title: Urinary TIMP-1 and MMP-2 levels detect the presence of pancreatic malignancies.
abstract: BACKGROUND
  A majority of patients with pancreatic malignancies, including both pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumours (pNETs), present with advanced disease due to a lack of specific symptoms and current diagnostic limitations, making this disease extremely difficult to detect. Our goal was to determine whether urinary matrix metalloproteases (uMMPs) and/or their endogenous inhibitors, urinary tissue inhibitor of metalloproteases (uTIMPs), could be detected in the urine of patients with pancreatic malignancies and whether they may serve as independent predictors of disease status.
  
  
  METHODS
  Retrospective analyses of urine samples (n=139) from PDAC and pNET patients as well as age- and sex-matched controls were conducted. Urinary MMP-2 and uTIMP-1 levels were determined using ELISA and zymography. Biomarker expression in tumour and normal pancreatic tissues was analysed via immunohistochemistry (IHC).
  
  
  RESULTS
  Multivariable logistic regression analyses indicated that, when controlling for age and sex, uMMP-2 (P<0.0001) and uTIMP-1 (P<0.0001) but not uMMP-9, were significant independent predictors for distinguishing between PDAC patients and healthy controls. Our data also indicated that uMMP-2 was an independent predictor of the presence of pNET. In addition, uTIMP-1 levels could differentiate the two cancer groups, PDAC and pNET, respectively. Immunohistochemistry analysis confirmed that MMP-2 and TIMP-1 protein expression is significantly upregulated in PDAC tissue compared with the normal pancreas.
  
  
  CONCLUSIONS
  Taken together, our results suggest that the detection of uMMP-2 and uTIMP-1 may have diagnostic value in the detection of pancreatic malignancies and that uTIMP-1 may be useful in distinguishing between pancreatic adenocarcinoma and neuroendocrine tumours.
authors.affiliation: 1] The Program in Vascular Biology and Department of Surgery, Boston Children's Hospital, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Roy
authors.affiliation: 1] Harvard Medical School, Boston, MA, USA [2] Department of Anesthesia, Boston Children's Hospital, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zurakowski
authors.affiliation: The Program in Vascular Biology and Department of Surgery, Boston Children's Hospital, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wischhusen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Frauenhoffer
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hooshmand
authors.affiliation: 1] Harvard Medical School, Boston, MA, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kulke
authors.affiliation: 1] The Program in Vascular Biology and Department of Surgery, Boston Children's Hospital, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Moses
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000652:urine*; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis / Q000652:urine*; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000652:urine*; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000175:diagnosis / Q000652:urine*; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000652:urine*; D011379:Prognosis; D012189:Retrospective Studies; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000652:urine*
chemical_list: D014408:Biomarkers, Tumor; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2