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Cathepsins in basal cell carcinomas: activity, immunoreactivity and mRNA staining of cathepsins B, D, H and L

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An Erratum to this article was published on 24 June 2004

Abstract

In the majority of neoplasms invasion is inevitably linked to metastasis and even small tumors have the dormant potential for metastasis. In basal cell carcinoma (BCC) invasion can be evaluated separately because local invasion but no metastasis occurs. Important proteases in invasion and metastasis are the cathepsins. Their activity and regulation has not yet been evaluated in BCC. We determined the activities, immunoreactivities and mRNA of cathepsins B, L and H in sections of different subtypes of BCC. BCC cells and peritumoral cells contained activities for cathepsins B and L. In all parts of the tumor, the reaction with cathepsin B and L substrate was stronger than in normal skin. The immunoreactive protein and mRNA for these proteases, in contrast, was elevated only occasionally in small tumor nodules. Immunoreactive protein and mRNA of cathepsin D was detected predominantly in the center of tumor nodules. Cathepsin H activities, immunoreactivities and mRNA in most BCCs were higher than in normal skin, and the reactive cells were located between and around tumor nodules, but not in the tumor nests. The results indicate that cathepsins B and L are involved in invasion of BCC cells. Cathepsin H of the peritumoral cells may either promote invasion of the tumor cells by degradation of the extracellular matrix or may reflect an elevated activity of the surrounding immunological cells. The pattern of cathepsin staining markedly differs from that observed in melanomas and may characterize locally invading non-metastatic tumors.

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References

  1. Abudula A, Rommerskirch W, Weber E, Gunther D, Wiederanders B (2001) Splice variants of human cathepsin L mRNA show different expression rates. Biol Chem 382:1583–1591

    CAS  PubMed  Google Scholar 

  2. Adenis A, Huet G, Zerimech F, Hecquet B, Balduyck M, Peyrat JP (1995) Cathepsin B, L, and D activities in colorectal carcinomas: relationship with clinico-pathological parameters. Cancer Lett 96:267–275

    Article  CAS  PubMed  Google Scholar 

  3. Arkona C, Wiederanders B (1996) Expression, subcellular distribution and plasma membrane binding of cathepsin B and gelatinases in bone metastatic tissue. Biol Chem 377:695–702

    CAS  PubMed  Google Scholar 

  4. Berquin I, Sloane B (1996) Cathepsin B expression in human tumors. Adv Exp Med Biol 389:281–294

    CAS  PubMed  Google Scholar 

  5. Breuninger H, Castanet P (1987) Method of histological control of the edges of surgical specimens of basal cell epitheliomas. Ann Dermatol Venereol 114:511–514

    CAS  PubMed  Google Scholar 

  6. Brubaker K, Vessella R, True L, Thomas R, Corey E (2003) Cathepsin K mRNA and protein expression in prostate cancer progression. J Bone Miner Res 18:222–230

    CAS  PubMed  Google Scholar 

  7. Budihna M, Strojan P, Smid L, Skrk J, Vrhovec I, Zupevc A, Rudolf Z, Zargi M, Krasovec M, Svetic B, Kopitar Jerala N, Kos J (1996) Prognostic value of cathepsins B, H, L, D and their endogenous inhibitors stefins A and B in head and neck carcinoma. Biol Chem Hoppe Seyler 377:385–390

    CAS  PubMed  Google Scholar 

  8. Capony F, Rougeot C, Montcourrier P, Cavailles V, Rochefort H (1989) Increased secretion, altered processing, and glycosylation of pro-cathepsin D in human mammary cancer cells. Cancer Res 49:3904–3909

    CAS  PubMed  Google Scholar 

  9. Chambers AF, Colella R, Denhardt DT, Wilson SM (1992) Increased expression of cathepsin L and B and decreased activity of their inhibitors in metastatic, ras-transformed NIH 3T3 cells. Mol Carcinog 5:238–245

    CAS  PubMed  Google Scholar 

  10. Chapman HA Jr, Munger JS, Shi GP (1994) The role of thiol proteases in tissue injury and remodeling. Am J Respir Crit Care Med 150:S155–159

