TY - JOUR
T1 - Upregulation of the tissue inhibitor of metalloproteinase-1 protein is associated with progression of human non-small-cell lung cancer
AU - Aljada, Ibrahim S.
AU - Ramnath, Nithya
AU - Donohue, Kathleen
AU - Harvey, Shashi
AU - Brooks, John J.
AU - Wiseman, Sam M.
AU - Khoury, Thaer
AU - Loewen, Gregory
AU - Slocum, Harry K.
AU - Anderson, Timothy M.
AU - Bepler, Gerold
AU - Tan, Dongfeng
PY - 2004
Y1 - 2004
N2 - Purpose: 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. Patients and 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. Conclusion: 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.
AB - Purpose: 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. Patients and 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. Conclusion: 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.
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U2 - 10.1200/JCO.2004.02.110
DO - 10.1200/JCO.2004.02.110
M3 - Article
C2 - 15249585
AN - SCOPUS:4344637105
SN - 0732-183X
VL - 22
SP - 3218
EP - 3229
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 16
ER -