Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 May;80(5-6):733–743. doi: 10.1038/sj.bjc.6690417

Expression of collagenases-1 and -3 and their inhibitors TIMP-1 and -3 correlates with the level of invasion in malignant melanomas

K Airola 1, T Karonen 1,2, M Vaalamo 1, K Lehti 2, J Lohi 2, A-L Kariniemi 1, J Keski-Oja 1,2, U K Saarialho-Kere 1
PMCID: PMC2362286  PMID: 10360651

Abstract

Since proteolysis of the dermal collagenous matrix and basement membranes is required for local invasive growth and early metastasis formation of cutaneous melanomas, we have analysed the activities/expression levels of certain metalloproteinases in melanomas and cultured melanoma cells by in situ hybridization and Northern analysis. In addition to collagenases-1 and -3 that have been implicated in invasive growth behaviour of various malignant tumours, we analysed the levels of 72-kDa gelatinase and its activators MT1-MMP and TIMP-2 in cultured melanoma cells. The lesions examined included three cases of lentigo maligna and 28 cases of Clark grade I–V melanomas. The premalignant as well as the grade I tumours were consistently negative for collagenase-1 and -3 and TIMP-1 and -3. The collagenases were predominantly expressed in the cancer cells of Clark grade III and IV tumours. TIMP-1 and -3 were abundantly expressed in the cancer and/or stromal cells of grade III and IV melanomas, while TIMP-2 protein was detected also in melanomas representing lower invasive potential. Northern analysis of seven melanoma cell lines showed that the expression of collagenase-1 and TIMPs-1 and -3 was associated with 72-kDa gelatinase positivity. All melanoma cell lines were positive for MTI-MMP and TIMP-2 mRNAs. Our results suggest that overexpression of collagenases-1 and -3 and TIMPs -1 and -3 is induced during melanoma progression. Expression of TIMPs may reflect host response to tumour invasion in an effort to control MMP activity and preserve extracellular matrix integrity. © 1999 Cancer Research Campaign

Keywords: MMP, cell invasion, angiogenesis, gelatinase

Full Text

The Full Text of this article is available as a PDF (1.0 MB).

