Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment
Author
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, ChristopherEntity
UAM. Departamento de Medicina Preventiva y Salud Pública y MicrobiologíaDate
2015-12-01Citation
10.1136/gutjnl-2014-308935
Gut 64.12 (2015): 1921-1935
ISSN
0017-5749; 1468-3288 (on line)DOI
10.1136/gutjnl-2014-308935Funded by
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 FellowshipProject
info:eu-repo/grantAgreement/EC/FP7/256974; Gobierno de España. PS09/02129; Gobierno de España. PI12/02643; info:eu-repo/grantAgreement/EC/FP7/233460Editor's Version
http://dx.doi.org/10.1136/gutjnl-2014-308935Subjects
Antibacterial peptide; Pancreatic cancer; Stem cells; Macrophages; MedicinaNote
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-2014-308935Abstract
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.
Files in this item
Google Scholar:Sainz, Bruno
-
Alcala, Sonia
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Garcia, Elena
-
Sanchez-Ripoll, Yolanda
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Azevedo, Maria M.
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Cioffi, Michele
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Tatari, Marianthi
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Miranda-Lorenzo, Irene
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Hidalgo, Manuel
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Gómez López, Gonzalo
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Cañamero, Marta
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Erkan, Mert
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Kleeff, Jörg
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García-Silva, Susana
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Sancho, Patricia
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Hermann, Patrick C.
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Heeschen, Christopher
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