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

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

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References

  1. Airola K, Johansson N, Kariniemi AL, Kähäri VM and Saarialho-Kere UK (1997) Human collagenase-3 is expressed in malignant squamous epithelium of the skin. J Invest Dermatol 109: 225–231

  2. Ala-aho R, Johansson N, Grénman R, Fusenig NE, López-Otín C and Kähäri V-M (2000) Inhibition of collagenase-3 (MMP-13) expression in transformed human keratinocytes by interferon-γ is associated with activation of extracellular signal-regulated kinase-1,2 and STAT1. Oncogene 19: 248–257

  3. Arany I, Fleischmann CM, Tyring SK and Fleischmann WR Jr (1997) Lack of mda-6/WAF1/CIP1-mediated inhibition of cyclin-dependent kinases in interferon-alpha resistant murine B16 melanoma cells. Cancer Lett 119: 237–240

  4. Birkedal-Hansen H, Moore WG, Bodden MK, Windsor LJ, Birkedal-Hansen B, De Carlo A and Engler JA (1993) Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 4: 197–250

  5. Bord S, Horner A, Hembry RM and Compston JE (1998) Stromelysin-1 (MMP-3) and stromelysin-2 (MMP-10) expression in developing human bone: potential roles in skeletal development. Bone 23: 7–12

  6. Chandler S, Miller KM, Clements JM, Lury J, Corkill D, Anthony DC, Adams SE and Gearing JA (1997) Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview. J Neuroimmunol 72: 155–161

  7. Chomczynski P and Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159

  8. d’Ortho MP, Will H, Atkinson S, Butler G, Messent A, Gavrilovic J, Smith B, Timpl R, Zardi L and Murphy G (1997) Membrane-type matrix metalloproteinases 1 and 2 exhibit broad-spectrum proteolytic capacities comparable to many matrix metalloproteinases. Eur J Biochem 250: 751–757

  9. Fort P, Marty L, Piechaczyk M, El Sabrouty S, Dani C, Jeanteur P and Blanchard JM (1985) Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. Nucleic Acids Res 13: 1431–1441

  10. Giannelli G, Pozzi A, Stetler-Stevenson WG, Gardner HA and Quaranta V (1999) Expression of matrix metalloprotease-2-cleaved laminin-5 in breast remodeling stimulated by sex steroids. Am J Pathol 154: 1193–1201

  11. Gilles C, Polette M, Piette J, Munaut C, Thompson EW, Birembaut P and Foidart JM (1996) High level of MT-MMP expression is associated with invasiveness of cervical cancer cells. Int J Cancer 65: 209–213

  12. Harada T, Arii S, Mise M, Imamura T, Higashitsuji H, Furutani M, Niwano M, Ishigami S, Fukumoto M, Seiki M, Sato H and Imamura M (1998) Membrane-type matrix metalloproteinase-1 (MT1-MTP) gene is overexpressed in highly invasive hepatocellular carcinomas. J Hepatol 28: 231–239

  13. Heppner KJ, Lynn MM, Jensen RA and Rodgers WH (1996) Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Pathol 149: 273–282

  14. Johansson N, Westermarck J, Leppä S, Häkkinen L, Koivisto L, López-Otín C, Peltonen J, Heino J and Kähäri VM (1997a) Collagenase-3 (MMP-13) gene expression by HaCaT keratinocytes is enhanced by tumor necrosis factor-α and transforming growth factor-β. Cell Growth Differ 8: 243–250

  15. Johansson N, Airola K, Grenman R, Kariniemi AL, Saarialho-Kere U and Kähäri VM (1997b) Expression of collagenase-3 (matrix metalloproteinase-13) in squamous cell carcinomas of the head and neck. Am J Pathol 151: 499–508

  16. Johansson N, Vaalamo M, Grénman S, Hietanen S, Klemi P, Saarialho-Kere U and Kähäri VM (1999) Collagenase-3 (MMP-13) is expressed by tumor cells in invasive vulvar squamous cell carcinomas. Am J Pathol 154: 469–480

  17. Kadono Y, Okada Y, Namiki M, Seiki M and Sato H (1998) Transformation of epithelial Madin-Darby canine kidney cells with p60(v-src) induces expression of membrane-type 1 matrix metalloproteinase and invasiveness. Cancer Res 58: 2240–2244

  18. Kähäri V-M and Saarialho-Kere U (1999) Matrix metalloproteinases and their inhibitors in tumour growth and invasion. Ann Med 31: 34–45

  19. Kainulainen T, Häkkinen L, Hamidi S, Larjava K, Kallioinen M, Peltonen J, Salo T, Larjava H and Oikarinen A (1998) Laminin-5 expression is independent of the injury and the microenvironment during reepithelialization of wounds. J Histochem Cytochem 46: 353–360

