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Collagen XVII is expressed in malignant but not in benign melanocytic tumors and it can mediate antibody induced melanoma apoptosis

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Abstract

The 180 kDa transmembrane collagen XVII is known to anchor undifferentiated keratinocytes to the basement membrane in hemidesmosomes while constitutively shedding a 120 kDa ectodomain. Inherited mutations or auto-antibodies targeting collagen XVII cause blistering skin disease. Collagen XVII is down-regulated in mature keratinocytes but re-expressed in skin cancer. By recently detecting collagen XVII in melanocyte hyperplasia, here we tested its expression in benign and malignant melanocytic tumors using endodomain and ectodomain selective antibodies. We found the full-length collagen XVII protein in proliferating tissue melanocytes, basal keratinocytes and squamous cell carcinoma whereas resting melanocytes were negative. Furthermore, the cell-residual 60 kDa endodomain was exclusively detected in 62/79 primary and 15/18 metastatic melanomas, 8/9 melanoma cell lines, HT199 metastatic melanoma xenografts and atypical nests in 8/63 dysplastic nevi. The rest of 19 nevi including common, blue and Spitz subtypes were also negative. In line with the defective ectodomain, sequencing of COL17A1 gene revealed aberrations in the ectodomain coding region including point mutations. Collagen XVII immunoreaction-stained spindle cell melanomas, showed partly overlapping profiles with those of S100B, Melan A and HMB45. It was concentrated at vertical melanoma fronts and statistically associated with invasive phenotype. Antibody targeting the extracellular aa507–529 terminus of collagen XVII endodomain promoted apoptosis and cell adhesion, while inhibiting proliferation in HT199 cells. These results suggest that the accumulation of collagen XVII endodomain in melanocytic tumors is associated with malignant transformation to be a potential marker of malignancy and a target for antibody-induced melanoma apoptosis.

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References

  • Alonso SR, Ortiz P, Pollan M, Perez-Gomez B, Sanchez L, Acuna MJ, Pajares R, Martinez-Tello FJ, Hortelano CM, Piris MA, Rodriguez-Peralto JL (2004) Progression in cutaneous malignant melanoma is associated with distinct expression profiles: a tissue microarray-based study. Am J Pathol 164:193–203

    Article  PubMed  CAS  Google Scholar 

  • Balla P, Moskovszky L, Sapi Z, Forsyth R, Knowles H, Athanasou NA, Szendroi M, Kopper L, Rajnai H, Pinter F, Petak I, Benassi MS, Picci P, Conti A, Krenacs T (2011) Epidermal growth factor receptor signalling contributes to osteoblastic stromal cell proliferation, osteoclastogenesis and disease progression in giant cell tumour of bone. Histopathology 59:376–389

    Article  PubMed  Google Scholar 

  • Bauer JW, Schaeppi H, Kaserer C, Hantich B, Hintner H (2001) Large melanocytic nevi in hereditary epidermolysis bullosa. J Am Acad Dermatol 44:577–584

    Article  PubMed  CAS  Google Scholar 

  • Bichel J, Metze D, Bruckner-Tuderman L, Stander S (2001) Large melanocytic nevi in generalized atrophic benign epidermolysis bullosa (epidermolysis bullosa nevi). Hautarzt 52:812–816

    Article  PubMed  CAS  Google Scholar 

  • Borradori L, Sonnenberg A (1999) Structure and function of hemidesmosomes: more than simple adhesion complexes. J Invest Dermatol 112:411–418

    Article  PubMed  CAS  Google Scholar 

  • Budinger L, Borradori L, Yee C, Eming R, Ferencik S, Grosse-Wilde H, Merk HF, Yancey K, Hertl M (1998) Identification and characterization of autoreactive T cell responses to bullous pemphigoid antigen 2 in patients and healthy controls. J Clin Invest 102:2082–2089

    Article  PubMed  CAS  Google Scholar 

  • Carlson JA, Ross JS, Slominski A, Linette G, Mysliborski J, Hill J, Mihm M Jr (2005) Molecular diagnostics in melanoma. J Am Acad Dermatol 52:743–775 (quiz 775–748)

    Article  PubMed  Google Scholar 

  • Cohen-Knafo E, al Saati T, Aziza J, Ralfkiaer E, Selves J, Gorguet B, Delsol G (1995) Production and characterisation of an antimelanoma monoclonal antibody KBA.62 using a new melanoma cell line reactive on paraffin wax embedded sections. J Clin Pathol 48:826–831

