Network and Gene Set Enrichment Analysis of Adipokine Drivers of Prostate Cancer; Unravelling the Mechanistic Link Between Excess Adiposity and Prostate Cancer Risk.

A literature search identified 14 prominent biomarkers influencing prostate cancer risk through multiple oncogenic mechanisms in the context of Adiposity-Based Chronic Disease.

• Literature search used terms 'prostate cancer' AND 'obesity' AND 'inflammation', yielding 629 references.
• From 629 references, 17 reviews were selected for biomarker identification.
• The 14 biomarkers were characterized by cellular origin, signaling pathway, and oncogenic effect.
• Oncogenic mechanisms identified included cellular proliferation, resisting cell death, metabolic reprogramming, tumor-promoting inflammation, avoiding immune destruction, angiogenesis, and activating invasion.

Network analyses of biomarker interactions highlighted prominent roles of monocyte chemoattractant protein-1 (MCP-1), interleukin-1β (IL-1β), and C-X-C motif chemokine ligand 1 (CXCL1) in the ABCD-prostate cancer relationship.

• The Webgestalt gene analysis toolkit was used to generate modular-based network analyses.
• MCP-1, IL-1β, and CXCL1 were identified as the most prominent nodes within the biomarker interaction network.
• These three biomarkers were identified as top hypotheses to guide molecular targeted therapies for prostate cancer in ABCD.
• These biomarkers also informed proposed lifestyle biomarker panels for prostate cancer management in the context of ABCD.

Top gene ontology (GO) categories for the wider ABCD-prostate cancer network identified key roles for gut microbiome dysbiosis and periprostatic white adipose tissue exposure to the prostate microbiome.

• Gene ontology analysis was performed using the Webgestalt toolkit on the identified biomarker set.
• Gut microbiome dysbiosis emerged as a key pathway in the top GO categories.
• Exposure of periprostatic white adipose tissue to the prostate microbiome was identified as a key mechanism.
• Bacterial and lipopolysaccharide-induced inflammation were specifically implicated as mechanisms within these GO categories.

Adiposity-Based Chronic Disease (ABCD) increases the risk of aggressive prostate cancer, posttreatment prostate cancer recurrence, and prostate cancer mortality.

• ABCD is described as a novel model housing obesity, insulin resistance, and adipokine-related inflammation.
• The relationship encompasses aggressive prostate cancer risk, not just any prostate cancer.
• ABCD is associated with posttreatment prostate cancer recurrence in addition to initial cancer risk.
• Prostate cancer mortality is also increased in the context of ABCD.

The authors propose that molecular targeted therapies and lifestyle biomarker panels for prostate cancer in ABCD should focus on MCP-1, IL-1β, and CXCL1 signaling as well as gut microbiome and periprostatic adipose tissue pathways.

• Top hypotheses for molecular targeted therapies relate to MCP-1, IL-1β, and CXCL1 signaling.
• Gut microbiome dysbiosis and periprostatic adipose tissue exposure to the prostate microbiome are highlighted as additional therapeutic targets.
• Lifestyle biomarker panels incorporating these biomarkers are proposed for clinical use in ABCD-associated prostate cancer.
• Further research and possible clinical trials allowing histological examination of pre- and post-lifestyle intervention prostate cancer tissue are recommended to provide further insights.