  20. Karelina TV, Goldberg GI and Eisen AZ (1994) Matrilysin (PUMP) correlates with dermal invasion during appendageal development and cutaneous neoplasia. J Invest Dermatol 103: 482–487

  21. Kim J, Modlin RL, Moy RL, Dubinett SM, McHugh T, Nickoloff BJ and Uyemura K (1995) IL-10 production in cutaneous basal and squamous cell carcinomas. A mechanism for evading the local T cell immune response. J Immunol 155: 2240–2247

  22. Knäuper V and Murphy G (1998) Membrane-type matrix metalloproteinases and cell-surface-associated activation cascades for matrix metalloproteinases. In: Matrix metalloproteinases, Parks WC, Mecham RP (eds) pp. 199–218, Academic Press: San Diego

  23. Knäuper V, Lopez-Otin C, Smith B, Knight G and Murphy G (1996a) Biochemical characterization of human collagenase-3. J Biol Chem 271: 1544–1550

  24. Knäuper V, Murphy G and Tschesche H (1996b) Activation of human neutrophil procollagenase by stromelysin 2. Eur J Biochem 235: 187–191

  25. Knäuper V, Will H, Lopez-Otin C, Smith B, Atkinson SJ, Stanton H, Hembry RM and Murphy G (1996c) 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 271: 17124–17131

  26. Koshikawa N, Giannelli G, Cirulli V, Miyazaki K and Quaranta V (2000) Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5. J Cell Biol 148: 615–624

  27. Lichtinghagen R, Helmbrecht T, Arndt B and Boker KH (1995) Expression pattern of matrix metalloproteinases in human liver. Eur J Clin Chem Clin Biochem 33: 65–71

  28. Llano E, Pendas AM, Freije JP, Nakano A, Knäuper V, Murphy G and Lopez-Otin C (1999) Identification and characterization of human MT5-MMP, a new membrane-bound activator of progelatinase a overexpressed in brain tumors. Cancer Res 59: 2570–2576

  29. Lohi J, Lehti K, Westermarck J and Kähäri V-M and Keski-Oja J (1996) Regulation of membrane type metalloproteinase-1 expression by growth factors and phorbol 12-myristate 13-acetate. Eur J Biochem 239: 239–247

  30. Madlener M, Mauch C, Conca W, Brauchle M, Parks WC and Werner S (1996) Regulation of the expression of stromelysin-2 by growth factors in keratinocytes: implications for normal and impaired wound healing. Biochem J 320: 659–664

  31. Matrisian LM, McDonnell S, Miller DB, Navre M, Seftor EA and Hendrix MJ (1991) The role of the matrix metalloproteinase stromelysin in the progression of squamous cell carcinomas. Am. J Med Sci 302: 157–162

  32. McDonnell S, Navre M, Coffey RJ Jr and Matrisian LM (1991) Expression and localization of the matrix metalloproteinase pump-1 (MMP-7) in human gastric and colon carcinomas. Mol Carcinog 4: 527–533

  33. Mori M, Mimori K, Shiraishi T, Fujie T, Baba K, Kusumoto H, Haraguchi M, Ueo H and Akiyoshi T (1997) Analysis of MT1-MMP and MMP2 expression in human gastric cancers. Int J Cancer 74: 316–321

  34. Muller D, Quantin B, Gesnel MC, Millon-Collard R, Abecassis J and Breathnach R (1988) The collagenase gene family in humans consists of at least four members. Biochem J 253: 187–192

  35. Muller D, Breathnach R, Engelmann A, Millon R, Brenner G, Flesch H, Dumont P, Eber M and Abecassis J (1991) Expression of collagenase-related metalloproteinase genes in human lung or head and neck tumours. Int J Cancer 48: 550–556

  36. Murphy G, Cockett MI, Ward RV and Docherty AJP (1991) 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 277: 277–279

  37. Nagase H (1998) Stromelysins 1 and 2. In: Matrix metalloproteinases, Parks WC, Mecham RP (eds) pp. 43–84, Academic Press: San Diego

  38. Nakamura H, Fujii Y, Ohuchi E, Yamamoto E and Okada Y (1998) Activation of the precursor of human stromelysin 2 and its interactions with other matrix metalloproteinases. Eur J Biochem 253: 67–75

  39. Nicholson R, Murphy G and Breathnach R (1989) Human and rat malignant-tumor-associated mRNAs encode stromelysin-like metalloproteinases. Biochemistry 28: 5195–5203

  40. Ohtani H, Motohashi H, Sato H, Seiki M and Nagura H (1996) 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 68: 565–570

  41. Ohuchi E, Imai K, Fujii Y, Sato H, Seiki M and Okada Y (1997) Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J Biol Chem 272: 2446–2451

  42. Okada A, Bellocq JP, Rouyer N, Chenard MP, Rio MC, Chambon P and Basset P (1995) 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 92: 2730–2734

  43. Pei D (1999) Leukolysin/MMP25/MT6-MMP: a novel matrix metalloproteinase specifically expressed in the leukocyte lineage. Cell Res 9: 291–303

  44. Polette M, Claver C, Muller D, Abecassis J, Binninger I and Birembaut P (1991) Detection of mRNAs encoding collagenase-1 and stromelysin-2 in carcinomas of the head and neck by in situ hybridization. Invasion Metast 11: 76–83

  45. Prosser IW, Stenmark KR, Suthar M, Crouch EC, Mecham RP and Parks WC (1989) Regional heterogeneity of elastin and collagen gene expression in intralobar arteries in response to hypoxic pulmonar hypertension as demonstrated by in situ hybridization. Am J Pathol 135: 1073–1088

  46. Pulyaeva H, Bueno J, Polette M, Birembaut P, Sato H, Seiki M and Thompson EW (1997) MT1-MMP correlates with MMP-2 activation potential seen after epithelial to mesenchymal transition in human breast carcinoma cells. Clin Exp Metastasis 15: 111–120

  47. Pyke C, Salo S, Ralfkiaer E, Romer J, Dano K and Tryggvason K (1995) 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 55: 4132–4139

  48. Saarialho-Kere UK, Chang ES, Welgus HG and Parks WC (1992) Distinct localization of collagenase and TIMP expression in wound healing associated with ulcerative pyogenic granuloma. J Clin Invest 90: 1952–1957

  49. Saarialho-Kere UK, Kovacs SO, Pentland AP, Olerud JE, Welgus HG and Parks WC (1993) Cell-matrix interactions modulate interstitial collagenase expression by human keratinocytes actively involved in wound healing. J Clin Invest 92: 2858–2866

  50. Saarialho-Kere UK, Pentland AP, Birkedal-Hansen H, Parks WC and Welgus HG (1994) Distinct populations of basal keratinocytes express stromelysin-1 and stromelysin-2 in chronic wounds. J Clin Invest 94: 79–88

  51. Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E and Seiki M (1994) A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370: 61–65

  52. Sirum KL and Brinckerhoff CE (1989) Cloning of the genes for human stromelysin and stromelysin 2: differential expression in rheumatoid synovial fibroblasts. Biochemistry 28: 8691–8698

  53. Skyldberg B, Salo S, Eriksson E, Aspenblad U, Moberger B, Tryggvason K and Auer G (1999) Laminin-5 as a marker of invasiveness in cervical lesions. J Natl Cancer Inst 91: 1882–1887

  54. Sreenath T, Matrisian LM, Stetler-Stevenson W, Gattoni-Celli S and Pozzatti RO (1992) Expression of matrix metalloproteinase genes in transformed rat cell lines of high and low metastatic potential. Cancer Res 52: 4942–4947

  55. Sympson CJ, Bissell MJ and Werb Z (1995) Mammary gland tumour formation in transgenic mice overexpressing stromelysin-1. Semin Cancer Biol 6: 159–163

  56. Tamai K, Ishikawa H, Mauviel A and Uitto J (1995) 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 104: 384–390

  57. Tsukifuji R, Tagawa K, Hatamochi A and Shinkai H (1999) Expression of matrix metalloproteinase-1, -2 and -3 in squamous cell carcinoma and actinic keratosis. Br J Cancer 80: 1087–1091

  58. Vaalamo M, Karjalainen-Lindsberg ML, Puolakkainen P, Kere J and Saarialho-Kere U (1998) 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 152: 1005–1014

  59. Werb Z, Vu TH, Rinkenberger JL and Coussens LM (1999) Matrix-degrading proteases and angiogenesis during development and tumor formation. APMIS 107: 11–18

  60. Windsor LJ, Grenett H, Birkedal-Hansen B, Bodden MK, Engler JA and Birkedal-Hansen H (1993) 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. Biol Chem 268: 17341–17347

  61. Yancey KB (1995) Adhesion molecules II: Interactions of keratinocytes with epidermal basement membrane. J Invest Dermatol 104: 1008–1014

  62. Yoshizaki T, Sato H, Maruyama Y, Murono S, Furukawa M and Park CS and Seiki M (1997) Increased expression of membrane type 1-matrix metalloproteinase in head and neck carcinoma. Cancer 79: 139–144

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Kerkelä, E., Ala-aho, R., Jeskanen, L. et al. Differential patterns of stromelysin-2 (MMP-10) and MT1-MMP (MMP-14) expression in epithelial skin cancers. Br J Cancer 84, 659–669 (2001). https://doi.org/10.1054/bjoc.2000.1634

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Keywords

  • laminin-5
  • stromelysin-1
  • cytokine

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