Alteration in urinary matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio predicts recurrence in nonmuscle-invasive bladder cancer.
OBJECTIVE
The purpose is to assess the prognostic significance of matrix metalloproteinase (MMP)-9 in patients with bladder cancer using a combination of ELISA (to measure MMP-9 in voided urine) and immunohistochemistry (to study MMP-9 in bladder tumors). The relationship between MMP-9 and its principal inhibitor, tissue inhibitor of metalloproteinase (TIMP)-1 (in voided urine samples) was also studied.


METHODS
A total of 134 patients with bladder tumors (7 cis, 76 T(a), 27 T(1), 24 T(2)-T(4); 40 G1, 43 G2, and 44 G3), 33 patients with benign urological conditions, and 36 healthy volunteers was studied. Samples from 106 patients with bladder cancer and 12 controls were stained for MMP-9. Clinical follow-up data were available on 116 patients (median: 25 months; range: 4-36 months).


RESULTS
MMP-9 was present in all urine samples analyzed. There were no differences between patients with cancer and patients with benign disorders. However, patients had significantly higher urinary MMP-9 than normal volunteers (P = 0.0167). Urinary MMP-9 was associated with bladder tumors of advanced stage (P = 0.0065) and large size (P < 0.0001) but not with grade (P = 0.14), multiplicity (P = 0.31), recurrence (P = 0.55), progression (P = 0.83), or survival (P = 0.55). Low MMP-9:TIMP-1 ratios in patients with nonmuscle-invasive tumors were associated with higher recurrence rates (P = 0.0035). Sixty percent (64 of 106) of bladder tumor specimens expressed MMP-9 compared with none of 12 normal urothelial biopsies (P < 0.0001). MMP-9 staining was associated with tumor size (P = 0.014), disease progression (P = 0.005), and poor disease-specific survival (P = 0.022) but was unrelated to tumor stage (P = 0.46), grade (P = 0.26), multiplicity (P = 0.85), or recurrence rate (P = 0.62).


CONCLUSIONS
High urinary MMP-9 levels are associated with large bladder tumors. A low urinary MMP-9:TIMP-1 ratio may indicate a higher risk of intraluminal nonmuscle-invasive tumor recurrence and may assist in planning follow-up surveillance protocols.
Durkan
Garrett C
GC
Department of Surgery, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom.
Nutt
Joyce E
JE
Marsh
Colin
C
Rajjayabun
Paul H
PH
Robinson
Mary C
MC
Neal
David E
DE
Lunec
John
J
Mellon
J Kilian
JK
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018450:Disease Progression; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000652:urine*; D008875:Middle Aged; D011379:Prognosis; D012008:Recurrence; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000652:urine*; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000652:urine
D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9