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 | Gómez López, 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) | |
dc.facultadUAM | Facultad de Medicina | |