| Title: |
Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment |
| Authors: |
Sainz, Bruno; Alcala, Sonia; Garcia, Elena; Sanchez-Ripoll, Yolanda; Azevedo, Maria M.; Cioffi, Michele; Tatari, Marianthi; Miranda-Lorenzo, Irene; Hidalgo, Manuel; Gómez López, Gonzalo; Cañamero, Marta; Erkan, Mert; Kleeff, Jörg; García-Silva, Susana; Sancho, Patricia; Hermann, Patrick C.; Heeschen, Christopher |
| Contributors: |
Departamento de Medicina Preventiva y Salud Pública y Microbiología; Facultad de Medicina |
| Publication Year: |
2016 |
| Collection: |
Universidad Autónoma de Madrid (UAM): Biblos-e Archivo |
| Subject Terms: |
Antibacterial peptide; Pancreatic cancer; Stem cells; Macrophages; Medicina |
| Description: |
This is the peer reviewed version of the following article: Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment. Gut 64.12 (2015): 1921-1935 and which has been published in final form at http://dx.doi.org/10.1136/gutjnl-2014-308935 ; 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 ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Gut; http://dx.doi.org/10.1136/gutjnl-2014-308935; info:eu-repo/grantAgreement/EC/FP7/256974; info:eu-repo/grantAgreement/EC/FP7/233460; Gobierno de España. PS09/02129; Gobierno de España. PI12/02643; https://hdl.handle.net/10486/672379; 1921; 12; 1935; 64 |
| DOI: |
10.1136/gutjnl-2014-308935 |
| Availability: |
https://hdl.handle.net/10486/672379; https://doi.org/10.1136/gutjnl-2014-308935 |
| Rights: |
open access |
| Accession Number: |
edsbas.FBD2B84D |
| Database: |
BASE |