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Gelatinase A expression and localization in human breast cancers. An in situ hybridization study and immunohistochemical detection using confocal microscopy

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Abstract

The gelatinase A (72 kDa type IV collagenase) is a matrix metallo-proteinase which degrades basement membrane collagens. Various studies emphasize its role in stromal invasion of cancers, but there is some controversy about its origin. Gelatinase A was localized by immunohistochemistry using confocal microscopy in 15 human mammary carcinomas. In addition, the cells responsible for the synthesis of this enzyme were detected by in situ hybridization. Most invasive and non-invasive tumour cells were labelled by immunohistochemistry. Of particular interest was the pattern observed in some pre-invasive areas. Gelatinase A was found in fibroblasts in close contact with pre-invasive tumour clusters. Confocal observation allowed a more precise localization of gelatinase A to the periphery of tumour clusters along the basement membranes and in peritumour fibroblasts. The malignant epithelial cells were negative by immunohistochemistry in these areas. By in situ hybridization, mRNAs encoding gelatinase A were detected only in fibroblasts in close contact with pre-invasive and well differentiated tumour clusters. These findings support the hypothesis that peritumour fibroblasts produce gelatinase A and that breast cancer cells may bind this enzyme to their cell surface and/or internalize it.

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References

  1. Bacon JP, Gonzales C, Hutchison CJ (1991) Applications of confocal laser microscopy. Trends Cell Biol 1:172–175

    Google Scholar 

  2. Barsky SH, Togo S, Garbisa S, Liotta LA (1983) Type IV collagenase immunoreactivity in invasive breast carcinoma. Lancet 19:296–297

    Google Scholar 

  3. Basset P, Bellocq JP, Wolf C, Stoll I, Limacher JM, Podjahcer OL, Chenard MP, Rio MC, Chambon (1990) A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature 348:699–704

    Google Scholar 

  4. Boag AH, Young ID (1993) Immunohistochemical analysis of type IV collaganase expression in prostatic hyperplasia and adenocarcinoma. Mod Pathol 6:65–68

    Google Scholar 

  5. Brown PD, Levy AT, Margulies IMK, Liotta LA, Stetler-Stevenson WG (1990) Independant expression and cellular processing of Mr 72,000 type IV collagenase and interstitial collagenase in human tumorigenic cell lines. Cancer Res 50:6184–6191

    Google Scholar 

  6. Brown PD, Kleiner DE, Unsworth EJ, Stetler-Stevenson WG (1993) Cellular activation of the 72 kDa type IV procollagenase/TIMP2 complex. Kidney Int 43:163–170

    Google Scholar 

  7. Brown PD, Bloxidge RE, Anderson E, Howell A (1993) Expression of activated gelatinase in human invasive breast carcinoma. Clin Exp Metastasis 11:183–189

    Google Scholar 

  8. Campo E, Merino MJ, Liotta LA, Neumann R, Stetler-Stevenson WG (1992) Distribution of the 72 kDa type IV collagenase in nonneoplastic and neoplastic thyroid tissue. Hum Pathol 23:1395–1401

    Google Scholar 

  9. Campo E, Merino MJ, Tavassoli FA, Charonis AS, Stetler-Stevenson WG, Liotta LA (1992) Evaluation of basement membrane components and the 72 kDa type IV collagenase in serous tumors in the ovary. Am J Surg Pathol 16:500–507

    Google Scholar 

  10. Daidone MG, Silvertrini R, D'Errico AD, Di Fronzo G, Benini E, Mancini AM, Garbisa S, Liotta LA, Grigioni WF (1991) Laminin receptors, collagenase IV and prognosis in node-negative breast cancers. Int J Cancer 48:529–532

    Google Scholar 

  11. Davis B, Miles DW, Happerfield LC, Naylor MS, Bobrow LG, Rubens RD, Balkwill FR (1993) Activity of type IV collagenases in benign and malignant breast disease. Br J Cancer 67:1126–1131

    Google Scholar 

  12. Emonard H, Remacle AG, Nöel AC, Grimaud JA, Stetler-Stevenson WG, Foidart JM (1992) Tumor cell surface associated binding site for the Mr 72,000 type IV collagenase. Cancer Res 52:5845–5848

