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Differential expression of stromal MMP-1, MMP-9 and TIMP-1 in basal cell carcinomas of immunosuppressed patients and controls

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Abstract

Matrix metalloproteinases (MMPs) have an important role in the initiation, growth, and invasion of malignant tumors. Basal cell cancer (BCC) is the most common human malignancy. The risk of BCC is 10–16 times higher among organ transplant recipients compared with the nontransplanted population. The aim of this study was to compare the expression of several MMPs and their tissue inhibitors (TIMPs) in BCCs from kidney transplant recipients and controls. Expression of MMPs-1, -7, -8, -9, -10, -13, -26, and TIMPs-1 and -3 was evaluated by immunohistochemistry in 25 samples of BCC of kidney transplant recipients and 25 matched controls representing superficial and nodular subtypes. No significant differences were detected in MMP expression of BCC tumor cells between immunocompetent and immunodeficient patients. However, MMPs-1 and -9 and TIMP-1 were expressed more frequently in stromal macrophages in the BCCs of immunocompetent patients. When tumor subtypes were compared irrespective of the patient group, more MMP-1-positive fibroblasts and MMP-9-positive neutrophils were detected in the superficial subtype, while stromal MMP-10 expression was more abundant in nodular tumors. Our results suggest that abundant peritumoral expression of TIMP-1 in non-immunocompromised patients limits ECM degradation permissive for cancer cell migration.

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Abbreviations

BCC:

basal cell carcinoma

ECM:

extracellular matrix

NMSC:

non-melanoma skin cancer

References

  1. Ahokas K, Skoog T, Suomela S, Jeskanen L, Impola U, Isaka K, Saarialho-Kere U (2005) Matrilysin-2 (Matrix metalloproteinase-26) is upregulated in keratinocytes during wound repair and early skin carcinogenesis. J Invest Dermatol 124:849–856

    Article  PubMed  CAS  Google Scholar 

  2. Bolzani G, Della Coletta R, Martelli Junior H, Graner E (2000) Cyclosporin A inhibits production and activity of matrix metalloproteinases by gingival fibroblasts. J Periodontal Res 35:51–58

    Article  PubMed  CAS  Google Scholar 

  3. De Angelis T, Noè A, Chatterjee M, Mulholland J (2002) Stromelysin-1 activation correlates with invasiveness in squamous cell carcinoma. J Invest Dermatol 118:759–766

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Balbin M, Fueyo A, Tester AM, Pendás AM, Pitiot AS, Astudillo A, Overall CM, Shapiro SD, López-Otín C (2003) Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nat Genet 35:252–257

    Article  PubMed  CAS  Google Scholar 

  6. Berg D, Otley CC (2002) Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 47:1–17

    Article  PubMed  Google Scholar 

  7. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744

    Article  PubMed  CAS  Google Scholar 

  8. Boyd AS, Shyr Y, King LE (2002) Basal cell carcinoma in young women: an evaluation of the association of tanning bed use and smoking. J Am Acad Dermatol 46:706–709

    Article  PubMed  Google Scholar 

  9. Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 7:267–283

    Google Scholar 

  10. Chang C, Werb Z (2001) The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis. Trends Cell Biol 11:S37–S43 (Review)

    PubMed  CAS  Google Scholar 

  11. Chebassier N, Leroy S, Tenaud I, Knol AC, Dreno B (2002) Overexpression of MMP-2 and MMP-9 in squamous cell carcinomas of immunosuppressed patients. Arch Dermatol Res 294:124–126

    Article  PubMed  CAS  Google Scholar 

  12. Cornelius L, Nehring LC, Harding E, Bolanowski M, Welgus HG, Kobayashi DK, Pierce RA, Shapiro SD (1998) Matrix metalloproteinases generate angiostatin: effects on neovascularization. J Immunol 161:6845–6852

    PubMed  CAS  Google Scholar 

  13. Coussens L, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  PubMed  CAS  Google Scholar 

  14. Curran S, Murray G (1999) Matrix metalloproteinases in tumour invasion and metastasis. J Pathol 189:300–308

    Article  PubMed  CAS  Google Scholar 

  15. Diepken TL, Mahler V (2002) The epidemiology of skin cancer. Br J Dermatol 146(Suppl 61):1–6

    Article  Google Scholar 

  16. Euvrard S, Kanitakis J, Pouteil-Noble C, Dureau G, Touraine JL, Faure M, Claudy A, Thivolet J (1995) Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation. J Am Acad Dermatol 33:222–229

    Article  PubMed  CAS  Google Scholar 

  17. Ferrándiz C, Fuente MJ, Ribera M, Bielsa I, Fernández MT, Lauzurica R, Roca J (1995) Epidermal dysplasia and neoplasia in kidney transplant recipients. J Am Acad Dermatol 33:590–596

