Abstract
Mutational activation of K-Ras is an initiating event of pancreatic ductal adenocarcinomas (PDAC) that may develop either from pancreatic intraepithelial neoplasia (PanIN) or intraductal papillary mucinous neoplasms (IPMN). Cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) is causally related to pancreatic carcinogenesis. Here, we deciphered the impact of COX-2, a key modulator of inflammation, in concert with active mutant K-RasG12D on tumor burden and gene expression signature using compound mutant mouse lines. Concomitant activation of COX-2 and K-RasG12D accelerated the progression of pancreatic intraepithelial lesions predominantly with a cystic papillary phenotype resembling human IPMN. Transcriptomes derived from laser capture microdissected preneoplastic lesions of single and compound mutants revealed a signature that was significantly enriched in Notch1 signaling components. In vitro, Notch1 signaling was COX-2-dependent. In line with these findings, human IPMN stratified into intestinal, gastric and pancreatobillary types displayed Notch1 immunosignals with high prevalence, especially in the gastric lesions. In conclusion, a yet unknown link between activated Ras, protumorigenic COX-2 and Notch1 in IPMN onset was unraveled.
Highlights
Despite innovations in basic research, diagnostic imaging, and surgery, patients with invasive pancreatic ductal adenocarcinoma (PDAC) still have a poor prognosis with an overall 5-year-survival rate of about 5%, mainly due to metastasis at the time of diagnosis in a high percentage of patients and lack of efficient therapy modalities[1]
While the previously studied homozygous Tg(K5-COX-2/675+/+) mouse line on the NMRI outbred background showed up with pronounced epithelial dysplasia in skin epidermis, mammary gland, urinary bladder and pancreas[15,20], the congenic heterozygous Tg(K5-COX/675+/wt) (C) mouse line on the C57BL/6N background used in this study displayed spontaneously less pronounced histological changes in pancreas when comparing 12-months-old transgenic and WT cohorts (SFig. 2)
Exposure of PK and CPK mice to the selective COX-2 inhibitor celebrex at days 1 to 30 postnatally (1M+CX) abolished formation of the described lesions (Fig. 1a). This effect correlated to reduced prostaglandin E2 (PGE2) levels indicating that disease progression towards high grade mPanIN and mIPMN lesions is COX-2-dependent
Summary
Despite innovations in basic research, diagnostic imaging, and surgery, patients with invasive pancreatic ductal adenocarcinoma (PDAC) still have a poor prognosis with an overall 5-year-survival rate of about 5%, mainly due to metastasis at the time of diagnosis in a high percentage of patients and lack of efficient therapy modalities[1]. Under the control of pancreas-specific P48-promoter, the heterozygous K-RasG12D knock-in allele is expressed in embryonic pancreatic progenitor cells, in centroacinar as well as acinar cells in the adult. This mouse mutant develops murine PanIN with 100% penetrance[8,9]. Aberrant COX-2 overexpression accompanies chronic pancreatitis[11]. Patients suffering from this disease have, as compared to the normal population, a 15-fold increased risk to develop pancreatic cancer[12]. Cerulein-induced chronic pancreatitis in adult mice, associated with aberrant COX-2 overexpression, is essential for the induction of classical PDAC by K-RasG12V oncogene[13,14]. Treatment of PK or C transgenic mouse lines with nonselective COX or selective COX-2 inhibitors respectively resulted in a reduced tumor load[15,19]
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