    Article  PubMed  CAS  Google Scholar 

  • Crowson AN, Magro CM, Mihm MC (2006) Prognosticators of melanoma, the melanoma report, and the sentinel lymph node. Mod Pathol 19(Suppl 2):S71–S87

    Article  PubMed  Google Scholar 

  • de Vries TJ, Smeets M, de Graaf R, Hou-Jensen K, Brocker EB, Renard N, Eggermont AM, van Muijen GN, Ruiter DJ (2001) Expression of gp100, MART-1, tyrosinase, and S100 in paraffin-embedded primary melanomas and locoregional, lymph node, and visceral metastases: implications for diagnosis and immunotherapy. A study conducted by the EORTC Melanoma Cooperative Group. J Pathol 193:13–20

    Article  PubMed  Google Scholar 

  • Franzke CW, Tasanen K, Borradori L, Huotari V, Bruckner-Tuderman L (2004) Shedding of collagen XVII/BP180: structural motifs influence cleavage from cell surface. J Biol Chem 279:24521–24529

    Article  PubMed  CAS  Google Scholar 

  • Franzke CW, Bruckner P, Bruckner-Tuderman L (2005) Collagenous transmembrane proteins: recent insights into biology and pathology. J Biol Chem 280:4005–4008

    Article  PubMed  CAS  Google Scholar 

  • Franzke CW, Bruckner-Tuderman L, Blobel CP (2009) Shedding of collagen XVII/BP180 in skin depends on both ADAM10 and ADAM9. J Biol Chem 284:23386–23396

    Article  PubMed  CAS  Google Scholar 

  • Giblin AV, Thomas JM (2007) Incidence, mortality and survival in cutaneous melanoma. J Plast Reconstr Aesthet Surg 60:32–40

    Article  PubMed  Google Scholar 

  • Giricz O, Lauer JL, Fields GB (2010) Variability in melanoma metalloproteinase expression profiling. J Biomol Tech 21:194–204

    PubMed  Google Scholar 

  • Gollob JA, Sciambi CJ, Huang Z, Dressman HK (2005) Gene expression changes and signaling events associated with the direct antimelanoma effect of IFN-gamma. Cancer Res 65:8869–8877

    Article  PubMed  CAS  Google Scholar 

  • Ha L, Merlino G, Sviderskaya EV (2008) Melanomagenesis: overcoming the barrier of melanocyte senescence. Cell Cycle 7:1944–1948

    Article  PubMed  CAS  Google Scholar 

  • Hofmann SC, Voith U, Schonau V, Sorokin L, Bruckner-Tuderman L, Franzke CW (2009) Plasmin plays a role in the in vitro generation of the linear IgA dermatosis antigen LADB97. J Invest Dermatol 129:1730–1739

    Article  PubMed  CAS  Google Scholar 

  • Hopkinson SB, Findlay K, deHart GW, Jones JC (1998) Interaction of BP180 (type XVII collagen) and alpha6 integrin is necessary for stabilization of hemidesmosome structure. J Invest Dermatol 111:1015–1022

    Article  PubMed  CAS  Google Scholar 

  • Huttenbach Y, Prieto VG, Reed JA (2002) Desmoplastic and spindle cell melanomas express protein markers of the neural crest but not of later committed stages of Schwann cell differentiation. J Cutan Pathol 29:562–568

    Article  PubMed  Google Scholar 

  • Jangi SM, Ruiz-Larrea MB, Nicolau-Galmes F, Andollo N, Arroyo-Berdugo Y, Ortega-Martinez I, Diaz-Perez JL, Boyano MD (2008) Terfenadine-induced apoptosis in human melanoma cells is mediated through Ca2+ homeostasis modulation and tyrosine kinase activity, independently of H1 histamine receptors. Carcinogenesis 29:500–509

    Article  PubMed  CAS  Google Scholar 

  • King R, Googe PB, Weilbaecher KN, Mihm MC Jr, Fisher DE (2001) Microphthalmia transcription factor expression in cutaneous benign, malignant melanocytic, and nonmelanocytic tumors. Am J Surg Pathol 25:51–57

    Article  PubMed  CAS  Google Scholar 

  • Kitajima Y, Hirako Y, Owaribe K, Mori S, Yaoita H (1994) Antibody-binding to the 180-kD bullous pemphigoid antigens at the lateral cell surface causes their internalization and inhibits their assembly at the basal cell surface in cultured keratinocytes. J Dermatol 21:838–846