Selected References

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

  1. Ahonen M., Baker A. H., Kähäri V. M. Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells. Cancer Res. 1998 Jun 1;58(11):2310–2315. [PubMed] [Google Scholar]
  2. Airola K., Ahonen M., Johansson N., Heikkilä P., Kere J., Kähäri V. M., Saarialho-Kere U. K. Human TIMP-3 is expressed during fetal development, hair growth cycle, and cancer progression. J Histochem Cytochem. 1998 Apr;46(4):437–447. doi: 10.1177/002215549804600403. [DOI] [PubMed] [Google Scholar]
  3. Airola K., Johansson N., Kariniemi A. L., Kähäri V. M., Saarialho-Kere U. K. Human collagenase-3 is expressed in malignant squamous epithelium of the skin. J Invest Dermatol. 1997 Aug;109(2):225–231. doi: 10.1111/1523-1747.ep12319441. [DOI] [PubMed] [Google Scholar]
  4. Anand-Apte B., Bao L., Smith R., Iwata K., Olsen B. R., Zetter B., Apte S. S. A review of tissue inhibitor of metalloproteinases-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth. Biochem Cell Biol. 1996;74(6):853–862. doi: 10.1139/o96-090. [DOI] [PubMed] [Google Scholar]
  5. Anand-Apte B., Pepper M. S., Voest E., Montesano R., Olsen B., Murphy G., Apte S. S., Zetter B. Inhibition of angiogenesis by tissue inhibitor of metalloproteinase-3. Invest Ophthalmol Vis Sci. 1997 Apr;38(5):817–823. [PubMed] [Google Scholar]
  6. Birkedal-Hansen H., Moore W. G., Bodden M. K., Windsor L. J., Birkedal-Hansen B., DeCarlo A., Engler J. A. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med. 1993;4(2):197–250. doi: 10.1177/10454411930040020401. [DOI] [PubMed] [Google Scholar]
  7. Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 1970 Nov;172(5):902–908. doi: 10.1097/00000658-197011000-00017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brooks P. C., Strömblad S., Sanders L. C., von Schalscha T. L., Aimes R. T., Stetler-Stevenson W. G., Quigley J. P., Cheresh D. A. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell. 1996 May 31;85(5):683–693. doi: 10.1016/s0092-8674(00)81235-0. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Butler G. S., Butler M. J., Atkinson S. J., Will H., Tamura T., Schade van Westrum S., Crabbe T., Clements J., d'Ortho M. P., Murphy G. The TIMP2 membrane type 1 metalloproteinase "receptor" regulates the concentration and efficient activation of progelatinase A. A kinetic study. J Biol Chem. 1998 Jan 9;273(2):871–880. doi: 10.1074/jbc.273.2.871. [DOI] [PubMed] [Google Scholar]
  11. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  12. Clark W. H., Jr, From L., Bernardino E. A., Mihm M. C. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res. 1969 Mar;29(3):705–727. [PubMed] [Google Scholar]
  13. Collier I. E., Wilhelm S. M., Eisen A. Z., Marmer B. L., Grant G. A., Seltzer J. L., Kronberger A., He C. S., Bauer E. A., Goldberg G. I. H-ras oncogene-transformed human bronchial epithelial cells (TBE-1) secrete a single metalloprotease capable of degrading basement membrane collagen. J Biol Chem. 1988 May 15;263(14):6579–6587. [PubMed] [Google Scholar]
  14. Deryugina E. I., Luo G. X., Reisfeld R. A., Bourdon M. A., Strongin A. Tumor cell invasion through matrigel is regulated by activated matrix metalloproteinase-2. Anticancer Res. 1997 Sep-Oct;17(5A):3201–3210. [PubMed] [Google Scholar]
  15. Durko M., Navab R., Shibata H. R., Brodt P. Suppression of basement membrane type IV collagen degradation and cell invasion in human melanoma cells expressing an antisense RNA for MMP-1. Biochim Biophys Acta. 1997 May 27;1356(3):271–280. doi: 10.1016/s0167-4889(97)00004-9. [DOI] [PubMed] [Google Scholar]
  16. Fong K. M., Kida Y., Zimmerman P. V., Smith P. J. TIMP1 and adverse prognosis in non-small cell lung cancer. Clin Cancer Res. 1996 Aug;2(8):1369–1372. [PubMed] [Google Scholar]
  17. Fort P., Marty L., Piechaczyk M., el Sabrouty S., Dani C., Jeanteur P., Blanchard J. M. Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. Nucleic Acids Res. 1985 Mar 11;13(5):1431–1442. doi: 10.1093/nar/13.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Freije J. M., Díez-Itza I., Balbín M., Sánchez L. M., Blasco R., Tolivia J., López-Otín C. Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas. J Biol Chem. 1994 Jun 17;269(24):16766–16773. [PubMed] [Google Scholar]
  19. Gomez D. E., Alonso D. F., Yoshiji H., Thorgeirsson U. P. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol. 1997 Oct;74(2):111–122. [PubMed] [Google Scholar]
  20. Herlyn M., Balaban G., Bennicelli J., Guerry D., 4th, Halaban R., Herlyn D., Elder D. E., Maul G. G., Steplewski Z., Nowell P. C. Primary melanoma cells of the vertical growth phase: similarities to metastatic cells. J Natl Cancer Inst. 1985 Feb;74(2):283–289. [PubMed] [Google Scholar]
