title: Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Bruno
authors.initials: B
authors.lastname: Sainz
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Alcala
authors.affiliation: Molecular Diagnostics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain Pathology Department, Hospital Universitario Fundacion Alcorcon, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Garcia
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Sanchez-Ripoll
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Azevedo
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Michele
authors.initials: M
authors.lastname: Cioffi
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Marianthi
authors.initials: M
authors.lastname: Tatari
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Miranda-Lorenzo
authors.affiliation: Gastrointestinal Cancer Clinical Research Unit, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.affiliation: Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gomez-Lopez
authors.affiliation: Histopathology Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany Koc University School of Medicine, Istanbul, Turkey.
authors.forename: Mert
authors.initials: M
authors.lastname: Erkan
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: García-Silva
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Sancho
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain Deptartment of Internal Medicine I, Ulm University, Ulm, Germany.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Hermann
authors.affiliation: Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
mesh_terms: D028341:Activins / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism* / Q000494:pharmacology; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000066673:Cell Self Renewal / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D040081:Protein Array Analysis; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D046888:Tissue Array Analysis; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D059016:Tumor Microenvironment; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D058920:Purinergic P2X Receptor Antagonists; D044042:Receptors, Formyl Peptide; D058486:Receptors, Purinergic P2X7; D053773:Transforming Growth Factor beta1; C422405:activin A; C481578:formyl peptide receptor 2, mouse; D028341:Activins; D054804:Cathelicidins
keywords: ANTIBACTERIAL PEPTIDE; MACROPHAGES; PANCREATIC CANCER; STEM CELLS