    Article  PubMed  Google Scholar 

  18. Fortina AB, Piaserico S, Caforio AL, Abeni D, Alaibac M, Angelini A, Iliceto S, Peserico A (2004) Immunosuppressive level and other risk factors for basal cell carcinoma and squamous cell carcinoma in heart transplant recipients. Arch Dermatol 140:1079–1085

    Article  PubMed  Google Scholar 

  19. Gomez DE, Alonso DF, Yoshiji H, Thorgeirsson UP (1997) Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol 74:111–122

    PubMed  CAS  Google Scholar 

  20. Guo HR, Yu HS, Hu H, Monson RR (2001) Arsenic in drinking water and skin cancers: cell-type specificity (Taiwan, ROC). Cancer Causes Control 12:909–916

    Article  PubMed  CAS  Google Scholar 

  21. Harwood CA, Proby CM, McGregor JM, Sheaff MT, Leigh IM, Cerio R (2006) Clinicopathologic features of skin cancer in organ transplant recipients: a retrospective case-control series. J Am Acad Dermatol 54:290–300

    Article  PubMed  Google Scholar 

  22. Howell B, Solish N, Lu C, Watanabe H, Mamelak AJ, Freed I, Wang B, Sauder DN (2005) Microarray profiles of human basal cell carcinoma: insights into tumor growth and behavior. J Dermatol Sci 39:39–51

    Article  PubMed  CAS  Google Scholar 

  23. Impola U, Jeskanen L, Ravanti L, Syrjänen S, Baldursson B, Kähäri V-M, Saarialho-Kere U (2005) Expression of matrix metalloproteinase (MMP)-7 and MMP-13 and loss of MMP-19 and p16 are associated with malignant progression in chronic wounds. Br J Dermatol 152:720–726

    Article  PubMed  CAS  Google Scholar 

  24. Isaka K, Nishi H, Nakai H, Nakada T, Feng Li Y, Ebihara Y, Takayama M (2003) Matrix metalloproteinase-26 is expressed in human endometrium but not in endometrial carcinoma. Cancer 97:79–89

    Article  PubMed  CAS  Google Scholar 

  25. Kanitakis J, Alhaj-Ibrahim L, Euvrard S, Claudy A (2003) Basal cell carcinomas developing in solid organ transplant recipients: clinicopathologic study of 176 cases. Arch Dermatol 139:1133–1137

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  27. Kaur P, Mulvaney M, Carlson J (2006) Basal cell carcinoma progression correlates with host immune response and stromal alterations: a histologic analysis. Am J Dermatopathol 28:293–307

    Article  PubMed  Google Scholar 

  28. Kerkelä E, Ala-aho R, Jeskanen L, Lohi J, Kähäri V-M, Saarialho-Kere U (2001) Differential patterns of stromelysin-2 (MMP-10) and MT1-MMP (MMP-14) expression in epithelial skin cancers. Br J Cancer 84:659–669

    Article  PubMed  Google Scholar 

  29. Kerkelä E, Saarialho-Kere U (2003) Matrix metalloproteinases in tumor progression: focus on basal and squamous cell skin cancer. Exp Dermatol 12:109–125

    Article  PubMed  Google Scholar 

  30. Kuivanen T, Jeskanen L, Kyllönen L, Impola U, Saarialho-Kere U (2006) Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13 are present in epithelial cells of keratoacanthomas. Modern Pathol 19:1203–1212

    Article  CAS  Google Scholar 

  31. Kylmäniemi M, Oikarinen A, Oikarinen K, Salo T (1996) Effects of dexamethasone and cell proliferation on the expression of matrix metalloproteinases in human mucosal normal and malignant cells. J Dent Res 75:919–926

    Article  PubMed  Google Scholar 

  32. Lear JT, Smith AG, Strange RD, Fryer AA (1998) Patients with truncal basal cell carcinoma represent a high-risk group. Arch Dermatol 134:373

    Article  PubMed  CAS  Google Scholar 

  33. LeBoit PE, Burg G, Weedon D, Sarasain A (eds) (2006) World Health Organization classification of tumours. Pathology and genetics of skin tumours. IARC, Lyon

    Google Scholar 

  34. Meyer E, Vollmer J, Bovey R, Stamenkovic I (2005) Matrix metalloproteinases 9 and 10 inhibit protein kinase C potentiated, p53-mediated apoptosis. Cancer Res 65:4261–4272

    Article  PubMed  CAS  Google Scholar 

  35. Micke P, Kappert K, Oshima M, Sundquist C, Scheidl S, Lindahl P, Heldin C-H, Botling J, Ponten F, Östman A (2007) In situ identification of genes regulated specifically in fibroblasts of human basal cell carcinoma. J Invest Dermatol 127:1516–1523

    Article  PubMed  CAS  Google Scholar 

  36. Mirastschijski U, Impola U, Jahkola T, Karlsmark T, Ågren M, Saarialho-Kere U (2002) Ectopic localization of matrix metalloproteinase-9 in chronic cutaneous wounds. Hum Pathol 33:355–364

    Article  PubMed  CAS  Google Scholar 

  37. Moloney FJ, Comber H, O, Lorcain P, O, Kelly P, Conlon PJ, Murphy GM (2006) A population-based study of skin cancer incidence and prevalence in renal transplant recipients. Brit J Dermatol 154:498–504

    Article  CAS  Google Scholar 

  38. Monhian N, Jewett B, Baker S, Varani J (2006) Matrix metalloproteinase expression in normal skin associated with basal cell carcinoma and in distal skin from the same patients. Arch Facial Plast Surg 7:238–243

    Article  Google Scholar 

  39. Nozawa H, Chiu C, Hanahan D (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci USA 103:12493–12498

    Article  PubMed  CAS  Google Scholar 

  40. Ohnishi Y, Tajima S, Akiyama M, Ishibashi A, Kobayashi R, Horii I (2000) Expression of elastin-related proteins and matrix metalloproteinases in actinic elastosis of sun-damaged skin. Arch Dermatol Res 292:27–31

    Article  PubMed  CAS  Google Scholar 

  41. Pantanowitz L, Dezube BJ, Hernandez-Barrantes S, Tahan SR, Dabbous MK (2006) Matrix metalloproteinases in the progression and regression of Kaposi’s sarcoma. J Cutan Pathol 33:793–796

    Article  PubMed  Google Scholar 

  42. Rosenthal E, Matrisian L (2006) Matrix metalloproteinases in head and neck cancer. Head Neck 28:639–648

    Article  PubMed  Google Scholar 

  43. Tanaka M, Itai T, Adachi M, Nagata S (1998) Downregulation of Fas ligand by shedding. Nat Med 4:31–36

    Article  PubMed  CAS  Google Scholar 

  44. Tilli CM, van Steensel MA, Krekels GA, Neumann HA, Ramaekers FC (2005) Molecular aetiology and pathogenesis of basal cell carcinoma. Br J Dermatol 152:1108–1124 (review)

    Article  PubMed  CAS  Google Scholar 

  45. Tran H, Chen K, Shumack S (2003) Epidemiology and aetiology of basal cell carcinoma. Br J Dermatol 149(Suppl 66):50–52

    Article  PubMed  Google Scholar 

  46. Varani J, Hattori Y, Chi Y, Schmidt T, Perone P, Zeigler ME, Fader DJ, Johnson TM (2000) Collagenolytic and gelatinolytic matrix metalloproteinases and their inhibitors in basal cell carcinoma of skin: comparison with normal skin. Br J Cancer 82:657–665

    Article  PubMed  CAS  Google Scholar 

  47. Yucel T, Mutnal A, Fay K, Fligiel SE, Wang T, Johnson T, Baker SR, Varani J (2005) Matrix metalloproteinase expression in basal cell carcinoma: relationship between enzyme profile and collagen fragmentation pattern. Exp Mol Pathol 79:151–160

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Ms. Alli Tallqvist for skillfull technical assistance and Prof. K. Isaka, Tokyo Medical University, for MMP-26 antibodies.

This study was supported by the Academy of Finland, Sigrid Juselius Foundation, Finnish Cancer Research Foundation, Ida Montin Foundation (TK), Maud Kuistila Foundation (TK), Emil Aaltonen Foundation (TK), and Helsinki University Central Hospital Research Fund (TYH 6241), Finland and Cancerfonden and Swedish Research Council, Sweden.

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Authors and Affiliations

  1. Department of Pathology, Helsinki University Central Hospital and Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

    Sonja Boyd & Susanna Virolainen

  2. Department of Dermatology, Helsinki University Central Hospital and Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

    Kalle Tolvanen, Susanna Virolainen, Tiina Kuivanen & Ulpu Saarialho-Kere

  3. Department of Transplantation Surgery, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland

    Lauri Kyllönen

  4. Department of Dermatology, Clinical Science and Education, Karolinska Institutet, Södersjukhuset, Stockholm, Sweden

    Ulpu Saarialho-Kere

  5. Department of Dermatology, Helsinki University Central Hospital, Meilahdentie 2, Helsinki, Finland

    Ulpu Saarialho-Kere

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  1. Sonja Boyd
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  2. Kalle Tolvanen
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  3. Susanna Virolainen
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  4. Tiina Kuivanen
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  6. Ulpu Saarialho-Kere
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Correspondence to Ulpu Saarialho-Kere.

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Boyd, S., Tolvanen, K., Virolainen, S. et al. Differential expression of stromal MMP-1, MMP-9 and TIMP-1 in basal cell carcinomas of immunosuppressed patients and controls. Virchows Arch 452, 83–90 (2008). https://doi.org/10.1007/s00428-007-0526-0

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  • DOI: https://doi.org/10.1007/s00428-007-0526-0

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