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. 1993 May;46(5):429–436. doi: 10.1136/jcp.46.5.429

Expression of gelatinase A and TIMP-2 mRNAs in desmoplastic fibroblasts in both mammary carcinomas and basal cell carcinomas of the skin.

R Poulsom 1, A M Hanby 1, M Pignatelli 1, R E Jeffery 1, J M Longcroft 1, L Rogers 1, G W Stamp 1
PMCID: PMC501252  PMID: 8391548

Abstract

AIMS--To compare the localisation of mRNAs for the basement membrane degrading enzyme gelatinase A (72 kilodalton type IV collagenase) and its inhibitor TIMP-2 in carcinomas of the breast and basal cell carcinomas of the skin which have little or no ability to metastasize. METHODS--In situ hybridisation was performed on formalin fixed, paraffin wax embedded blocks using 35S-labelled riboprobes on 16 mammary carcinomas, three fibroadenomas, and a benign phyllodes tumour, and on 15 basal cell carcinomas of the skin (BCC). RESULTS--Labelling for both mRNAs was detectable in 14 of 16 mammary carcinomas and in 13 of 15 BCC, most often over organising desmoplastic fibroblasts in the stroma around invasive epithelial aggregates. Some sparse labelling was seen over malignant epithelial cells in six of the mammary carcinomas but not in the BCC. Some expression of gelatinase A mRNA was also seen in fibroblasts of breast lobules adjacent to the mammary carcinomas and around engulfed adnexal elements in the BCC, but not in unaffected breast tissues, fibroadenomas, the phyllodes tumour or unaffected skin. CONCLUSIONS--Maximal expression of gelatinase A and TIMP-2 mRNAs occurs in malignant neoplasms as part of the host response to the presence of established neoplastic cells rather than as an initial response to invasion. The degree to which this is present suggests this may be a highly relevant mechanism modulating tumour differentiation, growth and progression, possibly entailing uptake via specific receptors on the tumour cell surface.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barsky S. H., Grossman D. A., Bhuta S. Desmoplastic basal cell carcinomas possess unique basement membrane-degrading properties. J Invest Dermatol. 1987 Mar;88(3):324–329. doi: 10.1111/1523-1747.ep12466209. [DOI] [PubMed] [Google Scholar]
  2. Basset P., Bellocq J. P., Wolf C., Stoll I., Hutin P., Limacher J. M., Podhajcer O. L., Chenard M. P., Rio M. C., Chambon P. A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature. 1990 Dec 20;348(6303):699–704. doi: 10.1038/348699a0. [DOI] [PubMed] [Google Scholar]
  3. Bauer E. A., Uitto J., Walters R. C., Eisen A. Z. Enhanced collagenase production by fibroblasts derived from human basal cell carcinomas. Cancer Res. 1979 Nov;39(11):4594–4599. [PubMed] [Google Scholar]
  4. Biswas C. Tumor cell stimulation of collagenase production by fibroblasts. Biochem Biophys Res Commun. 1982 Dec 15;109(3):1026–1034. doi: 10.1016/0006-291x(82)92042-3. [DOI] [PubMed] [Google Scholar]
  5. Brown P. D., Levy A. T., Margulies I. M., Liotta L. A., Stetler-Stevenson W. G. Independent expression and cellular processing of Mr 72,000 type IV collagenase and interstitial collagenase in human tumorigenic cell lines. Cancer Res. 1990 Oct 1;50(19):6184–6191. [PubMed] [Google Scholar]
  6. Chin J. R., Murphy G., Werb Z. Stromelysin, a connective tissue-degrading metalloendopeptidase secreted by stimulated rabbit synovial fibroblasts in parallel with collagenase. Biosynthesis, isolation, characterization, and substrates. J Biol Chem. 1985 Oct 5;260(22):12367–12376. [PubMed] [Google Scholar]
  7. Devereux J., Haeberli P., Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. doi: 10.1093/nar/12.1part1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Emonard H. P., Remacle A. G., Noël A. C., Grimaud J. A., Stetler-Stevenson W. G., Foidart J. M. Tumor cell surface-associated binding site for the M(r) 72,000 type IV collagenase. Cancer Res. 1992 Oct 15;52(20):5845–5848. [PubMed] [Google Scholar]
  9. Fessler L. I., Duncan K. G., Fessler J. H., Salo T., Tryggvason K. Characterization of the procollagen IV cleavage products produced by a specific tumor collagenase. J Biol Chem. 1984 Aug 10;259(15):9783–9789. [PubMed] [Google Scholar]
  10. Fidler I. J., Hart I. R. Biological diversity in metastatic neoplasms: origins and implications. Science. 1982 Sep 10;217(4564):998–1003. doi: 10.1126/science.7112116. [DOI] [PubMed] [Google Scholar]
  11. Forster S. J., Talbot I. C., Clayton D. G., Critchley D. R. Tumour basement membrane laminin in adenocarcinoma of rectum: an immunohistochemical study of biological and clinical significance. Int J Cancer. 1986 Jun 15;37(6):813–817. doi: 10.1002/ijc.2910370603. [DOI] [PubMed] [Google Scholar]
  12. Gusterson B. A., Warburton M. J., Mitchell D., Ellison M., Neville A. M., Rudland P. S. Distribution of myoepithelial cells and basement membrane proteins in the normal breast and in benign and malignant breast diseases. Cancer Res. 1982 Nov;42(11):4763–4770. [PubMed] [Google Scholar]
  13. Humphries M. J. The molecular basis and specificity of integrin-ligand interactions. J Cell Sci. 1990 Dec;97(Pt 4):585–592. doi: 10.1242/jcs.97.4.585. [DOI] [PubMed] [Google Scholar]
  14. Lefebvre V., Peeters-Joris C., Vaes G. Modulation by interleukin 1 and tumor necrosis factor alpha of production of collagenase, tissue inhibitor of metalloproteinases and collagen types in differentiated and dedifferentiated articular chondrocytes. Biochim Biophys Acta. 1990 May 22;1052(3):366–378. doi: 10.1016/0167-4889(90)90145-4. [DOI] [PubMed] [Google Scholar]
  15. Matrisian L. M. Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet. 1990 Apr;6(4):121–125. doi: 10.1016/0168-9525(90)90126-q. [DOI] [PubMed] [Google Scholar]
  16. McArdle J. P., Roff B. T., Muller H. K., Murphy W. H. The basal lamina in basal cell carcinoma, Bowen's disease, squamous cell carcinoma and keratoacanthoma: an immunoperoxidase study using an antibody to type IV collagen. Pathology. 1984 Jan;16(1):67–72. doi: 10.3109/00313028409067913. [DOI] [PubMed] [Google Scholar]
  17. McCune B. K., Mullin B. R., Flanders K. C., Jaffurs W. J., Mullen L. T., Sporn M. B. Localization of transforming growth factor-beta isotypes in lesions of the human breast. Hum Pathol. 1992 Jan;23(1):13–20. doi: 10.1016/0046-8177(92)90004-m. [DOI] [PubMed] [Google Scholar]
  18. Miller S. J. Biology of basal cell carcinoma (Part II). J Am Acad Dermatol. 1991 Feb;24(2 Pt 1):161–175. doi: 10.1016/0190-9622(91)70022-t. [DOI] [PubMed] [Google Scholar]
  19. Monteagudo C., Merino M. J., San-Juan J., Liotta L. A., Stetler-Stevenson W. G. Immunohistochemical distribution of type IV collagenase in normal, benign, and malignant breast tissue. Am J Pathol. 1990 Mar;136(3):585–592. [PMC free article] [PubMed] [Google Scholar]
  20. Muschel R. J., Williams J. E., Lowy D. R., Liotta L. A. Harvey ras induction of metastatic potential depends upon oncogene activation and the type of recipient cell. Am J Pathol. 1985 Oct;121(1):1–8. [PMC free article] [PubMed] [Google Scholar]
  21. Nagase H., Barrett A. J., Woessner J. F., Jr Nomenclature and glossary of the matrix metalloproteinases. Matrix Suppl. 1992;1:421–424. [PubMed] [Google Scholar]
  22. Okada Y., Tsuchiya H., Shimizu H., Tomita K., Nakanishi I., Sato H., Seiki M., Yamashita K., Hayakawa T. Induction and stimulation of 92-kDa gelatinase/type IV collagenase production in osteosarcoma and fibrosarcoma cell lines by tumor necrosis factor alpha. Biochem Biophys Res Commun. 1990 Sep 14;171(2):610–617. doi: 10.1016/0006-291x(90)91190-4. [DOI] [PubMed] [Google Scholar]
  23. Overall C. M., Wrana J. L., Sodek J. Transcriptional and post-transcriptional regulation of 72-kDa gelatinase/type IV collagenase by transforming growth factor-beta 1 in human fibroblasts. Comparisons with collagenase and tissue inhibitor of matrix metalloproteinase gene expression. J Biol Chem. 1991 Jul 25;266(21):14064–14071. [PubMed] [Google Scholar]
  24. Pauli B. U., Knudson W. Tumor invasion: a consequence of destructive and compositional matrix alterations. Hum Pathol. 1988 Jun;19(6):628–639. doi: 10.1016/s0046-8177(88)80168-0. [DOI] [PubMed] [Google Scholar]
  25. Pignatelli M., Cardillo M. R., Hanby A., Stamp G. W. Integrins and their accessory adhesion molecules in mammary carcinomas: loss of polarization in poorly differentiated tumors. Hum Pathol. 1992 Oct;23(10):1159–1166. doi: 10.1016/0046-8177(92)90034-z. [DOI] [PubMed] [Google Scholar]
