Expression of metalloproteinase-2, metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 in transitional cell carcinoma of upper urinary tract: correlation with tumor stage and survival.
OBJECTIVE
To investigate the relationship between the expression of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 and pT stage or survival in patients with transitional cell carcinoma of the upper urinary tract. MMP-2 and MMP-9 are associated with tumor invasion in several malignancies. TIMPs exert an anti-invasive effect by blocking MMP activity. Recent studies have shown, however, that TIMPs can also stimulate cell proliferation and angiogenesis.


METHODS
Tumor sections surgically removed from 91 patients were examined for expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 by immunohistochemistry. We also determined the proliferation index and microvessel density in each tumor and investigated the independent roles of these factors in tumor stage and survival using multivariate analysis.


RESULTS
Of 91 tissue samples, 50, 51, 45, and 39 were positive for MMP-2, MMP-9, TIMP-1, and TIMP-2 expression, respectively. Tumors positive for MMP-2, MMP-9, and TIMP-1 exhibited a greater proliferation index than tumors with negative expression (P <0.001, P = 0.013, and P <0.001, respectively). The microvessel density of tumors positive for MMP-2 and TIMP-1 was greater than that of negative tumors (P <0.001). The expression of MMP-2, MMP-9, and TIMP-1 was an independent predictor of high pT stage. Cox proportional hazard analysis identified TIMP-1 expression as an independent factor for cause-specific survival (odds ratio 5.2, P = 0.011), similar to microvessel density, pT4, and lymph node metastasis.


CONCLUSIONS
TIMP-1 expression correlated with pT stage and was an independent predictor of cause-specific survival. Our results suggest that TIMP-1 expression is a potentially useful tool for the selection of postoperative observation strategies in patients with transitional cell carcinoma of the upper urinary tract.
Miyata
Yasuyoshi
Y
Department of Urology, Nagasaki University School of Medicine, Nagasaki City, Nagasaki, Japan.
Kanda
Shigeru
S
Nomata
Koichiro
K
Hayashida
Yasushi
Y
Kanetake
Hiroshi
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002295:Carcinoma, Transitional Cell / Q000098:blood supply / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D002455:Cell Division; D004790:Enzyme Induction; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D007682:Kidney Pelvis / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000201:enzymology; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016019:Survival Analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis* / Q000235:genetics; D014516:Ureteral Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000401:mortality / Q000473:pathology
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9