Collagenase expression in transgenic mouse skin causes hyperkeratosis and acanthosis and increases susceptibility to tumorigenesis (original) (raw)

Abstract

In a series of transgenic mice, the human tissue collagenase gene was expressed in the suprabasal layer of the skin epidermis. Visually, the mice had dry and scaly skin which upon histological analysis revealed acanthosis, hyperkeratosis, and epidermal hyperplasia. At the ultrastructural level, intercellular granular materials were absent in the transgenic skin epidermis but contact was maintained through the intact desmosomes. Despite a diversity of underlying etiologies, similar morphological hyperproliferative changes in the epidermis are observed in the human skin diseases of lamellar ichthyosis, atopic dermatitis, and psoriasis. Subsequent experiments demonstrate that when the transgenic mouse skin was treated once with an initiator (7,12-dimethyl-benz[a]anthracene) and then twice weekly with a promoter (12-O-tetradecanoylphorbol-13-acetate), there was a marked increase in tumor incidence among transgenic mice compared with that among control littermates. These experiments demonstrate that by overexpressing the highly specific proteolytic enzyme collagenase, a cascade of events leading to profound morphological changes which augment the sensitivity of the skin towards carcinogenesis is initiated in the epidermis.

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Selected References

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  1. ABERCROMBIE M., AMBROSE E. J. The surface properties of cancer cells: a review. Cancer Res. 1962 Jun;22:525–548. [PubMed] [Google Scholar]
  2. Bailleul B., Brown K., Ramsden M., Akhurst R. J., Fee F., Balmain A. Chemical induction of oncogene mutations and growth factor activity in mouse skin carcinogenesis. Environ Health Perspect. 1989 May;81:23–27. doi: 10.1289/ehp.898123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bailleul B., Surani M. A., White S., Barton S. C., Brown K., Blessing M., Jorcano J., Balmain A. Skin hyperkeratosis and papilloma formation in transgenic mice expressing a ras oncogene from a suprabasal keratin promoter. Cell. 1990 Aug 24;62(4):697–708. doi: 10.1016/0092-8674(90)90115-u. [DOI] [PubMed] [Google Scholar]
  4. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  5. D'Armiento J., Dalal S. S., Okada Y., Berg R. A., Chada K. Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema. Cell. 1992 Dec 11;71(6):955–961. doi: 10.1016/0092-8674(92)90391-o. [DOI] [PubMed] [Google Scholar]
  6. DiGiovanni J. Multistage carcinogenesis in mouse skin. Pharmacol Ther. 1992;54(1):63–128. doi: 10.1016/0163-7258(92)90051-z. [DOI] [PubMed] [Google Scholar]
  7. Dominey A. M., Wang X. J., King L. E., Jr, Nanney L. B., Gagne T. A., Sellheyer K., Bundman D. S., Longley M. A., Rothnagel J. A., Greenhalgh D. A. Targeted overexpression of transforming growth factor alpha in the epidermis of transgenic mice elicits hyperplasia, hyperkeratosis, and spontaneous, squamous papillomas. Cell Growth Differ. 1993 Dec;4(12):1071–1082. [PubMed] [Google Scholar]
  8. Donoff R. B., McLennan J. E., Grillo H. C. Preparation and properties of collagenases from epithelium and mesenchyme of healing mammalian wounds. Biochim Biophys Acta. 1971 Mar 10;227(3):639–653. doi: 10.1016/0005-2744(71)90014-3. [DOI] [PubMed] [Google Scholar]
  9. Duncan M., DiCicco-Bloom E. M., Xiang X., Benezra R., Chada K. The gene for the helix-loop-helix protein, Id, is specifically expressed in neural precursors. Dev Biol. 1992 Nov;154(1):1–10. doi: 10.1016/0012-1606(92)90042-f. [DOI] [PubMed] [Google Scholar]
  10. Gack S., Vallon R., Schaper J., Rüther U., Angel P. Phenotypic alterations in fos-transgenic mice correlate with changes in Fos/Jun-dependent collagenase type I expression. Regulation of mouse metalloproteinases by carcinogens, tumor promoters, cAMP, and Fos oncoprotein. J Biol Chem. 1994 Apr 8;269(14):10363–10369. [PubMed] [Google Scholar]
  11. Gearing A. J., Beckett P., Christodoulou M., Churchill M., Clements J., Davidson A. H., Drummond A. H., Galloway W. A., Gilbert R., Gordon J. L. Processing of tumour necrosis factor-alpha precursor by metalloproteinases. Nature. 1994 Aug 18;370(6490):555–557. doi: 10.1038/370555a0. [DOI] [PubMed] [Google Scholar]
  12. Greenhalgh D. A., Rothnagel J. A., Wang X. J., Quintanilla M. I., Orengo C. C., Gagne T. A., Bundman D. S., Longley M. A., Fisher C., Roop D. R. Hyperplasia, hyperkeratosis and benign tumor production in transgenic mice by a targeted v-fos oncogene suggest a role for fos in epidermal differentiation and neoplasia. Oncogene. 1993 Aug;8(8):2145–2157. [PubMed] [Google Scholar]