    PubMed  Google Scholar 

  11. Datta C, Weinstein J, Bland J, Brager P, Stewart M (1998) A case of cervical lymph node metastasis resulting from glioblastoma multiforme. W V Med J 94:276–278

    CAS  PubMed  Google Scholar 

  12. Dennison C, Pike R, Coetzer T, Kirk K (1992) Characterisation of the activity and stability of single-chain cathepsin L and of proteolytically active cathepsin L/cystatin complexes. Biol Chem Hoppe Seyler 373:419–425

    CAS  PubMed  Google Scholar 

  13. Ebert E, Werle B, Julke B, Kopitar-Jerala N, Kos J, Lah T, Abrahamson M, Spiess E, Ebert W (1997) Expression of cysteine protease inhibitors stefin A, stefin B, and cystatin C in human lung tumor tissue. Adv Exp Med Biol 421:259–265

    CAS  PubMed  Google Scholar 

  14. Erdel M, Trefz G, Spiess E, Habermaas S, Spring H, Lah T, Ebert W (1990) Localisation of cathepsin B in two human lung cancer cell lines. J Histochem Cytochem 38:1313–1321

    CAS  PubMed  Google Scholar 

  15. Flannery T, Gibson D, Mirakhur M, McQuaid S, Greenan C, Trimble A, Walker B, McCormick D, Johnston P (2003) The clinical significance of cathepsin S expression in human astrocytomas. Am J Pathol 163:175–182

    CAS  PubMed  Google Scholar 

  16. Fröhlich E, Schlagenhauff B, Möhrle M, Weber E, Klessen C, Rassner G (2001) Activity, expression and transcription rate of the cathepsins B, D, H and L in cutaneous malignant melanoma. Cancer 91:972–982

    Article  PubMed  Google Scholar 

  17. Garcia-Arumi E, Andreu AL, Lopez-Hellin J, Schwartz S (1998) Effect of oxidative stress on lymphocytes from elderly subjects. Clin Sci (Lond) 94:447–452

    Google Scholar 

  18. Goldmann T, Suter L, Ribbert D, Otto F (1999) The expression of proteolytic enzymes at the dermal invading front of primary cutaneous melanoma predicts metastasis. Pathol Res Pract 195:171–175

    CAS  PubMed  Google Scholar 

  19. Graumann W (1953) Zur Standardisierung des Schiff’schen Reagenz. Z Wiss Mikr 61:225–226

    Google Scholar 

  20. Hara K, Kominami E, Katunuma N (1988) Effect of proteinase inhibitors on intracellular processing of cathepsin B, H and L in rat macrophages. FEBS Lett 231:229–231

    Article  CAS  PubMed  Google Scholar 

  21. Hirai K, Yokoyama M, Asano G, Tanaka S (1999) Expression of cathepsin B and cystatin C in human colorectal cancer. Hum Pathol 30:680–686

    CAS  PubMed  Google Scholar 

  22. Huang P, Allam A, Taghian A, Freeman J, Duffy M, Suit H (1995) Growth and metastatic behavior of five human glioblastomas compared with nine other histological types of human tumor xenografts in SCID mice. J Neurosurg 83:308–311

    CAS  PubMed  Google Scholar 

  23. Ishibashi O, Mori Y, Kurokawa T, Kumegawa M (1999) Breast cancer cells express cathepsins B and L but not cathepsins K or H. Cancer Biochem Biophys 17:69–78

    CAS  PubMed  Google Scholar 

  24. Ishii Y, Hashizume Y, Watanabe T, Waguri S, Sato N, Yamamoto M, Hasegawa S, Kominami E, Uchiyama Y (1991) Cysteine proteinases in bronchoalveolar epithelial cells and lavage fluid of rat lung. J Histochem Cytochem 39:461–468

    CAS  PubMed  Google Scholar 

  25. Jerala R, Zerovnik E, Kidric J, Turk V (1998) pH-induced conformational transitions of the propeptide of human cathepsin L. A role for a molten globule state in zymogen activation. J Biol Chem 273:11498–11504

    Article  CAS  PubMed  Google Scholar 

  26. Kageshita T, Yoshii A, Kimura T, Maruo K, Ono T, Himeno M, Nishimura Y (1995) Biochemical and immunohistochemical analysis of cathepsin B, H, L and D in human melanotic tumours. Arch Dermatol Res 287:266–272

    CAS  PubMed  Google Scholar 

  27. Kamboj RC, Pal S, Raghav N, Singh H (1993) A selective colorimetric assay for cathepsin L using Z-Phe-Arg-4-methoxy-beta-naphthylamide. Biochimie 75:873–878

    Article  CAS  PubMed  Google Scholar 

  28. Kawada A, Hara K, Kominami E, Kobayashi T, Hiruma M, Ishibashi A (1996) Cathepsin B and D expression in squamous cell carcinoma. Br J Dermatol 135:905–910

    Article  CAS  PubMed  Google Scholar 

  29. Kawada A, Hara K, Kominami E, Hiruma M, Akiyama M, Ishibashi A, Abe H, Ichikawa E, Nakamura Y, Watanabe S, Yamamoto T, Umeda T, Nishioka K (1997) Expression of cathepsin D and B in invasion and metastasis of squamous cell carcinoma. Br J Dermatol 137:361–366

    Article  CAS  PubMed  Google Scholar 

  30. Kawasaki G, Kato Y, Mizuno A (2002) Cathepsin expression in oral squamous cell carcinoma: relationship with clinicopathologic factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 93:446–454

    Article  PubMed  Google Scholar 

  31. Kominami E, Tsukahara T, Bando Y, Katunuma N (1985) Distribution of cathepsins B and H in rat tissues and peripheral blood cells. J Biochem (Tokyo) 98:87–93

    Google Scholar 

  32. Kos J, Smid A, Krasovec M, Svetic B, Lenarcic B, Vrhovec I, Skrk J, Turk V (1995) Lysosomal proteases cathepsins D, B, H, L and their inhibitors stefins A and B in head and neck cancer. Biol Chem Hoppe Seyler 376:401–405

    CAS  PubMed  Google Scholar 

  33. Krepela E, Prochazka J, Karova B (1999) Regulation of cathepsin B activity by cysteine and related thiols. Biol Chem 380:541–551

    CAS  PubMed  Google Scholar 

  34. Lah TT, Kokalj-Kunovar M, Strukeli B, Pungercar J, Barlic-Magania D, Drobnic-Kosorok M, Katelic L, Babnik J, Golough R, Turk V (1992) Stefins and lysosomal cathepsins B, L and D in human breast carcinoma. Int J Cancer 50:36–44

    CAS  PubMed  Google Scholar 

  35. Ledakis P, Tester W, Rosenberg N, Romero-Fischmann D, Daskal I, Lah T (1996) Cathepsins D, B, and L in malignant human lung tissue. Clin Cancer Res 2:561–568

    CAS  PubMed  Google Scholar 

  36. Lignelid H, Jacobsson B (1992) Cystatin C in the human pancreas and gut: an immunohistochemical study of normal and neoplastic tissues. Virchows Arch A Pathol Anat Histopathol 421:491–495

    CAS  PubMed  Google Scholar 

  37. Lojda Z, Gossrau R, Stoward PJ (1991) Proteases. In: Stoward PJ, Pearse AGE (eds) Histochemistry. Churchill Livingstone, Edinburgh, pp 281–335

  38. Mareel M, Leroy A (2003) Clinical, cellular, and molecular aspects of cancer invasion. Physiol Rev 83:337–376

    CAS  PubMed  Google Scholar 

  39. Mort JS, Recklies AD (1986) Interrelationship of active and latent secreted human cathepsin B precursors. Biochem J 233:57–63

    CAS  PubMed  Google Scholar 

  40. Mort JS, Leduc MS, Recklies AD (1983) Characterisation of a latent cysteine proteinase from ascites fluid as a high molecular weight form of cathepsin B. Biochim Biophys Acta 755:369–375

    Article  CAS  PubMed  Google Scholar 

  41. Nakao H, Takamori K, Ogawa H (1989) Interaction of tumor and surrounding tissue of mice inoculated B16 melanoma variants in terms of enzyme activity. Int J Biochem 21:739–743

    Article  CAS  PubMed  Google Scholar 

  42. Park IC, Lee SY, Jeon DG, Lee JS, Hwang CS, Hwang BG, Lee SH, Hong WS, Hong SI (1996) Enhanced expression of cathepsin L in metastatic bone tumors. J Korean Med Sci 11:144–148

