title: Senescent cancer-associated fibroblasts secrete active MMP-2 that promotes keratinocyte dis-cohesion and invasion.
abstract: BACKGROUND
  Previous studies have demonstrated that senescent cancer-associated fibroblasts (CAFs) derived from genetically unstable oral squamous cell carcinomas (GU-OSCC), unlike non-senescent CAFs from genetically stable carcinomas (GS-OSCC), promoted keratinocyte invasion in vitro in a paracrine manner. The mechanism by which this occurs is unclear.
  
  
  METHODS
  Previous work to characterise the senescent-associated secretory phenotype (SASP) has used antibody arrays, technology that is limited by the availability of suitable antibodies. To extend this work in an unbiased manner, we used 2D gel electrophoresis and mass spectroscopy for protein identification. Matrix metalloproteinases (MMPs) were investigated by gelatin zymography and western blotting. Neutralising antibodies were used to block key molecules in the functional assays of keratinocyte adhesion and invasion.
  
  
  RESULTS
  Among a variety of proteins that were differentially expressed between CAFs from GU-OSCC and GS-OSCC, MMP-2 was a major constituent of senescent CAF-CM derived from GU-OSCC. The presence of active MMP-2 was confirmed by gelatine zymography. MMP-2 derived from senescent CAF-CM induced keratinocyte dis-cohesion and epithelial invasion into collagen gels in a TGF-β-dependent manner.
  
  
  CONCLUSIONS
  Senescent CAFs from GU-OSCC promote a more aggressive oral cancer phenotype by production of active MMP-2, disruption of epithelial adhesion and induction of keratinocyte invasion.
authors.affiliation: 1] Department of Oral and Dental Sciences, University of Bristol, Bristol, UK [2] Department of Dentistry, University of Jordan, Amman, Jordan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hassona
authors.affiliation: 1] Melbourne Dental School and Oral Health CRC, University of Melbourne, 720 Swanston Street, Carlton, Victoria 3053, Australia [2] Centre for Innovation, Research, Education and Health (IRIS), Italy.
authors.forename: N
authors.initials: N
authors.lastname: Cirillo
authors.affiliation: Department of Biochemistry, University of Bristol, Bristol, UK.
authors.forename: K
authors.initials: K
authors.lastname: Heesom
authors.affiliation: Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Turner Street, London E1 2AD, UK.
authors.forename: E K
authors.initials: EK
authors.lastname: Parkinson
authors.affiliation: 1] Department of Oral and Dental Sciences, University of Bristol, Bristol, UK [2] Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Turner Street, London E1 2AD, UK.
authors.forename: S S
authors.initials: SS
authors.lastname: Prime
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D015180:Electrophoresis, Gel, Two-Dimensional; D005347:Fibroblasts / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000502:physiology*; D013058:Mass Spectrometry; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology; D019899:Paracrine Communication; D010641:Phenotype; D011506:Proteins / Q000032:analysis / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D017077:Culture Media, Conditioned; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011506:Proteins; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D020778:Matrix Metalloproteinase 2