  21. Herlyn M., Thurin J., Balaban G., Bennicelli J. L., Herlyn D., Elder D. E., Bondi E., Guerry D., Nowell P., Clark W. H. Characteristics of cultured human melanocytes isolated from different stages of tumor progression. Cancer Res. 1985 Nov;45(11 Pt 2):5670–5676. [PubMed] [Google Scholar]
  22. Höyhtyä M., Hujanen E., Turpeenniemi-Hujanen T., Thorgeirsson U., Liotta L. A., Tryggvason K. Modulation of type-IV collagenase activity and invasive behavior of metastatic human melanoma (A2058) cells in vitro by monoclonal antibodies to type-IV collagenase. Int J Cancer. 1990 Aug 15;46(2):282–286. doi: 10.1002/ijc.2910460224. [DOI] [PubMed] [Google Scholar]
  23. Iliopoulos D., Ernst C., Steplewski Z., Jambrosic J. A., Rodeck U., Herlyn M., Clark W. H., Jr, Koprowski H., Herlyn D. Inhibition of metastases of a human melanoma xenograft by monoclonal antibody to the GD2/GD3 gangliosides. J Natl Cancer Inst. 1989 Mar 15;81(6):440–444. doi: 10.1093/jnci/81.6.440. [DOI] [PubMed] [Google Scholar]
  24. Johansson N., Airola K., Grénman R., Kariniemi A. L., Saarialho-Kere U., Kähäri V. M. Expression of collagenase-3 (matrix metalloproteinase-13) in squamous cell carcinomas of the head and neck. Am J Pathol. 1997 Aug;151(2):499–508. [PMC free article] [PubMed] [Google Scholar]
  25. Johnson M. D., Kim H. R., Chesler L., Tsao-Wu G., Bouck N., Polverini P. J. Inhibition of angiogenesis by tissue inhibitor of metalloproteinase. J Cell Physiol. 1994 Jul;160(1):194–202. doi: 10.1002/jcp.1041600122. [DOI] [PubMed] [Google Scholar]
  26. Khokha R. Suppression of the tumorigenic and metastatic abilities of murine B16-F10 melanoma cells in vivo by the overexpression of the tissue inhibitor of the metalloproteinases-1. J Natl Cancer Inst. 1994 Feb 16;86(4):299–304. doi: 10.1093/jnci/86.4.299. [DOI] [PubMed] [Google Scholar]
  27. Knäuper V., Cowell S., Smith B., López-Otin C., O'Shea M., Morris H., Zardi L., Murphy G. The role of the C-terminal domain of human collagenase-3 (MMP-13) in the activation of procollagenase-3, substrate specificity, and tissue inhibitor of metalloproteinase interaction. J Biol Chem. 1997 Mar 21;272(12):7608–7616. doi: 10.1074/jbc.272.12.7608. [DOI] [PubMed] [Google Scholar]
  28. Knäuper V., López-Otin C., Smith B., Knight G., Murphy G. Biochemical characterization of human collagenase-3. J Biol Chem. 1996 Jan 19;271(3):1544–1550. doi: 10.1074/jbc.271.3.1544. [DOI] [PubMed] [Google Scholar]
  29. Kähäri V. M., Saarialho-Kere U. Matrix metalloproteinases in skin. Exp Dermatol. 1997 Oct;6(5):199–213. doi: 10.1111/j.1600-0625.1997.tb00164.x. [DOI] [PubMed] [Google Scholar]
  30. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  31. Lehti K., Lohi J., Valtanen H., Keski-Oja J. Proteolytic processing of membrane-type-1 matrix metalloproteinase is associated with gelatinase A activation at the cell surface. Biochem J. 1998 Sep 1;334(Pt 2):345–353. doi: 10.1042/bj3340345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Llano E., Pendás A. M., Knäuper V., Sorsa T., Salo T., Salido E., Murphy G., Simmer J. P., Bartlett J. D., López-Otín C. Identification and structural and functional characterization of human enamelysin (MMP-20). Biochemistry. 1997 Dec 9;36(49):15101–15108. doi: 10.1021/bi972120y. [DOI] [PubMed] [Google Scholar]
  33. Lohi J., Harvima I., Keski-Oja J. Pericellular substrates of human mast cell tryptase: 72,000 dalton gelatinase and fibronectin. J Cell Biochem. 1992 Dec;50(4):337–349. doi: 10.1002/jcb.240500402. [DOI] [PubMed] [Google Scholar]
  34. Lohi J., Keski-Oja J. Calcium ionophores decrease pericellular gelatinolytic activity via inhibition of 92-kDa gelatinase expression and decrease of 72-kDa gelatinase activation. J Biol Chem. 1995 Jul 21;270(29):17602–17609. doi: 10.1074/jbc.270.29.17602. [DOI] [PubMed] [Google Scholar]
  35. Lohi J., Lehti K., Westermarck J., Kähäri V. M., Keski-Oja J. Regulation of membrane-type matrix metalloproteinase-1 expression by growth factors and phorbol 12-myristate 13-acetate. Eur J Biochem. 1996 Jul 15;239(2):239–247. doi: 10.1111/j.1432-1033.1996.0239u.x. [DOI] [PubMed] [Google Scholar]
  36. MacDougall J. R., Bani M. R., Lin Y., Rak J., Kerbel R. S. The 92-kDa gelatinase B is expressed by advanced stage melanoma cells: suppression by somatic cell hybridization with early stage melanoma cells. Cancer Res. 1995 Sep 15;55(18):4174–4181. [PubMed] [Google Scholar]
  37. Mimori K., Mori M., Shiraishi T., Fujie T., Baba K., Haraguchi M., Abe R., Ueo H., Akiyoshi T. Clinical significance of tissue inhibitor of metalloproteinase expression in gastric carcinoma. Br J Cancer. 1997;76(4):531–536. doi: 10.1038/bjc.1997.420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Montgomery A. M., De Clerck Y. A., Langley K. E., Reisfeld R. A., Mueller B. M. Melanoma-mediated dissolution of extracellular matrix: contribution of urokinase-dependent and metalloproteinase-dependent proteolytic pathways. Cancer Res. 1993 Feb 1;53(3):693–700. [PubMed] [Google Scholar]
