Adiposity-Based Chronic Disease (ABCD) is known to increase the risk of aggressive prostate cancer (PCa), recurrent disease after treatment for localized PCa, and PCa mortality. A key mechanistic link contributing to this enhanced risk is chronic inflammation originating from excess white visceral adipose tissue (WAT; VAT) and periprostatic adipose tissue (ppWAT). Contributing to systemic inflammation is gut dysbiosis, which itself may be caused by ABCD as well as background local inflammation (prostatitis), which is common in aging men and may be exacerbated by the urinary microbiome. Investigating the molecular biology driving inflammation and its association with increased PCa risk, a recent paper applied a network and gene set enrichment to adipokine drivers in the ABCD-PCa network. It found prominent roles for MCP-1, IL-1β, and CXCL-1 in addition to confirming the importance of exposure to lipopolysaccharides and bacterial components, corroborating the role of gut dysbiosis. To further unravel the mechanistic links between ABCD and PCa risk, this critical review will discuss the current literature on prominent inflammatory signaling pathways activated in ABCD; the influence of gut dysbiosis, the urinary microbiome, and chronic prostatitis; and current hypotheses on how these domains may result in the development of aggressive PCa over a man’s life. Moreover, we performed a novel pathway enrichment analysis to further evaluate the associations between ABCD, PCa risk, gut dysbiosis, and the prostate microbiome, the results of which were partitioned into extracellular and intracellular signaling pathways. In the extracellular space, novel mechanistic links between gut dysbiosis and MCP-1, IL-1β, CXCL1, and leptin via bacterial pathogen signaling and the intestinal immune network (for IgA production), crucial for gut immune homeostasis, were found. Within the intracellular space, there were downstream signals activating chemokine and type 2 interferon pathways, focal adhesion PI3K/Akt/mTOR pathways, as well as the JAK/STAT, NF-κB, and PI3K/Akt pathways. Overall, these findings point to an emerging molecular pathway for PCa oncogenesis influenced by ABCD, gut dysbiosis, and inflammation, and further research, possibly with lifestyle program-based clinical trials, may discover novel biomarker panels and molecular targeted therapies for the prevention and treatment of PCa.
已知肥胖相关性慢性疾病（ABCD）会增加侵袭性前列腺癌（PCa）风险、局部前列腺癌治疗后疾病复发率以及前列腺癌死亡率。导致这种风险增加的关键机制联系源自过剩的白色内脏脂肪组织（WAT；VAT）和前列腺周围脂肪组织（ppWAT）引发的慢性炎症。肠道菌群失调会加剧全身性炎症，其本身可能由ABCD及作为背景的局部炎症（前列腺炎）引起——后者常见于老年男性，并可能因尿路微生物组而恶化。为探究驱动炎症的分子生物学机制及其与前列腺癌风险升高的关联，近期一篇论文对ABCD-前列腺癌网络中的脂肪因子驱动因子进行了网络与基因集富集分析。该研究除了证实脂多糖和细菌成分暴露的重要性外，还发现了MCP-1、IL-1β和CXCL-1的关键作用，从而佐证了肠道菌群失调的影响。为深入揭示ABCD与前列腺癌风险之间的机制联系，本关键性综述将讨论现有文献中关于ABCD激活的主要炎症信号通路；肠道菌群失调、尿路微生物组和慢性前列腺炎的影响；以及当前关于这些领域如何在男性生命进程中导致侵袭性前列腺癌形成的假说。此外，我们通过新颖的通路富集分析进一步评估了ABCD、前列腺癌风险、肠道菌群失调与前列腺微生物组之间的关联，并将结果划分为细胞外和细胞内信号通路。在细胞外空间，研究发现肠道菌群失调通过细菌病原体信号传导及对肠道免疫稳态至关重要的肠道免疫网络（用于IgA产生）与MCP-1、IL-1β、CXCL1和瘦素之间存在新的机制联系。在细胞内空间，存在激活趋化因子和2型干扰素通路、粘着斑PI3K/Akt/mTOR通路以及JAK/STAT、NF-κB和PI3K/Akt通路的下游信号。总体而言，这些发现指向了一条受ABCD、肠道菌群失调和炎症影响的前列腺癌发生新兴分子通路，未来研究（特别是基于生活方式干预的临床试验）可能发现用于前列腺癌预防和治疗的新型生物标志物组合及分子靶向疗法。
肿瘤(癌症)患者之家