Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment

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dc.contributor.author Sainz, Bruno
dc.contributor.author Alcala, Sonia
dc.contributor.author Garcia, Elena
dc.contributor.author Sanchez-Ripoll, Yolanda
dc.contributor.author Azevedo, Maria M.
dc.contributor.author Cioffi, Michele
dc.contributor.author Tatari, Marianthi
dc.contributor.author Miranda-Lorenzo, Irene
dc.contributor.author Hidalgo, Manuel
dc.contributor.author Gomez-Lopez, Gonzalo
dc.contributor.author Cañamero, Marta
dc.contributor.author Erkan, Mert
dc.contributor.author Kleeff, Jörg
dc.contributor.author García-Silva, Susana
dc.contributor.author Sancho, Patricia
dc.contributor.author Hermann, Patrick C.
dc.contributor.author Heeschen, Christopher
dc.contributor.other UAM. Departamento de Medicina Preventiva y Salud Pública y Microbiología es_ES
dc.date.accessioned 2016-08-04T15:47:56Z
dc.date.available 2016-08-04T15:47:56Z
dc.date.issued 2015-12-01
dc.identifier.citation Gut 64.12 (2015): 1921-1935 en_US
dc.identifier.issn 0017-5749 es_ES
dc.identifier.issn 1468-3288 (on line) es_ES
dc.identifier.uri http://hdl.handle.net/10486/672379
dc.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 en_US
dc.description.abstract 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. en_US
dc.description.sponsorship CH: ERC Advanced Investigator Grant (Pa-CSC 233460), European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 256974 (EPC-TM-NET) and n° 602783 (CAM-PaC), the Subdirección General de Evaluación y Fomento de la Investigación, Fondo de Investigación Sanitaria (PS09/02129 & 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. MC: La Caixa Predoctoral Fellowship en_US
dc.format.extent 44 pag. es_ES
dc.format.mimetype application/pdf en
dc.language.iso eng en
dc.relation.ispartof Gut en_US
dc.subject.other Antibacterial peptide en_US
dc.subject.other Pancreatic cancer en_US
dc.subject.other Stem cells en_US
dc.subject.other Macrophages en_US
dc.title Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment en_US
dc.type article en
dc.subject.eciencia Medicina es_ES
dc.date.embargoend 2016-12-01
dc.relation.publisherversion http://dx.doi.org/10.1136/gutjnl-2014-308935 en
dc.identifier.doi 10.1136/gutjnl-2014-308935 en
dc.identifier.publicationfirstpage 1921 es_ES
dc.identifier.publicationissue 12 es_ES
dc.identifier.publicationlastpage 1935 es_ES
dc.identifier.publicationvolume 64 es_ES
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/256974 en
dc.relation.projectID Gobierno de España. PS09/02129 es_ES
dc.relation.projectID Gobierno de España. PI12/02643 es_ES
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/233460 en
dc.type.version info:eu-repo/semantics/acceptedVersion en
dc.rights.accessRights openAccess en
dc.authorUAM Sainz Anding, Bruno (264918)

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