Endometrial cancer response to pro-EMT effects of type 2 diabetic exosomes.

Abstract

e22617 Background: According to the International Diabetes Federation, over 151 million adults globally suffer from Type 2 Diabetes Mellitus (T2D). New research is showing that the changes of metabolism that occur during T2D are starting to effect both incidence and progression of certain cancers. Endometrial cancer is one, with patients with T2D have an incidence rate ratio of 1.61 (95% CI, 1.51–1.71) and a mortality risk ratio of 1.32 (95% CI, 1.10–1.60) compared to those without T2D. Recent studies suggest that exosomes might explain this link. In models of prostate and breast cancer—both of which have higher incidences in patients with T2D— cancer cells exposed to exosomes from patients with T2D show increased expression of pro-EMT genes compared to those exposed to nondiabetic (ND) exosomes. Exosomes carry miRNAs that reflect the metabolic status of originating tissues and alter the tumor microenvironment. Given that endometrial cancer is also an epithelial cancer exhibiting a similar dangerous trend in T2D patients, we hypothesize that T2D exosomes will similarly induce epithelial-to-mesenchymal transition (EMT) in endometrial cancer, compared to ND exosomes. Methods: Ishikawa cells, a well-established endometrial cancer cell line, were treated with plasma-derived exosomes from whole blood of patients at Boston Medical Center’s endocrinology clinic, either with or without T2D. After 72 hours of treatment, total RNA was extracted, and qPCR was performed to analyze various EMT genes, including SNAI1, CHD1, CD274, and TWIST. An unbiased array using the Human RT2 Profiler PCR Array of 84 EMT genes was also conducted. Analysis was performed using Ct values normalized to ACTB (ΔCt) to determine the fold change in gene expression. Results: Fluorescent microscopy confirmed exosome uptake and nuclear localization in Ishikawa cells. However, contrary to our hypothesis, T2D exosomes did not induce EMT. Targeted qPCR showed no significant differences in EMT gene expression between T2D and non-diabetic exosome-treated cells. The unbiased array similarly revealed minimal changes, with only SOX11 demonstrating a twofold increase in expression. Conclusions: Despite increased endometrial cancer risk in T2D patients, T2D-derived exosomal miRNAs do not appear to drive EMT in Ishikawa cells. This contrasts with findings in other epithelial cancers and suggests that endometrial cancer cells may possess mechanisms that confer resistance to exosomal miRNA signaling. Identifying these mechanisms may offer novel therapeutic insights for malignancies in which T2D exacerbates tumor aggressiveness.