  26. Pignatelli M., Smith M. E., Bodmer W. F. Low expression of collagen receptors in moderate and poorly differentiated colorectal adenocarcinomas. Br J Cancer. 1990 Apr;61(4):636–638. doi: 10.1038/bjc.1990.141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Plantefaber L. C., Hynes R. O. Changes in integrin receptors on oncogenically transformed cells. Cell. 1989 Jan 27;56(2):281–290. doi: 10.1016/0092-8674(89)90902-1. [DOI] [PubMed] [Google Scholar]
  28. Ponte P., Gunning P., Blau H., Kedes L. Human actin genes are single copy for alpha-skeletal and alpha-cardiac actin but multicopy for beta- and gamma-cytoskeletal genes: 3' untranslated regions are isotype specific but are conserved in evolution. Mol Cell Biol. 1983 Oct;3(10):1783–1791. doi: 10.1128/mcb.3.10.1783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Poulsom R., Pignatelli M., Stetler-Stevenson W. G., Liotta L. A., Wright P. A., Jeffery R. E., Longcroft J. M., Rogers L., Stamp G. W. Stromal expression of 72 kda type IV collagenase (MMP-2) and TIMP-2 mRNAs in colorectal neoplasia. Am J Pathol. 1992 Aug;141(2):389–396. [PMC free article] [PubMed] [Google Scholar]
  30. Pyke C., Ralfkiaer E., Huhtala P., Hurskainen T., Danø K., Tryggvason K. Localization of messenger RNA for Mr 72,000 and 92,000 type IV collagenases in human skin cancers by in situ hybridization. Cancer Res. 1992 Mar 1;52(5):1336–1341. [PubMed] [Google Scholar]
  31. Salo T., Lyons J. G., Rahemtulla F., Birkedal-Hansen H., Larjava H. Transforming growth factor-beta 1 up-regulates type IV collagenase expression in cultured human keratinocytes. J Biol Chem. 1991 Jun 25;266(18):11436–11441. [PubMed] [Google Scholar]
  32. Senior P. V., Critchley D. R., Beck F., Walker R. A., Varley J. M. The localization of laminin mRNA and protein in the postimplantation embryo and placenta of the mouse: an in situ hybridization and immunocytochemical study. Development. 1988 Nov;104(3):431–446. doi: 10.1242/dev.104.3.431. [DOI] [PubMed] [Google Scholar]
  33. Shapiro S. D., Campbell E. J., Kobayashi D. K., Welgus H. G. Immune modulation of metalloproteinase production in human macrophages. Selective pretranslational suppression of interstitial collagenase and stromelysin biosynthesis by interferon-gamma. J Clin Invest. 1990 Oct;86(4):1204–1210. doi: 10.1172/JCI114826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Stetler-Stevenson W. G., Brown P. D., Onisto M., Levy A. T., Liotta L. A. Tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA expression in tumor cell lines and human tumor tissues. J Biol Chem. 1990 Aug 15;265(23):13933–13938. [PubMed] [Google Scholar]
  35. 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]
  36. Stetler-Stevenson W. G., Krutzsch H. C., Wacher M. P., Margulies I. M., Liotta L. A. The activation of human type IV collagenase proenzyme. Sequence identification of the major conversion product following organomercurial activation. J Biol Chem. 1989 Jan 25;264(3):1353–1356. [PubMed] [Google Scholar]
  37. Turpeenniemi-Hujanen T., Thorgeirsson U. P., Hart I. R., Grant S. S., Liotta L. A. Expression of collagenase IV (basement membrane collagenase) activity in murine tumor cell hybrids that differ in metastatic potential. J Natl Cancer Inst. 1985 Jul;75(1):99–103. [PubMed] [Google Scholar]
  38. Welgus H. G., Stricklin G. P. Human skin fibroblast collagenase inhibitor. Comparative studies in human connective tissues, serum, and amniotic fluid. J Biol Chem. 1983 Oct 25;258(20):12259–12264. [PubMed] [Google Scholar]
  39. Wilhelm S. M., Collier I. E., Marmer B. L., Eisen A. Z., Grant G. A., Goldberg G. I. SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages. J Biol Chem. 1989 Oct 15;264(29):17213–17221. [PubMed] [Google Scholar]
  40. Wilhelm S. M., Eisen A. Z., Teter M., Clark S. D., Kronberger A., Goldberg G. Human fibroblast collagenase: glycosylation and tissue-specific levels of enzyme synthesis. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3756–3760. doi: 10.1073/pnas.83.11.3756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Wright N. A., Poulsom R., Stamp G. W., Hall P. A., Jeffery R. E., Longcroft J. M., Rio M. C., Tomasetto C., Chambon P. Epidermal growth factor (EGF/URO) induces expression of regulatory peptides in damaged human gastrointestinal tissues. J Pathol. 1990 Dec;162(4):279–284. doi: 10.1002/path.1711620402. [DOI] [PubMed] [Google Scholar]

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