Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Mar;84(5):659–669. doi: 10.1054/bjoc.2000.1634

Differential patterns of stromelysin-2 (MMP-10) and MT1-MMP (MMP-14) expression in epithelial skin cancers

E Kerkelä 1, R Ala-aho 2,5, L Jeskanen, J Lohi 6, R Grénman 3, V M-Kähäri 4,5, U Saarialho-Kere 1
PMCID: PMC2363801  PMID: 11237387

Abstract

Co-expression of several members of the matrix metalloproteinase (MMP) family is characteristic of human malignant tumours. To investigate the role of stromelysin-2 (MMP-10) in growth and invasion of skin tumours, we studied cutaneous carcinomas with high metastatic capacity (squamous cell carcinomas, SCCs), only locally destructive tumours (basal cell carcinomas, BCCs) and pre-malignant lesions (Bowen's disease and actinic keratosis) using in situ hybridization. Expression of MMP-10 was compared with that of stromelysin-1 (MMP-3) and of MT1-MMP, the expression of which has been shown to correlate with tumour invasiveness. MMP-10 was expressed in 13/21 SSCs and 11/19 BCCs only in epithelial laminin-5 positive cancer cells, while premalignant lesions were entirely negative. MT1-MMP mRNA was detected in 19/21 SCCs both in epithelial cancer cells and stromal fibroblasts and in 14/18 BCCs only in fibroblasts. The level of MMP-10 was upregulated in a cutaneous SCC cell line (UT-SCC-7) by transforming growth factor-α and keratinocyte growth factor, and by interferon-γ in combination with transforming growth factor-β1 and tumour necrosis factor-α both in UT-SCC-7 and HaCaT cells. Our results show that MMP-10 expression does not correlate with the invasive behaviour of tumours as assessed by their histology and MT1-MMP expression, but may be induced by the wound healing and inflammatory matrix remodelling events associated with skin tumours. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: laminin-5, stromelysin-1, cytokine

Full Text

The Full Text of this article is available as a PDF (460.4 KB).

