title: Inhibition of CD47 Effectively Targets Pancreatic Cancer Stem Cells via Dual Mechanisms.
abstract: OBJECTIVE
  Pancreatic ductal adenocarcinoma (PDAC) is a cancer of the exocrine pancreas with unmet medical need and is strongly promoted by tumor-associated macrophages (TAM). The presence of TAMs is associated with poor clinical outcome, and their overall role, therefore, appears to be protumorigenic. The "don't eat me" signal CD47 on cancer cells communicates to the signal regulatory protein-α on macrophages and prevents their phagocytosis. Thus, inhibition of CD47 may offer a new opportunity to turn TAMs against PDAC cells, including cancer stem cells (CSC), as the exclusively tumorigenic population.
  
  
  METHODS
  We studied in vitro and in vivo the effects of CD47 inhibition on CSCs using a large set of primary pancreatic cancer (stem) cells as well as xenografts of primary human PDAC tissue.
  
  
  RESULTS
  CD47 was highly expressed on CSCs, but not on other nonmalignant cells in the pancreas. Targeting CD47 efficiently enhanced phagocytosis of a representative set of primary human pancreatic cancer (stem) cells and, even more intriguingly, also directly induced their apoptosis in the absence of macrophages during long-term inhibition of CD47. In patient-derived xenograft models, CD47 targeting alone did not result in relevant slowing of tumor growth, but the addition of gemcitabine or Abraxane resulted in sustained tumor regression and prevention of disease relapse long after discontinuation of treatment.
  
  
  CONCLUSIONS
  These data are consistent with efficient in vivo targeting of CSCs, and strongly suggest that CD47 inhibition could be a novel adjuvant treatment strategy for PDAC independent of underlying and highly variable driver mutations.
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. Centre for Stem Cells in Cancer and Ageing, Barts Cancer Institute, A CR-UK Centre of Excellence, Queen Mary University of London, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Trabulo
authors.affiliation: Gastrointestinal Cancer Clinical Research Unit, Clinical Research Programme, CNIO, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.affiliation: Liverpool Cancer Research UK Centre, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Eithne
authors.initials: E
authors.lastname: Costello
authors.affiliation: Liverpool Cancer Research UK Centre, University of Liverpool, Liverpool, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Greenhalf
authors.affiliation: Department of Surgery, Technical University Munich, Munich, Germany. Koc University School of Medicine, Instanbul, Turkey.
authors.forename: Mert
authors.initials: M
authors.lastname: Erkan
authors.affiliation: Department of Surgery, Technical University Munich, Munich, Germany.
authors.forename: Joerg
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: 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. Centre for Stem Cells in Cancer and Ageing, Barts Cancer Institute, A CR-UK Centre of Excellence, Queen Mary University of London, United Kingdom. c.heeschen@qmul.ac.uk.
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D051928:CD47 Antigen / Q000276:immunology / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006825:Hybridomas; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D051928:CD47 Antigen; C497894:CD47 protein, human; D003841:Deoxycytidine; D000093542:Gemcitabine