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. 1998 Feb;77(4):650–655. doi: 10.1038/bjc.1998.104

Imbalance between serum matrix metalloproteinase-2 and its inhibitor as a predictor of recurrence of urothelial cancer.

K Gohji 1, N Fujimoto 1, J Ohkawa 1, A Fujii 1, M Nakajima 1
PMCID: PMC2149919  PMID: 9484825

Abstract

Serum levels of matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinases-2 (TIMP-2) were evaluated as prognostic indicators of the recurrence of urothelial cancer. Sera were obtained from 127 healthy control subjects and 97 urothelial cancer patients who underwent complete resection and were measured for MMP-2 and TIMP-2 using a one-step enzyme immunoassay. The relationship between the serum MMP-2/TIMP-2 ratio and the recurrence of urothelial cancer was examined. The mean serum MMP-2/TIMP-2 ratio in the 31 advanced urothelial cancer patients with recurrence was significantly higher than that in the 22 patients without recurrence (P = 0.0029) and in the 44 superficial bladder cancer patients (P < 0.0001). The 1- and 3-year disease-free survival rates in the patients with high MMP-2/TIMP-2 ratios (50% and 12%) were significantly poorer than those of the patients with normal ratios (82% and 56%) (P = 0.0152). Univariate and multivariate analyses of recurrence demonstrated that the serum MMP-2/TIMP-2 ratio is a significant independent indicator of advanced urothelial cancer. Our results indicate that an imbalance between the serum levels of MMP-2 and TIMP-2 could be a new predictor of recurrence in advanced urothelial cancer patients.

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Selected References

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  1. Albini A., Melchiori A., Santi L., Liotta L. A., Brown P. D., Stetler-Stevenson W. G. Tumor cell invasion inhibited by TIMP-2. J Natl Cancer Inst. 1991 Jun 5;83(11):775–779. doi: 10.1093/jnci/83.11.775. [DOI] [PubMed] [Google Scholar]
  2. Alvarez O. A., Carmichael D. F., DeClerck Y. A. Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. J Natl Cancer Inst. 1990 Apr 4;82(7):589–595. doi: 10.1093/jnci/82.7.589. [DOI] [PubMed] [Google Scholar]
  3. Davies B., Waxman J., Wasan H., Abel P., Williams G., Krausz T., Neal D., Thomas D., Hanby A., Balkwill F. Levels of matrix metalloproteases in bladder cancer correlate with tumor grade and invasion. Cancer Res. 1993 Nov 15;53(22):5365–5369. [PubMed] [Google Scholar]
  4. DeClerck Y. A., Imren S. Protease inhibitors: role and potential therapeutic use in human cancer. Eur J Cancer. 1994;30A(14):2170–2180. doi: 10.1016/0959-8049(94)00460-m. [DOI] [PubMed] [Google Scholar]
  5. DeClerck Y. A., Perez N., Shimada H., Boone T. C., Langley K. E., Taylor S. M. Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res. 1992 Feb 1;52(3):701–708. [PubMed] [Google Scholar]
  6. DeClerck Y. A., Yean T. D., Chan D., Shimada H., Langley K. E. Inhibition of tumor invasion of smooth muscle cell layers by recombinant human metalloproteinase inhibitor. Cancer Res. 1991 Apr 15;51(8):2151–2157. [PubMed] [Google Scholar]
  7. Fujimoto N., Mouri N., Iwata K., Ohuchi E., Okada Y., Hayakawa T. A one-step sandwich enzyme immunoassay for human matrix metalloproteinase 2 (72-kDa gelatinase/type IV collagenase) using monoclonal antibodies. Clin Chim Acta. 1993 Nov 30;221(1-2):91–103. doi: 10.1016/0009-8981(93)90024-x. [DOI] [PubMed] [Google Scholar]
  8. Fujimoto N., Zhang J., Iwata K., Shinya T., Okada Y., Hayakawa T. A one-step sandwich enzyme immunoassay for tissue inhibitor of metalloproteinases-2 using monoclonal antibodies. Clin Chim Acta. 1993 Oct 29;220(1):31–45. doi: 10.1016/0009-8981(93)90004-n. [DOI] [PubMed] [Google Scholar]
  9. Grignon D. J., Sakr W., Toth M., Ravery V., Angulo J., Shamsa F., Pontes J. E., Crissman J. C., Fridman R. High levels of tissue inhibitor of metalloproteinase-2 (TIMP-2) expression are associated with poor outcome in invasive bladder cancer. Cancer Res. 1996 Apr 1;56(7):1654–1659. [PubMed] [Google Scholar]
  10. Khokha R. Suppression of the tumorigenic and metastatic abilities of murine B16-F10 melanoma cells in vivo by the overexpression of the tissue inhibitor of the metalloproteinases-1. J Natl Cancer Inst. 1994 Feb 16;86(4):299–304. doi: 10.1093/jnci/86.4.299. [DOI] [PubMed] [Google Scholar]
  11. Koop S., Khokha R., Schmidt E. E., MacDonald I. C., Morris V. L., Chambers A. F., Groom A. C. Overexpression of metalloproteinase inhibitor in B16F10 cells does not affect extravasation but reduces tumor growth. Cancer Res. 1994 Sep 1;54(17):4791–4797. [PubMed] [Google Scholar]
  12. Liotta L. A., Steeg P. S., Stetler-Stevenson W. G. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell. 1991 Jan 25;64(2):327–336. doi: 10.1016/0092-8674(91)90642-c. [DOI] [PubMed] [Google Scholar]
  13. Liotta L. A., Tryggvason K., Garbisa S., Hart I., Foltz C. M., Shafie S. Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature. 1980 Mar 6;284(5751):67–68. doi: 10.1038/284067a0. [DOI] [PubMed] [Google Scholar]
  14. Montgomery A. M., Mueller B. M., Reisfeld R. A., Taylor S. M., DeClerck Y. A. Effect of tissue inhibitor of the matrix metalloproteinases-2 expression on the growth and spontaneous metastasis of a human melanoma cell line. Cancer Res. 1994 Oct 15;54(20):5467–5473. [PubMed] [Google Scholar]
  15. Moses M. A., Sudhalter J., Langer R. Identification of an inhibitor of neovascularization from cartilage. Science. 1990 Jun 15;248(4961):1408–1410. doi: 10.1126/science.1694043. [DOI] [PubMed] [Google Scholar]
  16. Murphy A. N., Unsworth E. J., Stetler-Stevenson W. G. Tissue inhibitor of metalloproteinases-2 inhibits bFGF-induced human microvascular endothelial cell proliferation. J Cell Physiol. 1993 Nov;157(2):351–358. doi: 10.1002/jcp.1041570219. [DOI] [PubMed] [Google Scholar]
  17. Naito K., Kanbayashi N., Nakajima S., Murai T., Arakawa K., Nishimura S., Okuyama A. Inhibition of growth of human tumor cells in nude mice by a metalloproteinase inhibitor. Int J Cancer. 1994 Sep 1;58(5):730–735. doi: 10.1002/ijc.2910580518. [DOI] [PubMed] [Google Scholar]
  18. Nakajima M., Chop A. M. Tumor invasion and extracellular matrix degradative enzymes: regulation of activity by organ factors. Semin Cancer Biol. 1991 Apr;2(2):115–127. [PubMed] [Google Scholar]
  19. Schnaper H. W., Grant D. S., Stetler-Stevenson W. G., Fridman R., D'Orazi G., Murphy A. N., Bird R. E., Hoythya M., Fuerst T. R., French D. L. Type IV collagenase(s) and TIMPs modulate endothelial cell morphogenesis in vitro. J Cell Physiol. 1993 Aug;156(2):235–246. doi: 10.1002/jcp.1041560204. [DOI] [PubMed] [Google Scholar]
  20. Schultz R. M., Silberman S., Persky B., Bajkowski A. S., Carmichael D. F. Inhibition by human recombinant tissue inhibitor of metalloproteinases of human amnion invasion and lung colonization by murine B16-F10 melanoma cells. Cancer Res. 1988 Oct 1;48(19):5539–5545. [PubMed] [Google Scholar]
  21. Skinner D. G., Daniels J. R., Russell C. A., Lieskovsky G., Boyd S. D., Nichols P., Kern W., Sakamoto J., Krailo M., Groshen S. The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol. 1991 Mar;145(3):459–467. doi: 10.1016/s0022-5347(17)38368-4. [DOI] [PubMed] [Google Scholar]
  22. Stetler-Stevenson W. G., Krutzsch H. C., Liotta L. A. Tissue inhibitor of metalloproteinase (TIMP-2). A new member of the metalloproteinase inhibitor family. J Biol Chem. 1989 Oct 15;264(29):17374–17378. [PubMed] [Google Scholar]
  23. Takigawa M., Nishida Y., Suzuki F., Kishi J., Yamashita K., Hayakawa T. Induction of angiogenesis in chick yolk-sac membrane by polyamines and its inhibition by tissue inhibitors of metalloproteinases (TIMP and TIMP-2). Biochem Biophys Res Commun. 1990 Sep 28;171(3):1264–1271. doi: 10.1016/0006-291x(90)90822-5. [DOI] [PubMed] [Google Scholar]
  24. Wang X., Fu X., Brown P. D., Crimmin M. J., Hoffman R. M. Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice. Cancer Res. 1994 Sep 1;54(17):4726–4728. [PubMed] [Google Scholar]

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