Selected References

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

  1. 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]
  2. Ala-aho R., Johansson N., Grénman R., Fusenig N. E., López-Otín C., Kähäri V. M. Inhibition of collagenase-3 (MMP-13) expression in transformed human keratinocytes by interferon-gamma is associated with activation of extracellular signal-regulated kinase-1,2 and STAT1. Oncogene. 2000 Jan 13;19(2):248–257. doi: 10.1038/sj.onc.1203306. [DOI] [PubMed] [Google Scholar]
  3. Arany I., Fleischmann C. M., Tyring S. K., Fleischmann W. R., Jr Lack of mda-6/WAF1/CIP1-mediated inhibition of cyclin-dependent kinases in interferon-alpha resistant murine B16 melanoma cells. Cancer Lett. 1997 Nov 11;119(2):237–240. doi: 10.1016/s0304-3835(97)00288-7. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Bord S., Horner A., Hembry R. M., Compston J. E. Stromelysin-1 (MMP-3) and stromelysin-2 (MMP-10) expression in developing human bone: potential roles in skeletal development. Bone. 1998 Jul;23(1):7–12. doi: 10.1016/s8756-3282(98)00064-7. [DOI] [PubMed] [Google Scholar]
  6. Chandler S., Miller K. M., Clements J. M., Lury J., Corkill D., Anthony D. C., Adams S. E., Gearing A. J. Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview. J Neuroimmunol. 1997 Feb;72(2):155–161. doi: 10.1016/s0165-5728(96)00179-8. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. 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]
  9. Giannelli G., Pozzi A., Stetler-Stevenson W. G., Gardner H. A., Quaranta V. Expression of matrix metalloprotease-2-cleaved laminin-5 in breast remodeling stimulated by sex steroids. Am J Pathol. 1999 Apr;154(4):1193–1201. doi: 10.1016/S0002-9440(10)65371-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gilles C., Polette M., Piette J., Munaut C., Thompson E. W., Birembaut P., Foidart J. M. High level of MT-MMP expression is associated with invasiveness of cervical cancer cells. Int J Cancer. 1996 Jan 17;65(2):209–213. doi: 10.1002/(SICI)1097-0215(19960117)65:2<209::AID-IJC14>3.0.CO;2-8. [DOI] [PubMed] [Google Scholar]
  11. Harada T., Arii S., Mise M., Imamura T., Higashitsuji H., Furutani M., Niwano M., Ishigami S., Fukumoto M., Seiki M. Membrane-type matrix metalloproteinase-1(MT1-MTP) gene is overexpressed in highly invasive hepatocellular carcinomas. J Hepatol. 1998 Feb;28(2):231–239. doi: 10.1016/0168-8278(88)80010-2. [DOI] [PubMed] [Google Scholar]
  12. Heppner K. J., Matrisian L. M., Jensen R. A., Rodgers W. H. Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Pathol. 1996 Jul;149(1):273–282. [PMC free article] [PubMed] [Google Scholar]
  13. 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]
  14. Johansson N., Vaalamo M., Grénman S., Hietanen S., Klemi P., Saarialho-Kere U., Kähäri V. M. Collagenase-3 (MMP-13) is expressed by tumor cells in invasive vulvar squamous cell carcinomas. Am J Pathol. 1999 Feb;154(2):469–480. doi: 10.1016/S0002-9440(10)65293-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Johansson N., Westermarck J., Leppä S., Häkkinen L., Koivisto L., López-Otín C., Peltonen J., Heino J., Kähäri V. M. Collagenase 3 (matrix metalloproteinase 13) gene expression by HaCaT keratinocytes is enhanced by tumor necrosis factor alpha and transforming growth factor beta. Cell Growth Differ. 1997 Feb;8(2):243–250. [PubMed] [Google Scholar]
  16. Kadono Y., Okada Y., Namiki M., Seiki M., Sato H. Transformation of epithelial Madin-Darby canine kidney cells with p60(v-src) induces expression of membrane-type 1 matrix metalloproteinase and invasiveness. Cancer Res. 1998 May 15;58(10):2240–2244. [PubMed] [Google Scholar]
  17. Kainulainen T., Hakkinen L., Hamidi S., Larjava K., Kallioinen M., Peltonen J., Salo T., Larjava H., Oikarinen A. Laminin-5 expression is independent of the injury and the microenvironment during reepithelialization of wounds. J Histochem Cytochem. 1998 Mar;46(3):353–360. doi: 10.1177/002215549804600309. [DOI] [PubMed] [Google Scholar]
  18. Karelina T. V., Goldberg G. I., Eisen A. Z. Matrilysin (PUMP) correlates with dermal invasion during appendageal development and cutaneous neoplasia. J Invest Dermatol. 1994 Oct;103(4):482–487. doi: 10.1111/1523-1747.ep12395596. [DOI] [PubMed] [Google Scholar]
  19. Kim J., Modlin R. L., Moy R. L., Dubinett S. M., McHugh T., Nickoloff B. J., Uyemura K. IL-10 production in cutaneous basal and squamous cell carcinomas. A mechanism for evading the local T cell immune response. J Immunol. 1995 Aug 15;155(4):2240–2247. [PubMed] [Google Scholar]
  20. 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]
  21. Knäuper V., Murphy G., Tschesche H. Activation of human neutrophil procollagenase by stromelysin 2. Eur J Biochem. 1996 Jan 15;235(1-2):187–191. doi: 10.1111/j.1432-1033.1996.00187.x. [DOI] [PubMed] [Google Scholar]
  22. Knäuper V., Will H., López-Otin C., Smith B., Atkinson S. J., Stanton H., Hembry R. M., Murphy G. Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme. J Biol Chem. 1996 Jul 19;271(29):17124–17131. doi: 10.1074/jbc.271.29.17124. [DOI] [PubMed] [Google Scholar]
  23. Koshikawa N., Giannelli G., Cirulli V., Miyazaki K., Quaranta V. Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5. J Cell Biol. 2000 Feb 7;148(3):615–624. doi: 10.1083/jcb.148.3.615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kähäri V. M., Saarialho-Kere U. Matrix metalloproteinases and their inhibitors in tumour growth and invasion. Ann Med. 1999 Feb;31(1):34–45. doi: 10.3109/07853899909019260. [DOI] [PubMed] [Google Scholar]
  25. Lichtinghagen R., Helmbrecht T., Arndt B., Böker K. H. Expression pattern of matrix metalloproteinases in human liver. Eur J Clin Chem Clin Biochem. 1995 Feb;33(2):65–71. doi: 10.1515/cclm.1995.33.2.65. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Madlener M., Mauch C., Conca W., Brauchle M., Parks W. C., Werner S. Regulation of the expression of stromelysin-2 by growth factors in keratinocytes: implications for normal and impaired wound healing. Biochem J. 1996 Dec 1;320(Pt 2):659–664. doi: 10.1042/bj3200659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Matrisian L. M., McDonnell S., Miller D. B., Navre M., Seftor E. A., Hendrix M. J. The role of the matrix metalloproteinase stromelysin in the progression of squamous cell carcinomas. Am J Med Sci. 1991 Sep;302(3):157–162. doi: 10.1097/00000441-199109000-00008. [DOI] [PubMed] [Google Scholar]
  29. McDonnell S., Navre M., Coffey R. J., Jr, Matrisian L. M. Expression and localization of the matrix metalloproteinase pump-1 (MMP-7) in human gastric and colon carcinomas. Mol Carcinog. 1991;4(6):527–533. doi: 10.1002/mc.2940040617. [DOI] [PubMed] [Google Scholar]
  30. Mori M., Mimori K., Shiraishi T., Fujie T., Baba K., Kusumoto H., Haraguchi M., Ueo H., Akiyoshi T. Analysis of MT1-MMP and MMP2 expression in human gastric cancers. Int J Cancer. 1997 Jun 20;74(3):316–321. doi: 10.1002/(sici)1097-0215(19970620)74:3<316::aid-ijc14>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  31. Muller D., Breathnach R., Engelmann A., Millon R., Bronner G., Flesch H., Dumont P., Eber M., Abecassis J. Expression of collagenase-related metalloproteinase genes in human lung or head and neck tumours. Int J Cancer. 1991 Jun 19;48(4):550–556. doi: 10.1002/ijc.2910480412. [DOI] [PubMed] [Google Scholar]
  32. Muller D., Quantin B., Gesnel M. C., Millon-Collard R., Abecassis J., Breathnach R. The collagenase gene family in humans consists of at least four members. Biochem J. 1988 Jul 1;253(1):187–192. doi: 10.1042/bj2530187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Murphy G., Cockett M. I., Ward R. V., Docherty A. J. Matrix metalloproteinase degradation of elastin, type IV collagen and proteoglycan. A quantitative comparison of the activities of 95 kDa and 72 kDa gelatinases, stromelysins-1 and -2 and punctuated metalloproteinase (PUMP). Biochem J. 1991 Jul 1;277(Pt 1):277–279. doi: 10.1042/bj2770277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Nakamura H., Fujii Y., Ohuchi E., Yamamoto E., Okada Y. Activation of the precursor of human stromelysin 2 and its interactions with other matrix metalloproteinases. Eur J Biochem. 1998 Apr 1;253(1):67–75. doi: 10.1046/j.1432-1327.1998.2530067.x. [DOI] [PubMed] [Google Scholar]
  35. 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]
  36. Ohtani H., Motohashi H., Sato H., Seiki M., Nagura H. Dual over-expression pattern of membrane-type metalloproteinase-1 in cancer and stromal cells in human gastrointestinal carcinoma revealed by in situ hybridization and immunoelectron microscopy. Int J Cancer. 1996 Nov 27;68(5):565–570. doi: 10.1002/(SICI)1097-0215(19961127)68:5<565::AID-IJC2>3.0.CO;2-X. [DOI] [PubMed] [Google Scholar]
  37. Ohuchi E., Imai K., Fujii Y., Sato H., Seiki M., Okada Y. Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J Biol Chem. 1997 Jan 24;272(4):2446–2451. doi: 10.1074/jbc.272.4.2446. [DOI] [PubMed] [Google Scholar]
  38. Okada A., Bellocq J. P., Rouyer N., Chenard M. P., Rio M. C., Chambon P., Basset P. Membrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast, and head and neck carcinomas. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2730–2734. doi: 10.1073/pnas.92.7.2730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Pei D. Leukolysin/MMP25/MT6-MMP: a novel matrix metalloproteinase specifically expressed in the leukocyte lineage. Cell Res. 1999 Dec;9(4):291–303. doi: 10.1038/sj.cr.7290028. [DOI] [PubMed] [Google Scholar]
  40. Polette M., Clavel C., Muller D., Abecassis J., Binninger I., Birembaut P. Detection of mRNAs encoding collagenase I and stromelysin 2 in carcinomas of the head and neck by in situ hybridization. Invasion Metastasis. 1991;11(2):76–83. [PubMed] [Google Scholar]
