Mechanisms underlying obesity-malignancy connection: a systematic narrative review.

Area of Science:

• Oncology
• Metabolic Syndrome
• Molecular Biology

Background:

• Obesity is a major public health concern linked to increased cancer incidence and progression.
• Numerous cellular and molecular mechanisms mediate the relationship between obesity and cancer.
• Understanding these mechanisms is crucial for developing effective cancer prevention and treatment strategies.

Purpose of the Study:

• To systematically review and synthesize current research on the mechanisms linking obesity to cancer risk and progression.
• To identify novel molecular pathways and epigenetic modifications involved in obesity-driven oncogenesis.
• To highlight areas for future research and potential therapeutic targets.

Main Methods:

• Systematic narrative review adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
• Comprehensive literature search across multiple databases, yielding 221 selected articles from 1,288 initial publications.
• Analysis of cellular, molecular, hormonal, and epigenetic mechanisms implicated in obesity-associated cancers.

Main Results:

• Obesity promotes cancer via hormonal imbalances (e.g., estrogen, insulin resistance) and chronic inflammation.
• Novel mechanisms include adipose tissue secretome, extracellular vesicle transfer, metabolic reprogramming (CD36, FABP4, CPT1A), and ferroptosis resistance.
• Epigenetic memory (histone and DNA methylation, RNA modifications via FTO) sustains cancer risk post-weight loss.
• Organ/cell size expansion increases mutation susceptibility; VHL-HIF, PRDM16/UCP1, STAT3/FABP4, and YAP/TAZ pathways are implicated.

Conclusions:

• Obesity significantly elevates cancer risk through diverse and complex molecular and cellular pathways.
• Epigenetic alterations and metabolic reprogramming in adipose tissue are key drivers of obesity-induced oncogenesis.
• Future research should focus on weight-loss drugs, diverse demographics, biomarkers, and integrating advanced methodologies for novel therapeutic targets and prevention strategies.