fat immediately surrounding the prostate glands of TRAMP mice, concomitant with an adjustment of the metabolism. Castration increases body temperature, respiratory exchange rate, and energy expenditure. Also, in vitro, it is described that blocking androgen signaling by Casodex® increases the uncoupling protein 1 (UCP1) marker in 3T3-like adipocytes. Finally, the effect of brown/beige adipocyte secretome was studied on the proliferation of prostate cancer cells in vivo and in vitro. The secretome of brown/beige adipocytes reduces the proliferation of prostate cancer cells mediated partly by the secretion of extracellular vesicles.
Consequently, we concluded that hampering androgen signaling plays a crucial role in the browning of the periprostatic adipose tissue. Also, the presence of brown adipocytes exhibits the opposite effect to that of white adipocytes in vitro regulating processes that govern the mechanisms of cell proliferation of prostate cancer cells. And finally, promoting the browning of adipose tissue in the periprostatic adipose tissue might be a way to handle prostate cancer cell progression. Video Abstract.
脂肪组织因其潜在的旁分泌作用而受到关注。前列腺周围的脂肪组织包围着前列腺和前列腺尿道，是前列腺癌进展的重要参与者。由于肥胖与人类肿瘤的进展直接相关，而脂肪组织是肿瘤微环境的重要组成部分之一，因此脂肪细胞和上皮细胞之间通讯的分子介质成为焦点。尽管前列腺周围的白色脂肪组织有助于前列腺癌的进展，但棕色脂肪组织（BAT）在代谢性疾病中具有有益作用，关于其在癌症进展中的作用却鲜有研究。鉴于脂肪组织是雄激素信号的靶标，本研究旨在探讨去势对前列腺周围脂肪组织的实际影响。
采用转基因腺癌小鼠前列腺（TRAMP）的手术去势。通过组织学检查和软件分析，对 WAT 和 BAT 组织进行定量分析。使用 3T3 样脂肪细胞研究 Casodex®在改变脂肪细胞分化中的作用，并研究脂肪细胞分泌的细胞因子对雄激素依赖性和非依赖性前列腺癌细胞增殖的功能。最后，通过在存在 3T3 样脂肪细胞的情况下植入 TRAMP-C1 异种移植物来检测细胞通讯的作用。
去势增加了 TRAMP 小鼠前列腺周围脂肪中棕色/米色脂肪组织的含量，同时调整了代谢。去势增加了体温、呼吸交换率和能量消耗。此外，在体外，描述了 Casodex®阻断雄激素信号会增加 3T3 样脂肪细胞中的解偶联蛋白 1（UCP1）标志物。最后，研究了棕色/米色脂肪细胞分泌的细胞因子对前列腺癌细胞在体内和体外增殖的影响。棕色/米色脂肪细胞的分泌组减少了前列腺癌细胞的增殖，部分是通过细胞外囊泡的分泌来实现的。
因此，我们得出结论，阻断雄激素信号在前列腺周围脂肪组织的棕色化中起着至关重要的作用。此外，体外棕色脂肪细胞的存在对白色脂肪细胞具有相反的作用，调节了控制前列腺癌细胞增殖机制的过程。最后，促进前列腺周围脂肪组织的棕色化可能是控制前列腺癌细胞进展的一种方法。