  41. Prosser I. W., Stenmark K. R., Suthar M., Crouch E. C., Mecham R. P., Parks W. C. Regional heterogeneity of elastin and collagen gene expression in intralobar arteries in response to hypoxic pulmonary hypertension as demonstrated by in situ hybridization. Am J Pathol. 1989 Dec;135(6):1073–1088. [PMC free article] [PubMed] [Google Scholar]
  42. Pulyaeva H., Bueno J., Polette M., Birembaut P., Sato H., Seiki M., Thompson E. W. MT1-MMP correlates with MMP-2 activation potential seen after epithelial to mesenchymal transition in human breast carcinoma cells. Clin Exp Metastasis. 1997 Mar;15(2):111–120. doi: 10.1023/a:1018444609098. [DOI] [PubMed] [Google Scholar]
  43. Pyke C., Salo S., Ralfkiaer E., Rømer J., Danø K., Tryggvason K. Laminin-5 is a marker of invading cancer cells in some human carcinomas and is coexpressed with the receptor for urokinase plasminogen activator in budding cancer cells in colon adenocarcinomas. Cancer Res. 1995 Sep 15;55(18):4132–4139. [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. Saarialho-Kere U. K., Pentland A. P., Birkedal-Hansen H., Parks W. C., Welgus H. G. Distinct populations of basal keratinocytes express stromelysin-1 and stromelysin-2 in chronic wounds. J Clin Invest. 1994 Jul;94(1):79–88. doi: 10.1172/JCI117351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. 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]
  48. Sirum K. L., Brinckerhoff C. E. Cloning of the genes for human stromelysin and stromelysin 2: differential expression in rheumatoid synovial fibroblasts. Biochemistry. 1989 Oct 31;28(22):8691–8698. doi: 10.1021/bi00448a004. [DOI] [PubMed] [Google Scholar]
  49. Skyldberg B., Salo S., Eriksson E., Aspenblad U., Moberger B., Tryggvason K., Auer G. Laminin-5 as a marker of invasiveness in cervical lesions. J Natl Cancer Inst. 1999 Nov 3;91(21):1882–1887. doi: 10.1093/jnci/91.21.1882. [DOI] [PubMed] [Google Scholar]
  50. Sreenath T., Matrisian L. M., Stetler-Stevenson W., Gattoni-Celli S., Pozzatti R. O. Expression of matrix metalloproteinase genes in transformed rat cell lines of high and low metastatic potential. Cancer Res. 1992 Sep 15;52(18):4942–4947. [PubMed] [Google Scholar]
  51. Sympson C. J., Bissell M. J., Werb Z. Mammary gland tumor formation in transgenic mice overexpressing stromelysin-1. Semin Cancer Biol. 1995 Jun;6(3):159–163. doi: 10.1006/scbi.1995.0022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Tamai K., Ishikawa H., Mauviel A., Uitto J. Interferon-gamma coordinately upregulates matrix metalloprotease (MMP)-1 and MMP-3, but not tissue inhibitor of metalloproteases (TIMP), expression in cultured keratinocytes. J Invest Dermatol. 1995 Mar;104(3):384–390. doi: 10.1111/1523-1747.ep12665857. [DOI] [PubMed] [Google Scholar]
  53. Tsukifuji R., Tagawa K., Hatamochi A., Shinkai H. Expression of matrix metalloproteinase-1, -2 and -3 in squamous cell carcinoma and actinic keratosis. Br J Cancer. 1999 Jun;80(7):1087–1091. doi: 10.1038/sj.bjc.6690468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Vaalamo M., Karjalainen-Lindsberg M. L., Puolakkainen P., Kere J., Saarialho-Kere U. Distinct expression profiles of stromelysin-2 (MMP-10), collagenase-3 (MMP-13), macrophage metalloelastase (MMP-12), and tissue inhibitor of metalloproteinases-3 (TIMP-3) in intestinal ulcerations. Am J Pathol. 1998 Apr;152(4):1005–1014. [PMC free article] [PubMed] [Google Scholar]
  55. Werb Z., Vu T. H., Rinkenberger J. L., Coussens L. M. Matrix-degrading proteases and angiogenesis during development and tumor formation. APMIS. 1999 Jan;107(1):11–18. doi: 10.1111/j.1699-0463.1999.tb01521.x. [DOI] [PubMed] [Google Scholar]
  56. Windsor L. J., Grenett H., Birkedal-Hansen B., Bodden M. K., Engler J. A., Birkedal-Hansen H. Cell type-specific regulation of SL-1 and SL-2 genes. Induction of the SL-2 gene but not the SL-1 gene by human keratinocytes in response to cytokines and phorbolesters. J Biol Chem. 1993 Aug 15;268(23):17341–17347. [PubMed] [Google Scholar]
  57. Yancey K. B. Adhesion molecules. II: Interactions of keratinocytes with epidermal basement membrane. J Invest Dermatol. 1995 Jun;104(6):1008–1014. doi: 10.1111/1523-1747.ep12606244. [DOI] [PubMed] [Google Scholar]
  58. Yoshizaki T., Sato H., Maruyama Y., Murono S., Furukawa M., Park C. S., Seiki M. Increased expression of membrane type 1-matrix metalloproteinase in head and neck carcinoma. Cancer. 1997 Jan 1;79(1):139–144. doi: 10.1002/(sici)1097-0142(19970101)79:1<139::aid-cncr20>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
  59. d'Ortho M. P., Will H., Atkinson S., Butler G., Messent A., Gavrilovic J., Smith B., Timpl R., Zardi L., Murphy G. Membrane-type matrix metalloproteinases 1 and 2 exhibit broad-spectrum proteolytic capacities comparable to many matrix metalloproteinases. Eur J Biochem. 1997 Dec 15;250(3):751–757. doi: 10.1111/j.1432-1033.1997.00751.x. [DOI] [PubMed] [Google Scholar]

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

RESOURCES