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Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment
  1. Bruno Sainz Jr1,2,
  2. Sonia Alcala1,2,
  3. Elena Garcia3,4,
  4. Yolanda Sanchez-Ripoll1,
  5. Maria M Azevedo1,
  6. Michele Cioffi1,
  7. Marianthi Tatari1,
  8. Irene Miranda-Lorenzo1,
  9. Manuel Hidalgo5,
  10. Gonzalo Gomez-Lopez6,
  11. Marta Cañamero7,
  12. Mert Erkan8,9,
  13. Jörg Kleeff8,
  14. Susana García-Silva1,
  15. Patricia Sancho1,
  16. Patrick C Hermann1,10,
  17. Christopher Heeschen1,11
  1. 1Stem Cells and Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  2. 2Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma de Madrid, Madrid, Spain
  3. 3Molecular Diagnostics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  4. 4Pathology Department, Hospital Universitario Fundacion Alcorcon, Madrid, Spain
  5. 5Gastrointestinal Cancer Clinical Research Unit, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  6. 6Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  7. 7Histopathology Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  8. 8Department of Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany
  9. 9Koc University School of Medicine, Istanbul, Turkey
  10. 10Deptartment of Internal Medicine I, Ulm University, Ulm, Germany
  11. 11Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, UK
  1. Correspondence to Dr Bruno Sainz Jr, Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma de Madrid, E-28029 Madrid, Spain; bruno.sainz@uam.es and Dr Christopher Heeschen, Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, Charterhouse Sqr, London EC1M 6BQ, UK; c.heeschen{at}qmul.ac.uk

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.

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