Journal of Gastrointestinal & Digestive System
Open Access

Abstract

Among cancers in critical clinical needs, pancreatic ductal adenocarcinoma (PDAC) is the most intractable. Patients are frequently diagnosed too late to be eligible for surgical resection. Chemotherapy (gemcitabine) has provided almost no survival benefit. There is an urgent need to understand the pathobiology of its premalignant stages, and the mechanisms for cancer cell chemoresistance. The KRAS gene is mutated in most PDAC. Pancreatic expression in mice of the Kras oncoprotein efficiently initiates carcinogenesis but not progression to cancer, which necessitates other inputs. Phosphoinositide 3-Kinase (PI3K) activation is required for Krasinduced PDAC initiation and maintenance. Strikingly, somatostatin sst2 receptor loss of gene (SSTR2) expression is observed in most PDAC and inhibits PI3K when re-expressed in cancer cells. We showed that sstr2 monoallelic loss in mice is per se sufficient to activate the PI3K/AKT pathway and, when combined with mutated Kras, to enhance the occurrence of premalignant lesions that rapidly progress to malignancy and metastase to lymph nodes. Additionally, we showed that sst2 expression is progressively lost in mutated Kras-initiated lesions that spontaneously progress to cancer, this expression loss involving PI3K activity. We propose that sst2 expression loss and consequent relief of the physiological brake limiting PI3K/AKT amplifies Kras-driven pathways thus fostering pancreatic carcinogenesis. PDAC is extremely stroma-rich. Cancer-associated fibroblasts (CAFs) secrete proteins that promote cancer cell chemoresistance. We demonstrated that CAF secretome-triggered chemoresistance is abolished upon inhibition of the protein synthesis PI3K/mTOR regulatory pathway which we found highly activated in primary cultures of CAFs, isolated from human PDAC resections. CAFs selectively express the sst1 somatostatin receptor. The SOM230 analogue (Pasireotide) activates the sst1 receptor and inhibits the PI3K/mTOR pathway and the synthesis of secreted proteins. Consequently, tumour growth and chemoresistance in nude mice xenografted with pancreatic cancer cells and CAFs are reduced when chemotherapy (gemcitabine) is combined with SOM230 treatment.

Biography

Email: corinne.bousquet@inserm.fr