title: Upregulation of the tissue inhibitor of metalloproteinase-1 protein is associated with progression of human non-small-cell lung cancer.
abstract: OBJECTIVE
  Tissue inhibitors of metalloproteinases (TIMPs) are naturally occurring inhibitors of matrix metalloproteinases (MMPs). It has been shown that TIMP-1 may be a multifunctional protein. Little is known about the role of TIMP-1 in progression and metastasis of human lung cancer (tumor inhibiting or tumor promoting), although studies using a variety of techniques have analyzed the expression of TIMP-1 mRNA and/or protein in human cancers.
  
  
  METHODS
  We examined the expression of TIMP-1 protein by immunohistochemistry in patients (n = 160) with primary respectable (stage I to IIIA) non-small-cell lung cancer (NSCLC).
  
  
  RESULTS
  Twenty-seven percent of the tumors (43 of 160) demonstrated elevated expression of this protein. We demonstrate that overexpression of TIMP-1 protein is associated with an adverse outcome. In addition, disease stage, patient's age, and performance status were all significantly related to survival. In multivariate analyses, patients with high TIMP-1 expression had a 90% increased risk of death when compared with those with low expression (relative risk, 1.92; 95% CI, 1.19 to 3.09; P =.008). TIMP-1 expression did not correlate with expression of MMP-2 and MMP-9.
  
  
  CONCLUSIONS
  These results suggest that TIMP-1, independent of its inhibiting activity of MMPs, may have other function(s) critical for NSCLCs. The significance of our results is two-fold. The adverse outcome in patients with overexpression of TIMP-1 indicates its potential prognostic value in NSCLC. Thus, TIMP-1 overexpression may serve to help identify patients with particularly aggressive disease for adjuvant treatments. In addition, the TIMP-1 molecule may represent a novel therapeutic target for treatment of some NSCLCs.
authors.affiliation: Roswell Park Cancer Institute, State University of New York, Buffalo, Elm and Carlton Sts, Buffalo, NY 14263, USA.
authors.forename: Ibrahim S
authors.initials: IS
authors.lastname: Aljada
authors.forename: Nithya
authors.initials: N
authors.lastname: Ramnath
authors.forename: Kathleen
authors.initials: K
authors.lastname: Donohue
authors.forename: Shashi
authors.initials: S
authors.lastname: Harvey
authors.forename: John J
authors.initials: JJ
authors.lastname: Brooks
authors.forename: Sam M
authors.initials: SM
authors.lastname: Wiseman
authors.forename: Thaer
authors.initials: T
authors.lastname: Khoury
authors.forename: Gregory
authors.initials: G
authors.lastname: Loewen
authors.forename: Harry K
authors.initials: HK
authors.lastname: Slocum
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Anderson
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Tan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000096:biosynthesis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016019:Survival Analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis / Q000096:biosynthesis*; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D019715:Tissue Inhibitor of Metalloproteinase-1