Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1992 Aug;141(2):389–396.

Stromal expression of 72 kda type IV collagenase (MMP-2) and TIMP-2 mRNAs in colorectal neoplasia.

R Poulsom 1, M Pignatelli 1, W G Stetler-Stevenson 1, L A Liotta 1, P A Wright 1, R E Jeffery 1, J M Longcroft 1, L Rogers 1, G W Stamp 1
PMCID: PMC1886613  PMID: 1323219

Abstract

We undertook an in situ hybridization study to localize the mRNAs for the 72 kda type IV collagenase (MMP-2) and its specific inhibitor (TIMP-2) in 12 colorectal carcinomas, 3 adenomas, and 4 uninvolved resection margins to see how their distributions correlated with that of the reported distribution of MMP-2 protein. Labeling for MMP-2 and TIMP-2 mRNAs was detectable in 10 of 12 carcinomas and in 2 of 3 adenomas. Unexpectedly, we found much stronger signals for MMP-2 and TIMP-2 mRNAs within the mesenchymal cells in the desmoplastic stroma, of endothelial and/or (myo)fibroblastic nature, rather than in tumor epithelial cells in which localization of MMP-2 was anticipated. Our data indicate that stromal cells may have the ability to synthesize a metalloproteinase that degrades basement membrane, and may together with the neoplastic epithelial cells participate actively in the tissue remodeling and disruption of the basement membrane integrity which is characteristic of invasive tumors.

Full text

PDF
389

Images in this article

392Figure 1 to 6
on p.392

Selected References

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

  1. 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]
  2. Bauer E. A., Gordon J. M., Reddick M. E., Eisen A. Z. Quantitation and immunocytochemical localization of human skin collagenase in basal cell carcinoma. J Invest Dermatol. 1977 Oct;69(4):363–367. doi: 10.1111/1523-1747.ep12510240. [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. Charpin C., Lissitzky J. C., Jacquemier J., Lavaut M. N., Kopp F., Pourreau-Schneider N., Martin P. M., Toga M. Immunohistochemical detection of laminin in 98 human breast carcinomas: a light and electron microscopic study. Hum Pathol. 1986 Apr;17(4):355–365. doi: 10.1016/s0046-8177(86)80458-0. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. 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]
  9. Durbin H., Rodrigues N., Bodmer W. F. Further characterization, isolation and identification of the epithelial cell-surface antigen defined by monoclonal antibody AUA1. Int J Cancer. 1990 Mar 15;45(3):562–565. doi: 10.1002/ijc.2910450331. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. Fini M. E., Girard M. T. Expression of collagenolytic/gelatinolytic metalloproteinases by normal cornea. Invest Ophthalmol Vis Sci. 1990 Sep;31(9):1779–1788. [PubMed] [Google Scholar]
  13. 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]
  14. Garbisa S., Ballin M., Daga-Gordini D., Fastelli G., Naturale M., Negro A., Semenzato G., Liotta L. A. Transient expression of type IV collagenolytic metalloproteinase by human mononuclear phagocytes. J Biol Chem. 1986 Feb 15;261(5):2369–2375. [PubMed] [Google Scholar]
  15. 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]
  16. Huhtala P., Chow L. T., Tryggvason K. Structure of the human type IV collagenase gene. J Biol Chem. 1990 Jul 5;265(19):11077–11082. [PubMed] [Google Scholar]
  17. Kalebic T., Garbisa S., Glaser B., Liotta L. A. Basement membrane collagen: degradation by migrating endothelial cells. Science. 1983 Jul 15;221(4607):281–283. doi: 10.1126/science.6190230. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Levy A. T., Cioce V., Sobel M. E., Garbisa S., Grigioni W. F., Liotta L. A., Stetler-Stevenson W. G. Increased expression of the Mr 72,000 type IV collagenase in human colonic adenocarcinoma. Cancer Res. 1991 Jan 1;51(1):439–444. [PubMed] [Google Scholar]
  20. 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]
  21. 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]
  22. 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]
  23. Morikawa K., Walker S. M., Nakajima M., Pathak S., Jessup J. M., Fidler I. J. Influence of organ environment on the growth, selection, and metastasis of human colon carcinoma cells in nude mice. Cancer Res. 1988 Dec 1;48(23):6863–6871. [PubMed] [Google Scholar]
  24. 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]
  25. Nicholson R., Murphy G., Breathnach R. Human and rat malignant-tumor-associated mRNAs encode stromelysin-like metalloproteinases. Biochemistry. 1989 Jun 13;28(12):5195–5203. doi: 10.1021/bi00438a042. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Overall C. M., Wrana J. L., Sodek J. Independent regulation of collagenase, 72-kDa progelatinase, and metalloendoproteinase inhibitor expression in human fibroblasts by transforming growth factor-beta. J Biol Chem. 1989 Jan 25;264(3):1860–1869. [PubMed] [Google Scholar]
  28. 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]
  29. 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]
  30. Sang Q. X., Stetler-Stevenson W. G., Liotta L. A., Byers S. W. Identification of type IV collagenase in rat testicular cell culture: influence of peritubular-Sertoli cell interactions. Biol Reprod. 1990 Dec;43(6):956–964. doi: 10.1095/biolreprod43.6.956. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. 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]
  33. 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]
  34. 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]
  35. 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]
  36. 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]
  37. Watt S. M., Karhi K., Gatter K., Furley A. J., Katz F. E., Healy L. E., Altass L. J., Bradley N. J., Sutherland D. R., Levinsky R. Distribution and epitope analysis of the cell membrane glycoprotein (HPCA-1) associated with human hemopoietic progenitor cells. Leukemia. 1987 May;1(5):417–426. [PubMed] [Google Scholar]
  38. Weidner N., Semple J. P., Welch W. R., Folkman J. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med. 1991 Jan 3;324(1):1–8. doi: 10.1056/NEJM199101033240101. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. 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]
  41. 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]
  42. Woolley D. E. Collagenolytic mechanisms in tumor cell invasion. Cancer Metastasis Rev. 1984;3(4):361–372. doi: 10.1007/BF00051460. [DOI] [PubMed] [Google Scholar]
  43. 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]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES