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Early-onset Colorectal Cancer - New Insights On Macrophage Function, Itaconate And Obesity
*Katharina M Scheurlen, *Dylan Snook, *Mary N Walter, Susan Galandiuk
University of Louisville, Louisville, KY

Objectives: Obesity and metabolic dysfunction may promote early-onset colorectal cancer(EOCRC) in young patients(<50 yrs) through chronic inflammation. Anti-inflammatory tumor-associated macrophages(M2-like) and cytokines(IL-1β, IL-8, IL-10) as well as downregulation of peroxisome proliferator-activated receptor gamma(PPARγ), a regulator of macrophage polarization and lipid metabolism have been shown to be associated with tumor progression and decreased survival. Recent unpublished findings in human colon cancer samples show that the macrophage-specific metabolite itaconate and its derivatives 4-octyl itaconate(4-OI) and dimethyl itaconate(DI) can provide a link between obesity, chronic inflammation and EOCRC. The aim of this study was to investigate the effect of the obesity hormone leptin, 4-OI and DI on M2-like macrophages and their expression profiles in vitro. Methods: Human THP-1 monocytes were differentiated and polarized into M2-like macrophages within 14 days and then incubated with different doses of leptin, 4-OI, DI or PBS(negative control). Total cellular RNA was extracted and TaqMan qRT-PCR was performed, analyzing PPARγ, IL-1β, IL-8 and IL-10. Gene expression(delta CT values) between treated cells and negative controls was compared using a Studentís t-test, and maximum fold-changes reported. Results: Relative PPARγ gene expression was impaired after 4-OI and DI treatment(20-fold, p<0.001 and 1.3-fold, p=0.001(Table 1). IL-1β expression decreased following 4-OI treatment(7-fold, p=0.021), but increased in macrophages treated with either leptin or DI (6-fold, p=0.001 and 4-fold, p<0.001). IL-8 expression increased after all treatments, with the highest increase after incubation with DI (172-fold, p<0.001). Relative IL-10 expression decreased in 4-OI treated macrophages (99-fold, p<0.001), but increased after leptin and DI incubation (2-fold, p<0.001 and 2-fold, p<0.001). Conclusion: The obesity hormone leptin, and itaconate derivatives 4-OI and DI can all shift tumor-associated M2-polarized macrophages towards an even further anti-inflammatory phenotype and induce expression of proinflammatory IL-1β, as well as downregulation of the metabolic regulator PPARγ. Chronic inflammation and metabolic dysfunction in obesity could promote EOCRC through tumor-associated macrophages and itaconate. Itaconate and its derivatives may serve as novel therapeutic targets for immunotherapy in young obese patients with sporadic colon cancer.


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