TY - JOUR T1 - Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment JF - Gut JO - Gut SP - 1921 LP - 1935 DO - 10.1136/gutjnl-2014-308935 VL - 64 IS - 12 AU - Bruno Sainz, Jr AU - Sonia Alcala AU - Elena Garcia AU - Yolanda Sanchez-Ripoll AU - Maria M Azevedo AU - Michele Cioffi AU - Marianthi Tatari AU - Irene Miranda-Lorenzo AU - Manuel Hidalgo AU - Gonzalo Gomez-Lopez AU - Marta Cañamero AU - Mert Erkan AU - Jörg Kleeff AU - Susana García-Silva AU - Patricia Sancho AU - Patrick C Hermann AU - Christopher Heeschen Y1 - 2015/12/01 UR - http://gut.bmj.com/content/64/12/1921.abstract N2 - Objectives The tumour stroma/microenvironment not only provides structural support for tumour development, but more importantly it provides cues to cancer stem cells (CSCs) that regulate their self-renewal and metastatic potential. This is certainly true for pancreatic ductal adenocarcinomas (PDAC), where tumour-associated fibroblasts, pancreatic stellate cells and immune cells create an abundant paracrine niche for CSCs via microenvironment-secreted factors. Thus understanding the role that tumour stroma cells play in PDAC development and CSC biology is of utmost importance.Design Microarray analyses, tumour microarray immunohistochemical assays, in vitro co-culture experiments, recombinant protein treatment approaches and in vivo intervention studies were performed to understand the role that the immunomodulatory cationic antimicrobial peptide 18/LL-37 (hCAP-18/LL-37) plays in PDAC biology.Results We found that hCAP-18/LL-37 was strongly expressed in the stroma of advanced primary and secondary PDAC tumours and is secreted by immune cells of the stroma (eg, tumour-associated macrophages) in response to tumour growth factor-β1 and particularly CSC-secreted Nodal/ActivinA. Treatment of pancreatic CSCs with recombinant LL-37 increased pluripotency-associated gene expression, self-renewal, invasion and tumourigenicity via formyl peptide receptor 2 (FPR2)- and P2X purinoceptor 7 receptor (P2X7R)-dependent mechanisms, which could be reversed by inhibiting these receptors. Importantly, in a genetically engineered mouse model of K-Ras-driven pancreatic tumourigenesis, we also showed that tumour formation was inhibited by either reconstituting these mice with bone marrow from cathelicidin-related antimicrobial peptide (ie, murine homologue of hCAP-18/LL-37) knockout mice or by pharmacologically inhibiting FPR2 and P2X7R.Conclusions Thus, hCAP-18/LL-37 represents a previously unrecognised PDAC microenvironment factor that plays a critical role in pancreatic CSC-mediated tumourigenesis. ER -