    Google Scholar 

  13. Liotta LA (1986) Tumor invasion and metastases: role of the extracellular matrix. Rhoads memorial award lecture. Cancer Res 46:1–7

    Google Scholar 

  14. Liotta LA, Steegs PS, Stetler-Stevenson WG (1991) Cancer metastases and angiogenesis: an imbalance of positive and negative regulation. Cell 64:327–336

    Google Scholar 

  15. Montegudo C, Merino MJ, San-Juan J, Liotta LA, Stetler-Stevenson WG (1990) Immunohistochemical distribution of type IV collagenase in normal, benign, and malignant breast tissue. Am J Pathol 136:585–592

    Google Scholar 

  16. Nakajima M, Welch DR, Belloni PN, Nicholson GL (1987) Degradation of basement membrane type IV collagen and lung subendothelial matrix by rat mammary adenocarcinoma cell clones of differing metastatic potentials. Cancer Res 47:4869–4876

    Google Scholar 

  17. Nöel AC, Polette M, Munaut C, Emonard HP, Birembaut P, Foidart JM (1994) Coordinate enhancement of gelatinase A mRNA and activity levels in human fibroblasts in response to breast adenocarcinoma cells. Int J Cancer 36:331–336

    Google Scholar 

  18. Overall CM, Wrana JL, Sodek J (1989) Independent regulation of collagenases, 72 kDa progelatinase and metalloendopeptidase inhibitor expression in human fibroblasts by transforming growth factor beta. J Biol Chem. 264:1860–1869

    Google Scholar 

  19. Polette M, Clavel C, Cockett M, Girod de Bentzmann S, Murphy G, Birembaut P (1993) Detection and localization of mRNAs encoding matrix metalloproteinases and their tissue inhibitor in human breast pathology. Invasion Metastasis 13:31–37

    Google Scholar 

  20. Poulsom R, Pignatelli M, Stetler-Stevenson WG, Liotta LA, Wright PA, Jeffrey RE, Longcroft JM, Rogers L, Stamp GWH (1992) Stromal expression of 72 kDa type IV collagenase (MMP-2) and TIMP-2 in colorectal neoplasia. Am J Pathol 141:389–396

    Google Scholar 

  21. Poulsom R, Hanby AM, Pignatelli M, Jeffery RE, Longcroft JM, Rogers L, Stamp GWH (1993) Expression of gelatinase A and TIMP-2 mRNAs in desmoplastic fibroblasts in both mammary carcinomas and basal cell carcinomas of the skin. J Clin Pathol 46:429–436

    Google Scholar 

  22. Pyke C, Ralfkiaer E, Huhtala P, Hurskainen T, Dano K, Tryggvason K (1992) Localization of messenger RNA for 72,000 and 92,000 type IV collagenases in human skin cancers by in situ hybridization. Cancer Res 52:1336–1341

    Google Scholar 

  23. Pyke C, Ralfkiaer E, Tryggvason K, Dano K (1993) Messenger RNA for two type IV collagenases is located in stromal cells in human colon cancer. Am J Pathol 142:359–365

    Google Scholar 

  24. Stetler-Stevenson WG (1990) Type IV collagenase in tumor invasion and metastases. Cancer Metastasis Rev 9:289–303

    Google Scholar 

  25. Turpeenniemi-Hujanen T, Thorgeirsson UP, Hart IR (1985) Expression of collagenase IV (basement membrane collagenase) activity in murine tumor cell hybrids that differ in metastatic potential. J Natl Cancer Inst 75:99–103

    Google Scholar 

  26. Ward RV, Atkison SJ, Slocombe PM, Docherty AJP, Reynolds JJ, Murphy G (1991) Tissue inhibitor of metallo-proteinase-2 inhibits the activation of 72 kDa pro-gelatinase by fibroblast membranes. Biochim Biophys Acta 1079:242–246

    Google Scholar 

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Polette, M., Gilbert, N., Nawrocki, B. et al. Gelatinase A expression and localization in human breast cancers. An in situ hybridization study and immunohistochemical detection using confocal microscopy. Vichows Archiv A Pathol Anat 424, 641–645 (1994). https://doi.org/10.1007/BF00195779

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  • DOI: https://doi.org/10.1007/BF00195779

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