Obesity and Inflammatory Factors in the Progression of Early-Onset Colorectal Cancer

Simple Summary The incidence of colorectal cancer (CRC) in the United States (US) has decreased significantly over the last several decades, but primarily in those 65 years of age and older. However, there has been a dramatic global increase in the incidence of colorectal cancer in patients younger than 50 years old. This cohort is known as early-onset colorectal cancer (EOCRC) and is projected to rise in incidence. This epidemiologic change is poorly understood, but the sharp increase in the incidence of obesity and metabolic dysfunction have been linked to this phenomenon. The aim of our study is to examine the complex inflammatory mechanisms affecting EOCRC, including obesity, hormonal effects, inflammatory processes, and the tumor environment. With an improved understanding of these interactions, new methods to prevent and treat EOCRC could reduce its incidence and prolong survival in affected patients.Abstract Metabolic dysfunction associated with obesity leads to a chronic pro-inflammatory state with systemic effects, including the alteration of macrophage metabolism. Tumor-associated macrophages have been linked to the formation of cancer through the production of metabolites such as itaconate. Itaconate downregulates peroxisome proliferator-activated receptor gamma as a tumor-suppressing factor and upregulates anti-inflammatory cytokines in M2-like macrophages. Similarly, leptin and adiponectin also influence macrophage cytokine expression and contribute to the progression of colorectal cancer via changes in gene expression within the PI3K/AKT pathway. This pathway influences cell proliferation, differentiation, and tumorigenesis. This work provides a review of obesity-related hormones and inflammatory mechanisms leading to the development and progression of early-onset colorectal cancer (EOCRC). A literature search was performed using the PubMed and Cochrane databases to identify studies related to obesity and EOCRC, with keywords including 'EOCRC', 'obesity', 'obesity-related hormones', 'itaconate', 'adiponectin', 'leptin', 'M2a macrophage', and 'microbiome'. With this concept of pro-inflammatory markers contributing to EOCRC, increased use of chemo-preventative agents such as aspirin may have a protective effect. Elucidating this association between obesity-related, hormone/cytokine-driven inflammatory effects with EOCRC may help lead to new therapeutic targets in preventing and treating EOCRC.