title: Tumour microenvironments induce expression of urokinase plasminogen activator receptor (uPAR) and concomitant activation of gelatinolytic enzymes.
abstract: BACKGROUND
  The urokinase plasminogen activator receptor (uPAR) is associated with poor prognosis in oral squamous cell carcinoma (OSCC), and increased expression of uPAR is often found at the invasive tumour front. The aim of the current study was to elucidate the role of uPAR in invasion and metastasis of OSCC, and the effects of various tumour microenvironments in these processes. Furthermore, we wanted to study whether the cells' expression level of uPAR affected the activity of gelatinolytic enzymes.
  
  
  METHODS
  The Plaur gene was both overexpressed and knocked-down in the murine OSCC cell line AT84. Tongue and skin tumours were established in syngeneic mice, and cells were also studied in an ex vivo leiomyoma invasion model. Soluble factors derived from leiomyoma tissue, as well as purified extracellular matrix (ECM) proteins, were assessed for their ability to affect uPAR expression, glycosylation and cleavage. Activity of gelatinolytic enzymes in the tissues were assessed by in situ zymography.
  
  
  RESULTS
  We found that increased levels of uPAR did not induce tumour invasion or metastasis. However, cells expressing low endogenous levels of uPAR in vitro up-regulated uPAR expression both in tongue, skin and leiomyoma tissue. Various ECM proteins had no effect on uPAR expression, while soluble factors originating from the leiomyoma tissue increased both the expression and glycosylation of uPAR, and possibly also affected the proteolytic processing of uPAR. Tumours with high levels of uPAR, as well as cells invading leiomyoma tissue with up-regulated uPAR expression, all displayed enhanced activity of gelatinolytic enzymes.
  
  
  CONCLUSIONS
  Although high levels of uPAR are not sufficient to induce invasion and metastasis, the activity of gelatinolytic enzymes was increased. Furthermore, several tumour microenvironments have the capacity to induce up-regulation of uPAR expression, and soluble factors in the tumour microenvironment may have an important role in the regulation of posttranslational modification of uPAR.
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway.
authors.forename: Synnøve
authors.initials: S
authors.lastname: Magnussen
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway.
authors.forename: Elin
authors.initials: E
authors.lastname: Hadler-Olsen
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway.
authors.forename: Nadezhda
authors.initials: N
authors.lastname: Latysheva
authors.affiliation: Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, and Medical Research Center, Oulu University Hospital, Oulu, Finland.
authors.forename: Emma
authors.initials: E
authors.lastname: Pirila
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway; Diagnostic Clinic - Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway.
authors.forename: Sonja E
authors.initials: SE
authors.lastname: Steigen
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway.
authors.forename: Robert
authors.initials: R
authors.lastname: Hanes
authors.affiliation: Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, and Medical Research Center, Oulu University Hospital, Oulu, Finland; Institute of Dentistry, University of Helsinki, Helsinki, Finland.
authors.forename: Tuula
authors.initials: T
authors.lastname: Salo
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway.
authors.forename: Jan-Olof
authors.initials: JO
authors.lastname: Winberg
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway; Diagnostic Clinic - Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Uhlin-Hansen
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway.
authors.forename: Gunbjørg
authors.initials: G
authors.lastname: Svineng
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007889:Leiomyoma / Q000378:metabolism* / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D014062:Tongue Neoplasms / Q000378:metabolism* / Q000473:pathology; D015533:Transcriptional Activation; D059016:Tumor Microenvironment
chemical_list: D017077:Culture Media, Conditioned; D055293:Receptors, Urokinase Plasminogen Activator; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse