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Sequential activation and production of matrix metalloproteinase-2 during breast cancer progression

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Abstract

The proteolytic processes are thought to be the critical point in tumor invasion and metastasis, mainly by matrix metalloproteinases (MMPs) and serine proteases. We measured the activity of MMP-2 from 28 normal, 12 benign and 126 breast cancer tissues using gelatin zymography. Inactive MMP-2 (72 kD) was expressed in 53.6% of the normal and 66.6% of the cancer tissues, respectively (P= 0.77), while active MMP-2 (62 kD) was expressed in 28.6% and 73.0%, respectively (P = 0.003). The enzymatic activity of active MMP-2 (62 kD) measured in the gel band area was 4.0 ± 7.2 mm2 in normal breasts, 7.7 ± 9.8 mm2 in benign breast diseases, 9.5 ± 8.5 mm2 in ductal carcinoma in situ (DCIS), and 12.0 ± 13.7 mm2 in invasive cancers. The MMP-2 activation ratio (62 kD/62 kD + 72 kD) was 0.12 ± 0.18 in normal tissues, 0.10 ± 0.20 in benign diseases, 0.61 ± 0.22 in DCIS, and 0.50 ± 0.28 in invasive cancers. In conclusion, MMP-2 activation was the main cause of the increased 62 kD MMP-2 activity during the early phase of breast cancer, while production of MMP-2 supplemented the increased 62 kD activity in the late phase. We suggest, therefore, that these differential expressions of MMP-2 activation and production during the different stages of breast cancer progression are potential therapeutic targets for biological or gene therapy under the concept of stage-oriented cancer treatment.[⇃]

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References

  1. Stetler-Stevenson WG, 1990, Type IV collagenases in tumor invasion and metastasis. Cancer Metast Rev, 9, 289–303.

    Google Scholar 

  2. Tryggvason K, Hoyhtya M and Pyke C, 1993, Type IV collagenases in invasive tumors. Breast Cancer Res Treat, 24, 209–18.

    Google Scholar 

  3. Stetler-Stevenson WG, Krutzsch HC, Wacher MP, Marguiles IMK and Liotta LA, 1989, The activation of human type IV collagenase proenzyme. Sequence identification of the major conversion product following organomercurial activation. J Biol Chem, 264, 1353–6.

    Google Scholar 

  4. Thompson EW, Paik SM, Brunner N, et al. 1992, Association of increased basement membrane invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines. J Cell Physiol, 150, 534–44.

    Google Scholar 

  5. Azzam HS, Arand GA, Lippman ME and Thompson EW, 1993, MMP-2 activation potential associates with metastatic progression in human breast cancer cell lines, and is independent of MMP-2 production. J Natl Cancer Inst, 85, 1758–64.

    Google Scholar 

  6. Sato H, Takino T, Okada Y, et al. 1994, A matrix metalloproteinase expressed on the surface of invasive tumor cells. Nature, 370, 61–5.

    Google Scholar 

  7. Okada A, Belloco JP, Rouyer N, et al. 1994, Membrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast, and head and neck carcinomas. Proc Natl Acad Sci USA, 92, 2730–4.

    Google Scholar 

  8. Nomura H, Sato H, Seiki M, Masayoshi M and Okada Y, 1995, Expression of membrane-type matrix metalloproteinase in human gastric carcinomas. Cancer Res, 55, 3263–6.

    Google Scholar 

  9. Yu M, Sato H, Seiki M and Thompson EW, 1995, Complex regulation of MT-MMP expression and MMP-2 activation by concanavalin A in MDA-MB231 human breast cancer cells. Cancer Res, 55, 3272–7.

    Google Scholar 

  10. Garbisa S, Negro A, Kalbic T, et al. 1988, Type IV collagenolytic activity linkage with the metastatic phenotype induced by ras transfection. Adv Exp Med Biol, 233, 179–86.

    Google Scholar 

  11. Nakajima M, Welch DR, Wynn DM, Tsuruo T and Nicolson GL, 1993, Serum and plasma Mr 92,000 progelatinase levels correlate with spontaneous metastasis of rat 13762NF mammary adenocarcinoma. Cancer Res, 53, 5802–7.

    Google Scholar 

  12. Naito K, Kanbayashi N, Nakajima S, Murai T, Arakawa K, Nishimura S and Okuyama A, 1994, Inhibition of growth of human tumor cells in nude mice by a metalloproteinase inhibitor. Int J Cancer, 58, 730–5.

    Google Scholar 

  13. Taraboletti G, Garofalo A, Belotti D, et al. 1995, Inhibition of angiogenesis and murine hemangioma growth by batimastat, a synthetic inhibitor of matrix metalloproteinases. J Natl Cancer Inst, 87, 293–8.

    Google Scholar 

  14. Alexander CM and Werb E, 1992, Targeted disruption of the tissue inhibitor of metallopro teinases gene increases the invasive behavior of primitive mesenchymal cells derived from embryonic stem cells in vitro. J Cell Biol, 118, 727–39.

    Google Scholar 

  15. DeClark YA, Yean TD, Lu HS, Ting J and Langley KE, 1991, Inhibition of autoproteolytic activation of interstitial procollagenase by recombinant metalloproteinase inhibitor MI1TIMP-2. J Biol Chem, 266, 3893–9.

    Google Scholar 

  16. DeClark YA, Perez N, Shimada H, Boone TC, Langley KE and Taylor SM, 1992, Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res, 52, 701–7.

    Google Scholar 

  17. Reponen P, Sahlberg C, Huhtala P, Hurskainen T, Thesleff I and Tryggvason K, 1992, Molecular cloning of murine 70-kD type IV collagenase and its expres sion during mouse development. J Biol Chem, 267, 7856–62.

    Google Scholar 

  18. Pyke C, Ralkiaer E, Huhtala P, Hurskainen T, Dano K and Tryggvason K, 1992, Localization of messenger RNA for Mr 72,000 and 92,000 type IV collagenases in human skin cancers by in situ hybridization. Cancer Res, 52, 1336–41.

    Google Scholar 

  19. Pyke, C, Ralfkiaer E, Tryggvason K and Dano K, 1993, Messenger RNA for two type IV collagenases is located in non-malignant stromal cells in human colon cancer. Am J Pathol, 142, 359–65.

    Google Scholar 

  20. Levy AT, Cioce V, Sobel ME, et al. 1991, Increased expression of the Mr 72,000 type IV collagenase in human colonic adenocarcinoma. Cancer Res, 51,439–44.

    Google Scholar 

  21. Boag AH and Young ID, 1994, Increased expression of the 72-kD type IV collagenase in prostatic adenocarcinoma. Demonstration by immunohistochemistry and in situ hybridization. Am J Pathol, 144, 585–91.

    Google Scholar 

  22. Stearns ME and Wang M, 1993, Type IV collagenase (Mr 72,000) expression in human prostate: benign and malignant tissue. Cancer Res, 53, 878–83.

    Google Scholar 

  23. Monteagudo C, Merino MJ, San-Juan J, Liotta LA and Stetler-Stevenson WG, 1990, Immunohistochemical distribution and type IV collagenase in normal, benign, and malignant breast tissue. Am J Pathol, 136, 585–92.

    Google Scholar 

  24. Polette M, Clavel C, Cockett M, Girod de Bentzmann S, Murphy and Birembaut P, 1993, Detection and localization of mRNAs encoding matrix metalloproteinases and their tissue inhibitor in human breast pathology. Invasion and Metastasis, 13, 31–7.

    Google Scholar 

  25. Davies B, Waxman J, Wasan H, et al. 1993, Levels of matrix metalloproteases in bladder cancer correlate with tumor grade and invasion. Cancer Res, 53, 5365–9.

    Google Scholar 

  26. David L, Nesland JM, Holm R and Sobrinho-Simoes M, 1994, Expression of laminin, collagen IV, fibronectin, and type IV collagenase in gastric carcinoma. Cancer, 73, 518–27.

    Google Scholar 

  27. Daidone MG, Silvestrini R, D'Errico A, et al. 1991, Laminin receptors, collagenase IV and prognosis in node negative breast cancers. Int J Cancer, 48, 529–32.

    Google Scholar 

  28. Heussen C and Dowdle EB, 1980, Electrophoretic analysis of plasminogen activators in polyacrylamide gel containing sodium dodecyl sulphate and co-polymerized substrates. Analyt Biochem, 102, 196–202.

    Google Scholar 

  29. Beahrs OH and Meyers MH, 1992, Manual for Staging of Cancer, 4th edn. Philadelphia: Lippincott.

    Google Scholar 

  30. Doussal VL, Tubiana-Hulin M, Friedman S, Hacerne K, Spyratos F and Brunet M, 1989, Prognostic value of histologic grade nuclear components of Scarff-Bloom-Richardson (SBR): an improved score modification based on a multivariate analysis of 1262 invasive ductal breast carcinomas. Cancer, 64, 1914–22.

    Google Scholar 

  31. Yates F, 1956, Analysis of contingency tables with grouping based on quantitative characters. Biometrika, 35, 176–81.

    Google Scholar 

  32. Brown PD, Bloxidge RE, Anderson E and Howell A, 1993, Expression of activated gelatinase in human invasive breast carcinoma. Clin Exp Metastasis, 11, 183–9.

    Google Scholar 

  33. Davies B, Miles DW, Happerfield LC, et al. 1993, L-myc, et al. 1993, Activity of type IV collagenases in benign and malignant breast disease. Br J Cancer, 67, 1126–31.

    Google Scholar 

  34. Brown PD, Bloxidge RE, Stuart NSA, Gatter KC and Carmichael J, 1993, Association between expression of activated 72-kilodalton gelatinase and tumor spread in non-small-cell lung carcinoma. J Natl Cancer Inst, 87, 574–8.

    Google Scholar 

  35. Kleiner DE and Stetler-Stevenson WG, 1994, Quantitative zymography: detection of picogram quantities of gelatinase. Analyt Biochem, 218, 325–9.

    Google Scholar 

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Authors and Affiliations

  1. Yonsei Cancer Center, Institute for Cancer Research, Department of General Surgery, Internal Medicine, Yonsei University College of Medicine, Seoul, Korea

    Kyong Sik Lee, Sun Young Rha, Sea Joong Kim, Joo Hang Kim, Jae Kyong Roh, Byung Soo Kim & Hyun Cheol Chung

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  1. Kyong Sik Lee
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Sik Lee, K., Young Rha, S., Joong Kim, S. et al. Sequential activation and production of matrix metalloproteinase-2 during breast cancer progression. Clin Exp Metast 14, 512–519 (1996). https://doi.org/10.1007/BF00115111

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