Diet-induced obesity is an inflammatory state that accelerates pancreatic carcinogenesis; its effect on EMT and E-cadherin expression in the development of pancreatic ductal adenocarcinoma is usually unclear

Diet-induced obesity is an inflammatory state that accelerates pancreatic carcinogenesis; its effect on EMT and E-cadherin expression in the development of pancreatic ductal adenocarcinoma is usually unclear. Methods Conditional KrasG12D mice were fed a control diet (CD) or a high Evatanepag excess fat, high calorie (HFCD) for 3 or 9 months (n = 10 each). and accelerated carcinogenesis, the HFCD did not induce changes in E-cadherin expression in PanIN lesions of all stages. Invasive lesions exhibited aberrant cytoplasmic E-cadherin staining. Loss of normal membranous localization may reflect a functional loss of E-cadherin. INTRODUCTION The incidence of pancreatic malignancy in the United States is rising, and despite advancement in diagnostic imaging, surgical management, and the rise of specialized centers in the treatment of pancreatic ductal adenocarcinoma (PDAC), the prognosis for the majority of these patients remains strikingly poor.1, 2 Complete surgical resection remains the only chance for remedy, however 80C90% of patients present with evidence of metastatic or locally advanced disease precluding curative resection.3 Because early invasion and metastasis present such a barrier to treatment in PDAC, attention is increasingly geared towards understanding the mechanism and risk factors for the epithelial-mesenchymal transition (EMT), a critical process in the development of invasive disease. In the context of carcinoma progression, EMT is the process by which a transformed epithelial cell loses its normal attachments and inherent polaritythereby exhibiting a mesenchymal phenotypeand crosses the basement membrane. In addition to promoting invasiveness, EMT may play a role in resistance to cell death and senescence, resistance to chemo- and immunotherapy, and may impart cells with stem cell like properties.4, 5 The transmembrane glycoprotein E-cadherin is a prototypic type I cadherin that functions primarily to mediate cell-cell adhesion by way of adherens junctions. The loss of E-cadherin is usually highly indicative of a loss of an epithelial phenotype. 6 EMT inducing transcription factors Snail and Slug actively repress E-cadherin expression.7 Loss of E-cadherin has been shown to be a key step in the progression from adenoma to carcinoma.8 In PDAC, reduced E-cadherin expression may be found in as many as 60% of resected tumors, and is correlated with tumor dedifferentiation, increasing stage, and lymph node involvement.9 Although tumors with total loss of E-cadherin are associated with the worst prognosis, partial E-cadherin loss has been shown an independent predictor of poor outcome, and the percentage of E-cadherin loss has been shown Evatanepag inversely related to overall survival.10, 11 Interestingly, there has been recent evidence in a mouse model of PDAC to suggest that EMT and dissemination may occur prior to bona fide tumor formation in the pancreas. Circulating pancreatic cells with a mesenchymal phenotypedemonstrating E-cadherin loss and/or upregulated upstream EMT transcription factorswere recognized in the pancreatic stroma, blood, and liver in mice that did not have demonstrable carcinoma in the pancreas, only pre-invasive pancreatic intraepithelial neoplasia (PanIN). Furthermore, this early EMT was accelerated by inflammation.12 Evatanepag Obesity is now widely considered to promote a systemic, inflammatory state with elevations in reactive oxygen species, pro-inflammatory cytokines, eicosanoids, circulating growth factors (e.g. insulin IGF-1), and leptin.13 This pro-inflammatory state is a leading theory to explain the growing link between obesity and PDAC, as posited by epidemiological studies such as the National Cancer Institute Pancreatic Cancer Cohort Consortium.14, 15 We have previously shown in a mouse model of PDAC that a high fat, high calorie diet (HFCD) leads to obesity, pancreatic inflammation, and accelerated pancreatic carcinogenesis.16 Although data is limited, there is preliminary Rabbit Polyclonal to Synaptotagmin (phospho-Thr202) evidence that serum from obese mice and leptin can promote EMT, decreased E-cadherin expression, and invasiveness in prostate, breast, and lung cancer cell lines.17C19 The present study was undertaken to determine whether early loss of E-cadherin is part of the mechanism by which diet-induced obesity accelerates pancreatic carcinogenesis in the conditional KrasG12D mouse model. METHODS Mouse Model and Experimental Diet To study the effects of diet-induced obesity on E-cadherin expression during pancreatic carcinogenesis, the conditional KrasG12D (and alleles were confirmed by PCR in all experimental mice, as previously described.21 Animals were fed either a control diet (CD) or the HFCD. Compared to the CD the HFCD contains increased calories (4,536 kcal/kg vs. 3,726 kcal/kg),.