Originally published as JCO Early Release 10.1200/JCO.2004.02.110 on July 12 2004

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Upregulation of the Tissue Inhibitor of Metalloproteinase-1 Protein Is Associated With Progression of Human Non–Small-Cell Lung Cancer

Roswell Park Cancer Institute, State University of New York, Buffalo, NY; University of Pennsylvania, Philadelphia, PA; H. Lee Moffitt Cancer Center, Tampa, FL; and Tufts New England Medical Center, Boston, MA

Address reprint requests to Dongfeng Tan, MD, Departments of Pathology and Cancer Genetics, Roswell Park Cancer Institute, State University of New York, Buffalo, Elm and Carlton Sts, Buffalo, NY 14263; e-mail: dongfeng.tan{at}roswellpark.org

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.

Supported in part by a grant from the Roswell Park Cancer Institute and by shared resources of the Roswell Park Cancer Institute core grant NIH P30 CA016056-27.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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