title: A Novel Model of Metastatic Conjunctival Melanoma in Immune-Competent Mice.
abstract: OBJECTIVE
  Conjunctival melanoma (CM) is an ocular surface tumor that can lead to fatal metastases. Patients developing, tumor-associated lymphangiogenesis have a significantly increased risk of metastatic disease, because tumor spread primarily occurs via lymphatic vessels to the draining lymph node. Here, we describe a novel immune-competent mouse model of CM that displays tumor-associated lymphangiogenesis with development of metastatic tumors.
  
  
  METHODS
  C57BL/6N mice received C57BL/6N-derived dermal melanoma cells (hepatocyte growth factor [HGF] cyclin dependent kinase-4 [Cdk4]+) or B16F10 via subconjunctival injection. A clinical score quantified primary tumor growth and metastases were identified by macroscopic examination of the draining lymph nodes, lung, and spleen. Confirmation of tumors and metastases was achieved by immunohistochemical staining for markers of pigmented cells (tyrosinase related protein-2 [TRP2]) and S-100, and of cell proliferation (Ki67). The intra- and peritumoral CD31+ blood and lymphatic vessel endothelium hyaluronan receptor-1 (LYVE-1)+ lymphatic vessels were quantified immunohistochemically.
  
  
  RESULTS
  All mice rapidly developed aggressive TRP2+, S100+, and Ki67+ CM. Metastatic tumors were found in the lymph node (9%) and lung (6%) of HGF-Cdk4(R24C)-treated mice and in the spleen (8%) and lung (17%) of B16F10-treated mice. The amount of peri- and intratumoral blood vessels was significantly increased compared with lymphatic vessels.
  
  
  CONCLUSIONS
  This CM model in immune-competent animals offers new possibilities to study the pathobiology of tumor growth, invasion, and mechanisms of metastatic tumor spread, and provides a robust model to explore new immune-based and antilymphangiogenic treatment modalities of this malignancy.
authors.affiliation: Department of Ophthalmology University of Cologne, Cologne, Germany.
authors.forename: Simona L
authors.initials: SL
authors.lastname: Schlereth
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Iden
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Melina
authors.initials: M
authors.lastname: Mescher
authors.affiliation: Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, Massachusetts, United States.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Ksander
authors.affiliation: Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Jacobus J
authors.initials: JJ
authors.lastname: Bosch
authors.affiliation: Department of Ophthalmology University of Cologne, Cologne, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Cursiefen
authors.affiliation: Department of Ophthalmology University of Cologne, Cologne, Germany.
authors.forename: Ludwig M
authors.initials: LM
authors.lastname: Heindl
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation; D003230:Conjunctival Neoplasms / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D007121:Immunocompetence; D007150:Immunohistochemistry; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis / Q000473:pathology*; D008297:Male; D008545:Melanoma / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D011379:Prognosis; D014407:Tumor Cells, Cultured / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor