TY - JOUR
T1 - Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment
AU - Sainz, Bruno
AU - Alcala, Sonia
AU - Garcia, Elena
AU - Sanchez-Ripoll, Yolanda
AU - Azevedo, Maria M.
AU - Cioffi, Michele
AU - Tatari, Marianthi
AU - Miranda-Lorenzo, Irene
AU - Hidalgo, Manuel
AU - Gomez-Lopez, Gonzalo
AU - Cañamero, Marta
AU - Erkan, Mert
AU - Kleeff, Jörg
AU - García-Silva, Susana
AU - Sancho, Patricia
AU - Hermann, Patrick C.
AU - Heeschen, Christopher
N1 - Funding Information:
We are indebted to Sara M Trabulo and Alexandra Aicher for their technical in vivo assistance and to the CNIO Histopathology Core Unit, particularly Raquel Pajares and Maria Lozano. CH: ERC Advanced Investigator Grant (Pa-CSC 233460), European Community''s Seventh Framework Programme (FP7/2007-2013) under grant agreement no 256974 (EPC-TM-NET) and no 602783 (CAM-PaC), the Subdirección General de Evaluación y Fomento de la Investigación, Fondo de Investigación Sanitaria (PS09/02129 and PI12/02643) and the Programa Nacional de Internacionalización de la I+D, Subprogramma: FCCI 2009 (PLE2009-0105; both Ministerio de Economía y Competitividad (es), Spain). BSJr: Rámon y Cajal Merit Award from the Ministerio de Economía y Competitividad, Spain and Clinic and Laboratory Integration Program (CLIP) grant from the Cancer Research Institute, NY, NY. MCi: La Caixa Predoctoral Fellowship.
PY - 2015/12/1
Y1 - 2015/12/1
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 pluripotencyassociated 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.
AB - 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 pluripotencyassociated 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.
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U2 - 10.1136/gutjnl-2014-308935
DO - 10.1136/gutjnl-2014-308935
M3 - Article
C2 - 25841238
AN - SCOPUS:84954363411
SN - 0017-5749
VL - 64
SP - 1921
EP - 1935
JO - Gut
JF - Gut
IS - 12
ER -