  39. Mueller B. M. Different roles for plasminogen activators and metalloproteinases in melanoma metastasis. Curr Top Microbiol Immunol. 1996;213(Pt 1):65–80. doi: 10.1007/978-3-642-61107-0_5. [DOI] [PubMed] [Google Scholar]
  40. Murphy G., Knäuper V. Relating matrix metalloproteinase structure to function: why the "hemopexin" domain? Matrix Biol. 1997 Mar;15(8-9):511–518. doi: 10.1016/s0945-053x(97)90025-1. [DOI] [PubMed] [Google Scholar]
  41. Opdenakker G., Ashino-Fuse H., Van Damme J., Billiau A., De Somer P. Effects of 12-O-tetradecanoylphorbol 13-acetate on the production of mRNAs for human tissue-type plasminogen activator. Eur J Biochem. 1983 Apr 5;131(3):481–487. doi: 10.1111/j.1432-1033.1983.tb07287.x. [DOI] [PubMed] [Google Scholar]
  42. Pendás A. M., Knäuper V., Puente X. S., Llano E., Mattei M. G., Apte S., Murphy G., López-Otín C. Identification and characterization of a novel human matrix metalloproteinase with unique structural characteristics, chromosomal location, and tissue distribution. J Biol Chem. 1997 Feb 14;272(7):4281–4286. doi: 10.1074/jbc.272.7.4281. [DOI] [PubMed] [Google Scholar]
  43. Powe D. G., Brough J. L., Carter G. I., Bailey E. M., Stetler-Stevenson W. G., Turner D. R., Hewitt R. E. TIMP-3 mRNA expression is regionally increased in moderately and poorly differentiated colorectal adenocarcinoma. Br J Cancer. 1997;75(11):1678–1683. doi: 10.1038/bjc.1997.285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Saarialho-Kere U. K., Chang E. S., Welgus H. G., Parks W. C. Distinct localization of collagenase and tissue inhibitor of metalloproteinases expression in wound healing associated with ulcerative pyogenic granuloma. J Clin Invest. 1992 Nov;90(5):1952–1957. doi: 10.1172/JCI116073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Saarialho-Kere U. K., Kovacs S. O., Pentland A. P., Olerud J. E., Welgus H. G., Parks W. C. Cell-matrix interactions modulate interstitial collagenase expression by human keratinocytes actively involved in wound healing. J Clin Invest. 1993 Dec;92(6):2858–2866. doi: 10.1172/JCI116906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., Seiki M. A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature. 1994 Jul 7;370(6484):61–65. doi: 10.1038/370061a0. [DOI] [PubMed] [Google Scholar]
  47. Stetler-Stevenson W. G., Liotta L. A., Kleiner D. E., Jr Extracellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis. FASEB J. 1993 Dec;7(15):1434–1441. doi: 10.1096/fasebj.7.15.8262328. [DOI] [PubMed] [Google Scholar]
  48. Strongin A. Y., Collier I., Bannikov G., Marmer B. L., Grant G. A., Goldberg G. I. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem. 1995 Mar 10;270(10):5331–5338. doi: 10.1074/jbc.270.10.5331. [DOI] [PubMed] [Google Scholar]
  49. Uría J. A., Ståhle-Bäckdahl M., Seiki M., Fueyo A., López-Otín C. Regulation of collagenase-3 expression in human breast carcinomas is mediated by stromal-epithelial cell interactions. Cancer Res. 1997 Nov 1;57(21):4882–4888. [PubMed] [Google Scholar]
  50. Valente P., Fassina G., Melchiori A., Masiello L., Cilli M., Vacca A., Onisto M., Santi L., Stetler-Stevenson W. G., Albini A. TIMP-2 over-expression reduces invasion and angiogenesis and protects B16F10 melanoma cells from apoptosis. Int J Cancer. 1998 Jan 19;75(2):246–253. doi: 10.1002/(sici)1097-0215(19980119)75:2<246::aid-ijc13>3.0.co;2-b. [DOI] [PubMed] [Google Scholar]
  51. Väisänen A., Tuominen H., Kallioinen M., Turpeenniemi-Hujanen T. Matrix metalloproteinase-2 (72 kD type IV collagenase) expression occurs in the early stage of human melanocytic tumour progression and may have prognostic value. J Pathol. 1996 Nov;180(3):283–289. doi: 10.1002/(SICI)1096-9896(199611)180:3<283::AID-PATH662>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
  52. Yoshiji H., Gomez D. E., Thorgeirsson U. P. Enhanced RNA expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) in human breast cancer. Int J Cancer. 1996 Apr 22;69(2):131–134. doi: 10.1002/(SICI)1097-0215(19960422)69:2<131::AID-IJC11>3.0.CO;2-C. [DOI] [PubMed] [Google Scholar]
  53. de Vries T. J., Quax P. H., Denijn M., Verrijp K. N., Verheijen J. H., Verspaget H. W., Weidle U. H., Ruiter D. J., van Muijen G. N. Plasminogen activators, their inhibitors, and urokinase receptor emerge in late stages of melanocytic tumor progression. Am J Pathol. 1994 Jan;144(1):70–81. [PMC free article] [PubMed] [Google Scholar]
  54. van den Oord J. J., Paemen L., Opdenakker G., de Wolf-Peeters C. Expression of gelatinase B and the extracellular matrix metalloproteinase inducer EMMPRIN in benign and malignant pigment cell lesions of the skin. Am J Pathol. 1997 Sep;151(3):665–670. [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES