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Tumor-Specific Urinary Matrix Metalloproteinase Fingerprinting: Identification of High Molecular Weight Urinary Matrix Metalloproteinase Species

Authors' Affiliations: ¹ Program in Vascular Biology and Department of Surgery, Children's Hospital Boston, ² Brigham and Women's Hospital, ³ Beth Israel Deaconess Medical Center, and ⁴ Harvard Medical School, Boston, Massachusetts

Requests for reprints: Marsha A. Moses, Program in Vascular Biology and Department of Surgery, 12.214, Karp Family Research Building, Children's Hospital/Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115. Phone: 617-919-2207; Fax: 617-730-0231; E-mail: marsha.moses{at}childrens.harvard.edu.

Purpose: We have previously reported that matrix metalloproteinases MMP-2, MMP-9, and the complex MMP-9/NGAL can be detected in urine of patients with a variety of cancers including prostate and bladder carcinoma. In addition, we also detected several unidentified urinary gelatinase activities with molecular weights >125 kDa. The objective of the current study was to identify these high molecular weight (HMW) species, determine their potential as predictors of disease status, and ask whether a tumor-specific pattern existed based on urinary MMP analysis.

Experimental Design: Chromatography, zymography, and mass spectrometry was used to identify HMW gelatinase species of 140, 190, and >220 kDa in urine of cancer patients. To determine whether a tumor-specific pattern of appearance existed among the MMPs detected, we analyzed the urine of 189 patients with prostate or bladder cancer and controls.

Results: The 140, >220 kDa, and 190 HMW gelatinase species were identified as MMP-9/tissue inhibitor of metalloproteinase 1 complex, MMP-9 dimer, and ADAMTS-7, respectively. The frequency of detection of any MMP species was significantly higher in urine from prostate and bladder cancer groups than controls. MMP-9 dimer and MMP-9 were independent predictors for distinguishing between patients with prostate and bladder cancer (P < 0.001 for each) by multivariable analysis.

Conclusions: This study is the first to identify a tumor-specific urinary MMP fingerprint that may noninvasively facilitate identification of cancer presence and type. This information may be of diagnostic and prognostic value in the detection and/or clinical monitoring of disease progression and therapeutic efficacy in patients with bladder or prostate cancer.