    CAS  PubMed  Google Scholar 

  43. Podhajcer OL, Bover L, Bravo AI, Ledda MF, Kairiyama C, Calb I, Guerra L, Capony F, Mordoh J (1995) Expression of cathepsin D in primary and metastatic human melanoma and dysplastic nevi. J Invest Dermatol 104:340–344

    Google Scholar 

  44. Rinne A, Räsänen O, Järvinen M, Dammert K, Kallioinen M, Hopsu-Havu VK (1984) Occurrence of acid and neutral cysteine proteinase inhibitors in epidermal malignancies: immunohistochemical study. Acta Histochem 74:75–79

    CAS  PubMed  Google Scholar 

  45. Rinne A, Jarvinen M, Dorn A, Alavaikko M, Jokinen K, Hopsu Havu VK (1986) Low-molecular cysteine protease inhibitors in the human palatal tonsil (in German). Anat Anz 161:215–230

    CAS  PubMed  Google Scholar 

  46. Robson D, Ironside J, Reid W, Bogue P (1990) Immunolocalization of cathepsin D in the human central nervous system and central nervous system neoplasms. Neuropathol Appl Neurobiol 16:39–44

    CAS  PubMed  Google Scholar 

  47. Rochefort H, Cavailles V, Augereau P, Capony F, Maudelonde T, Touitou I, Garcia M (1989) Overexpression and hormonal regulation of pro-cathepsin D in mammary and endometrial cancer. J Steroid Biochem 34:177–182

    Article  CAS  PubMed  Google Scholar 

  48. Romeis B (1989) Mikroskopische Technik. Urban & Schwarzenberg, München Wien Baltimore

  49. Rozhin J, Wade RL, Honn KV, Sloane BF (1989) Membrane-associated cathepsin L: a role in metastasis of melanomas. Biochim Biophys Res Commun 164:556–561

    CAS  Google Scholar 

  50. Safai B, Good R (1977) Basal cell carcinoma with metastasis. Review of literature. Arch Pathol Lab Med 101:327–331

    CAS  PubMed  Google Scholar 

  51. Schweiger A, Staib A, Werle B, Krasovec M, Lah T, Ebert W, Turk V, Kos J (2000) Cysteine proteinase cathepsin H in tumours and sera of lung cancer patients: relation to prognosis and cigarette smoking. Br J Cancer 82:782–788

    Article  CAS  PubMed  Google Scholar 

  52. Shuja S, Murnane MJ (1996) Marked increases in cathepsin B and L activities distinguish papillary carcinoma of the thyroid from normal thyroid or thyroid with non-neoplastic disease. Int J Cancer 66:420–426

    Article  CAS  PubMed  Google Scholar 

  53. Sivaparvathi M, Sawaya R, Wang S, Rayford A, Yamamoto M, Liotta L, Nicolson G, Rao J (1995) Overexpression and localization of cathepsin B during the progression of human gliomas. Clin Exp Metastasis 13:49–56

    CAS  PubMed  Google Scholar 

  54. Sivaparvathi M, Sawaya R, Chintala SK, Go Y, Gokaslan ZL, Rao JS (1996) Expression of cathepsin D during the progression of human gliomas. Neurosci Lett 208:171–178

    Article  CAS  PubMed  Google Scholar 

  55. Sivaparvathi M, Sawaya R, Gokaslan ZL, Chintala SK, Rao JS, Chintala KS (1996) Expression and the role of cathepsin H in human glioma progression and invasion. Cancer Lett 104:121–126

    Article  CAS  PubMed  Google Scholar 

  56. Sivaparvathi M, Yamamoto M, Nicolson GL, Gokaslan ZL, Fuller GN, Liotta LA, Sawaya R, Rao JS (1996) Expression and immunohistochemical localization of cathepsin L during the progression of human gliomas. Clin Exp Metastasis 14:27–37

    CAS  PubMed  Google Scholar 

  57. Sloane BF, Dunn JR, Honn KV (1981) Lysosomal cathepsin B: correlation with metastatic potential. Science 212:1151–1153