    PubMed  CAS  Google Scholar 

  • Krenacs T, Krenacs L, Raffeld M (2010) Multiple antigen immunostaining procedures. Methods Mol Biol 588:281–300

    Article  PubMed  CAS  Google Scholar 

  • Ladanyi A, Timar J, Bocsi J, Tovari J, Lapis K (1995) Sex-dependent liver metastasis of human melanoma lines in SCID mice. Melanoma Res 5:83–86

    Article  PubMed  CAS  Google Scholar 

  • Lanschuetzer CM, Emberger M, Hametner R, Klausegger A, Pohla-Gubo G, Hintner H, Bauer JW (2003) Pathogenic mechanisms in epidermolysis bullosa naevi. Acta Derm Venereol 83:332–337

    Article  PubMed  CAS  Google Scholar 

  • Lin MS, Gharia MA, Swartz SJ, Diaz LA, Giudice GJ (1999) Identification and characterization of epitopes recognized by T lymphocytes and autoantibodies from patients with herpes gestationis. J Immunol 162:4991–4997

    PubMed  CAS  Google Scholar 

  • Lin MS, Fu CL, Giudice GJ, Olague-Marchan M, Lazaro AM, Stastny P, Diaz LA (2000) Epitopes targeted by bullous pemphigoid T lymphocytes and autoantibodies map to the same sites on the bullous pemphigoid 180 ectodomain. J Invest Dermatol 115:955–961

    Article  PubMed  CAS  Google Scholar 

  • Magro CM, Crowson AN, Mihm MC (2006) Unusual variants of malignant melanoma. Mod Pathol 19(Suppl 2):S41–S70

    Article  PubMed  Google Scholar 

  • Moore MW, Gasparini R (2011) FISH as an effective diagnostic tool for the management of challenging melanocytic lesions. Diagn Pathol 6:76

    Article  PubMed  Google Scholar 

  • Nishie W, Lamer S, Schlosser A, Licarete E, Franzke CW, Hofmann SC, Jackow J, Sitaru C, Bruckner-Tuderman L (2010) Ectodomain shedding generates neoepitopes on collagen XVII, the major autoantigen for bullous pemphigoid. J Immunol 185:4938–4947

    Article  PubMed  CAS  Google Scholar 

  • Nishie W, Kiritsi D, Nystrom A, Hofmann SC, Bruckner-Tuderman L (2011) Dynamic interactions of epidermal collagen XVII with the extracellular matrix: laminin 332 as a major binding partner. Am J Pathol 179:829–837

    Article  PubMed  CAS  Google Scholar 

  • Ogawa H, Sakuma M, Morioka S, Kitamura K, Sasai Y, Imamura S, Inaba Y (1995) The incidence of internal malignancies in pemphigus and bullous pemphigoid in Japan. J Dermatol Sci 9:136–141

    Article  PubMed  CAS  Google Scholar 

  • Ohsie SJ, Sarantopoulos GP, Cochran AJ, Binder SW (2008) Immunohistochemical characteristics of melanoma. J Cutan Pathol 35:433–444

    Article  PubMed  Google Scholar 

  • Parikka M, Kainulainen T, Tasanen K, Vaananen A, Bruckner-Tuderman L, Salo T (2003) Alterations of collagen XVII expression during transformation of oral epithelium to dysplasia and carcinoma. J Histochem Cytochem 51:921–929

    Article  PubMed  CAS  Google Scholar 

  • Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108

    Article  PubMed  Google Scholar 

  • Pinon P, Wehrle-Haller B (2011) Integrins: versatile receptors controlling melanocyte adhesion, migration and proliferation. Pigment Cell Melanoma Res 24:282–294

    Article  PubMed  CAS  Google Scholar 

  • Qiao H, Shibaki A, Long HA, Wang G, Li Q, Nishie W, Abe R, Akiyama M, Shimizu H, McMillan JR (2009) Collagen XVII participates in keratinocyte adhesion to collagen IV, and in p38MAPK-dependent migration and cell signaling. J Invest Dermatol 129:2288–2295

    Article  PubMed  CAS  Google Scholar 

  • Seppanen A, Autio-Harmainen H, Alafuzoff I, Sarkioja T, Veijola J, Hurskainen T, Bruckner-Tuderman L, Tasanen K, Majamaa K (2006) Collagen XVII is expressed in human CNS neurons. Matrix Biol 25:185–188

    Article  PubMed  Google Scholar 

  • Seppanen A, Suuronen T, Hofmann SC, Majamaa K, Alafuzoff I (2007) Distribution of collagen XVII in the human brain. Brain Res 1158:50–56