  13. Grillo H. C., Gross J. Collagenolytic activity during mammalian wound repair. Dev Biol. 1967 Apr;15(4):300–317. doi: 10.1016/0012-1606(67)90029-2. [DOI] [PubMed] [Google Scholar]
  14. Hennings H., Glick A. B., Greenhalgh D. A., Morgan D. L., Strickland J. E., Tennenbaum T., Yuspa S. H. Critical aspects of initiation, promotion, and progression in multistage epidermal carcinogenesis. Proc Soc Exp Biol Med. 1993 Jan;202(1):1–8. doi: 10.3181/00379727-202-43511a. [DOI] [PubMed] [Google Scholar]
  15. Iversen O. H. Is a high rate of cell proliferation carcinogenic in itself? Hum Exp Toxicol. 1992 Nov;11(6):437–441. doi: 10.1177/096032719201100601. [DOI] [PubMed] [Google Scholar]
  16. Krieg P. A., Melton D. A. In vitro RNA synthesis with SP6 RNA polymerase. Methods Enzymol. 1987;155:397–415. doi: 10.1016/0076-6879(87)55027-3. [DOI] [PubMed] [Google Scholar]
  17. Lin H. Y., Wells B. R., Taylor R. E., Birkedal-Hansen H. Degradation of type I collagen by rat mucosal keratinocytes. Evidence for secretion of a specific epithelial collagenase. J Biol Chem. 1987 May 15;262(14):6823–6831. [PubMed] [Google Scholar]
  18. 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]
  19. Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Miller M. W., Nowakowski R. S. Use of bromodeoxyuridine-immunohistochemistry to examine the proliferation, migration and time of origin of cells in the central nervous system. Brain Res. 1988 Aug 2;457(1):44–52. doi: 10.1016/0006-8993(88)90055-8. [DOI] [PubMed] [Google Scholar]
  21. Nickoloff B. J., Karabin G. D., Barker J. N., Griffiths C. E., Sarma V., Mitra R. S., Elder J. T., Kunkel S. L., Dixit V. M. Cellular localization of interleukin-8 and its inducer, tumor necrosis factor-alpha in psoriasis. Am J Pathol. 1991 Jan;138(1):129–140. [PMC free article] [PubMed] [Google Scholar]
  22. Orfanos C. E., Schaumburg-Lever G., Mahrle G., Lever W. F. Alterations of cell surfaces as a pathogenetic factor in psoriasis. Possible loss of contact inhibition of growth. Arch Dermatol. 1973 Jan;107(1):38–46. [PubMed] [Google Scholar]
  23. Petersen M. J., Woodley D. T., Stricklin G. P., O'Keefe E. J. Constitutive production of procollagenase and tissue inhibitor of metalloproteinases by human keratinocytes in culture. J Invest Dermatol. 1989 Feb;92(2):156–159. doi: 10.1111/1523-1747.ep12276678. [DOI] [PubMed] [Google Scholar]
  24. Petersen M. J., Woodley D. T., Stricklin G. P., O'Keefe E. J. Production of procollagenase by cultured human keratinocytes. J Biol Chem. 1987 Jan 15;262(2):835–840. [PubMed] [Google Scholar]
  25. Sandberg M., Tamminen M., Hirvonen H., Vuorio E., Pihlajaniemi T. Expression of mRNAs coding for the alpha 1 chain of type XIII collagen in human fetal tissues: comparison with expression of mRNAs for collagen types I, II, and III. J Cell Biol. 1989 Sep;109(3):1371–1379. doi: 10.1083/jcb.109.3.1371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sisskin E. E., Gray T., Barrett J. C. Correlation between sensitivity to tumor promotion and sustained epidermal hyperplasia of mice and rats treated with 12-O-tetra-decanoylphorbol-13-acetate. Carcinogenesis. 1982;3(4):403–407. doi: 10.1093/carcin/3.4.403. [DOI] [PubMed] [Google Scholar]
  27. Sottrup-Jensen L., Birkedal-Hansen H. Localization of cleavage sites for human fibroblast collagenase in the bait region of five mammalian alpha-macroglobulins. Matrix Suppl. 1992;1:263–268. [PubMed] [Google Scholar]
  28. Vassar R., Fuchs E. Transgenic mice provide new insights into the role of TGF-alpha during epidermal development and differentiation. Genes Dev. 1991 May;5(5):714–727. doi: 10.1101/gad.5.5.714. [DOI] [PubMed] [Google Scholar]
  29. Vassar R., Hutton M. E., Fuchs E. Transgenic overexpression of transforming growth factor alpha bypasses the need for c-Ha-ras mutations in mouse skin tumorigenesis. Mol Cell Biol. 1992 Oct;12(10):4643–4653. doi: 10.1128/mcb.12.10.4643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Welgus H. G., Campbell E. J., Bar-Shavit Z., Senior R. M., Teitelbaum S. L. Human alveolar macrophages produce a fibroblast-like collagenase and collagenase inhibitor. J Clin Invest. 1985 Jul;76(1):219–224. doi: 10.1172/JCI111949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Wilson J. B., Weinberg W., Johnson R., Yuspa S., Levine A. J. Expression of the BNLF-1 oncogene of Epstein-Barr virus in the skin of transgenic mice induces hyperplasia and aberrant expression of keratin 6. Cell. 1990 Jun 29;61(7):1315–1327. doi: 10.1016/0092-8674(90)90695-b. [DOI] [PubMed] [Google Scholar]