    CAS  PubMed  Google Scholar 

  58. Sloane BF, Honn KV, Sadler JG, Turner WA, Kimpson JJ, Taylor JD (1982) Cathepsin B activity in B 16 melanoma cells: a possible marker for metastatic potential. Cancer Res 42:980–986

    CAS  PubMed  Google Scholar 

  59. Smid L, Strojan P, Budihna M, Skrk J, Vrhovec I, Zargi M, Kos J (1997) Prognostic value of cathepsins B, D and steffins A and B in laryngeal carcinoma. Eur Arch Otorhinolaryngol Suppl 1:150–153

    Google Scholar 

  60. Sotiropoulou G, Anisowicz A, Sager R (1997) Identification, cloning, and characterization of cystatin M, a novel cysteine proteinase inhibitor, down-regulated in breast cancer. Biol Chem 272:903–910

    Article  CAS  Google Scholar 

  61. Strojnik T, Zidanik B, Kos J, Lah T (2001) Cathepsins B and L are markers for clinically invasive types of meningiomas. Neurosurgery 48:598–605

    CAS  PubMed  Google Scholar 

  62. Tsuboi R, Yamaguchi T, Kurita Y, Nakao H, Ogawa H, Ishihara K (1988) Comparison of proteinase activities in squamous cell carcinoma, basal cell epithelioma, and seborrheic keratosis. J Invest Dermatol 90:869–872

    Google Scholar 

  63. Van Noorden CJ, Smith RE, Rasnick D (1988) Cysteine proteinase activity in arthritic rat knee joints and the effects of a selective systemic inhibitor, Z-Phe-AlaCH2F. J Rheumatol 15:1525–1535

    PubMed  Google Scholar 

  64. Vigneswaran N, Wu J, Zacharias W (2003) Upregulation of cystatin M during the progression of oropharyngeal squamous cell carcinoma from primary tumor to metastasis. Oral Oncol 39:559–568

    Article  CAS  PubMed  Google Scholar 

  65. Warich M, von Bossanyi P, Dietzmann K (1995) Expression of cathepsin D in human astrocytic neoplasias. Gen Diagn Pathol 141:93–96

    CAS  PubMed  Google Scholar 

  66. Weber E, Bahn H, Gunther D (1997) Monoclonal antibodies against cathepsin L and procathepsin L of different species. Hybridoma 16:159–166

    CAS  PubMed  Google Scholar 

  67. Werle B, Julke B, Lah T, Spiess E, Ebert W (1997) Cathepsin B fraction active at physiological pH of 7.5 is of prognostic significance in squamous cell carcinoma of human lung. Br J Cancer 75:1137–1143

    CAS  PubMed  Google Scholar 

  68. Wiederanders B, Kirschke H (1986) Antibodies to rat liver cathepsins: characterization and use for the identification of enzyme precursors. Biomed Biochim Acta 45:1421–1431

    CAS  PubMed  Google Scholar 

  69. Yano M, Hirai K, Naito Z, Yokoyama M, Ishiwata T, Shiraki Y, Inokuchi M, Asano G (2001) Expression of cathepsin B and cystatin C in human breast cancer. Surg Today 31:385–389

    Article  CAS  PubMed  Google Scholar 

  70. Yoshii A, Kageshita T, Tsushima H, Ono T (1995) Clinical relevance of cathepsin B-like enzyme activity and cysteine proteinase inhibitor in melanocytic tumours. Arch Dermatol Res 287:209–213

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Elke Maier for excellent technical assistance and Andreas Mack for laser scan microscopy. The work was supported by fortüne Projekt 383-0-1.

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  1. Anatomisches Institut, Österbergstr. 3, 72074, Tübingen, Germany

    Eleonore Fröhlich & C. Klessen

  2. Universitäts-Hautklinik, Liebermeisterstr. 25, 72076, Tübingen, Germany

    Matthias Möhrle

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  1. Eleonore Fröhlich
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Correspondence to Eleonore Fröhlich.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00403-004-0484-1

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Fröhlich, E., Möhrle, M. & Klessen, C. Cathepsins in basal cell carcinomas: activity, immunoreactivity and mRNA staining of cathepsins B, D, H and L. Arch Dermatol Res 295, 411–421 (2004). https://doi.org/10.1007/s00403-003-0449-9

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