    Article  PubMed  Google Scholar 

  • Slominski A (2002) Coming of age of melanogenesis-related proteins. Arch Pathol Lab Med 126:775–777

    PubMed  Google Scholar 

  • Stelkovics E, Korom I, Marczinovits I, Molnar J, Rasky K, Raso E, Ficsor L, Molnar B, Kopper L, Krenacs T (2008) Collagen XVII/BP180 protein expression in squamous cell carcinoma of the skin detected with novel monoclonal antibodies in archived tissues using tissue microarrays and digital microscopy. Appl Immunohistochem Mol Morphol 16:433–441

    Article  PubMed  CAS  Google Scholar 

  • Suzuki M, Murata S, Yaoita H, Nakagawa H (2002) An antibody to BP 180 kDa antigen is able to induce an increase of intracellular Ca2+ concentration in DJM-1 (human squamous cell carcinoma) cells. Autoimmunity 35:271–276

    Article  PubMed  CAS  Google Scholar 

  • Szabad G, Kormos B, Pivarcsi A, Szell M, Kis K, Kenderessy Szabo A, Dobozy A, Kemeny L, Bata-Csorgo Z (2007) Human adult epidermal melanocytes cultured without chemical mitogens express the EGF receptor and respond to EGF. Arch Dermatol Res 299:191–200

    Article  PubMed  CAS  Google Scholar 

  • Tasanen K, Floeth M, Schumann H, Bruckner-Tuderman L (2000) Hemizygosity for a glycine substitution in collagen XVII: unfolding and degradation of the ectodomain. J Invest Dermatol 115:207–212

    Article  PubMed  CAS  Google Scholar 

  • Vergier B, Prochazkova-Carlotti M, de la Fouchardiere A, Cerroni L, Massi D, De Giorgi V, Bailly C, Wesselmann U, Karlseladze A, Avril MF, Jouary T, Merlio JP (2011) Fluorescence in situ hybridization, a diagnostic aid in ambiguous melanocytic tumors: European study of 113 cases. Mod Pathol 24:613–623

    Article  PubMed  CAS  Google Scholar 

  • Yamada T, Endo R, Tsukagoshi K, Fujita S, Honda K, Kinoshita M, Hasebe T, Hirohashi S (1996) Aberrant expression of a hemidesmosomal protein, bullous pemphigoid antigen 2, in human squamous cell carcinoma. Lab Invest 75:589–600

    PubMed  CAS  Google Scholar 

  • Zone JJ, Taylor TB, Meyer LJ, Petersen MJ (1998) The 97 kDa linear IgA bullous disease antigen is identical to a portion of the extracellular domain of the 180 kDa bullous pemphigoid antigen, BPAg2. J Invest Dermatol 110:207–210

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors are indebted to Jeno Ormos for inspiration, Janos Molnar for initiation of this work, Klara Rasky for contribution in antibody development, Ilona Marczinovics and Zsuzsanna Bata for help in antibody characterization, Laszlo Krenacs and Zsolt Orosz for sharing some of their facilities and melanoma cases and to Bela Molnar and 3DHistech staff, as well as Edit Parsch, Katalin Szekeres, Aniko Sarro, Violetta Piurko and Bernadett Kormos for excellent technical assistance. This work was supported by OTKA T62758 of Hungary.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Ulloi ut 26, Budapest, 1085, Hungary

    T. Krenacs, G. Kiszner, P. Balla & I. Teleki

  2. Laboratory of Tumor Pathology and Molecular Diagnostics, Bay Zoltan Foundation for Applied Research, Szeged, Hungary

    E. Stelkovics

  3. Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary

    I. Nemeth, E. Varga & I. Korom

  4. 2nd Department of Pathology, Semmelweis University, Budapest, Hungary

    T. Barbai, J. Timar & E. Raso

  5. Oncopathology Department, National Institute of Oncology, Budapest, Hungary

    V. Plotar

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  1. T. Krenacs
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  2. G. Kiszner
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  3. E. Stelkovics
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  4. P. Balla
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Correspondence to T. Krenacs.

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G. Kiszner and E. Stelkovics equally contributed to this work.

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Krenacs, T., Kiszner, G., Stelkovics, E. et al. Collagen XVII is expressed in malignant but not in benign melanocytic tumors and it can mediate antibody induced melanoma apoptosis. Histochem Cell Biol 138, 653–667 (2012). https://doi.org/10.1007/s00418-012-0981-9

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