Exploring the role of obesity-induced extracellular vesicles secretion and associated oncogenic proteins in endometrial cancer pathogenesis.

Abstract

Endometrial cancer (EC) is the leading gynecologic malignancy in the United States with obesity implicated in 57% of cases. This research delves into the molecular complexities of extracellular vesicle (EV) secretion as carriers of oncogenic protein expression and their involvement in obesity-mediated EC. An understanding of these mechanisms is pivotal for unraveling pathways relevant to obesity-associated EC, thereby guiding the development of innovative prevention and treatment strategies. Our investigation revealed a significant increase in EV secretion carrying oncogenic proteins (TMEM205, STAT5, and FAS) in adipose and uterine tissues/serum samples from obese EC patients compared to their non-obese counterparts. We identified alterations in EV-regulating proteins (Rab7, Rab11, and Rab27a) in obesity-mediated EC patient adipose and uterine samples. Through a 24-week analysis of the effects of a 45% kcal high-fat diet (HFD) on mice, we observed heightened body weight, increased adipose tissue, enlarged uterine horns, and heightened inflammation in the HFD group. This correlated with elevated levels of EV secretion and increased expression of oncogenic proteins TMEM205, FAS, and STAT5, while the tumor suppressor gene PIAS3 was downregulated in adipose and uterine tissues in HFD treated mice. Furthermore, our study confirmed that adipocyte derived EVs increased EC cell proliferation and migration. Additionally, we identified that the small molecule inhibitors (HO-3867) or Metformin inhibited EV secretion in vitro and in vivo, demonstrating significant inhibition of high glucose or adipocyte-mediated EC cell proliferation and a reduction in body weight and adipose tissue accumulation when administered to HFD mice. Moreover, HO-3867 or Metformin treatment inhibits HFD induced hyperplasia by altered the expression of EV-regulated proteins (Rab7, Rab11, and Rab27a) and decreased oncogenic protein expression (TMEM205, FAS and STAT5) levels. This study provides critical insights into the mechanisms supporting obesity-mediated EV secretion with oncogenic protein expression, shedding light on their role in EC pathogenesis. Additionally, it offers pre-clinical evidence supporting the initiation of novel studies for EV-targeted therapies aimed at preventing obesity-mediated EC.