title: The metastatic microenvironment: Claudin-1 suppresses the malignant phenotype of melanoma brain metastasis.
abstract: Brain metastases occur frequently in melanoma patients with advanced disease whereby the prognosis is dismal. The underlying mechanisms of melanoma brain metastasis development are not well understood. Identification of molecular determinants regulating melanoma brain metastasis would advance the development of prevention and therapy strategies for this disease. Gene expression profiles of cutaneous and brain-metastasizing melanoma variants from three xenograft tumor models established in our laboratory revealed that expression of tight junction component CLDN1 was lower in the brain-metastasizing variants than in cutaneous variants from the same melanoma. The objective of our study was to determine the significance of CLDN1 downregulation/loss in metastatic melanoma and its role in melanoma brain metastasis. An immunohistochemical analysis of human cells of the melanocyte lineage indicated a significant CLDN1 downregulation in metastatic melanomas. Transduction of melanoma brain metastatic cells expressing low levels of CLDN1 with a CLDN1 retrovirus suppressed their metastatic phenotype. CLDN1-overexpressing melanoma cells expressed a lower ability to migrate and adhere to extracellular matrix, reduced tumor aggressiveness in nude mice and, most importantly, eliminated the formation of micrometastases in the brain. In sharp contrast, the ability of the CLDN1-overexpressing cells to form lung micrometastases was not impaired. CLDN1-mediated interactions between these cells and brain endothelial cells constitute the mechanism underlying these results. Taken together, we demonstrated that downregulation or loss of CLDN1 supports the formation of melanoma brain metastasis, and that CLDN1 expression could be a useful prognostic predictor for melanoma patients with a high risk of brain metastasis.
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Sivan
authors.initials: S
authors.lastname: Izraely
authors.forename: Orit
authors.initials: O
authors.lastname: Sagi-Assif
authors.forename: Anat
authors.initials: A
authors.lastname: Klein
authors.forename: Tsipi
authors.initials: T
authors.lastname: Meshel
authors.forename: Shlomit
authors.initials: S
authors.lastname: Ben-Menachem
authors.forename: Assaf
authors.initials: A
authors.lastname: Zaritsky
authors.forename: Marcelo
authors.initials: M
authors.lastname: Ehrlich
authors.forename: Victor G
authors.initials: VG
authors.lastname: Prieto
authors.forename: Menashe
authors.initials: M
authors.lastname: Bar-Eli
authors.forename: Christine
authors.initials: C
authors.lastname: Pirker
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Clara
authors.initials: C
authors.lastname: Nahmias
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.forename: Dave S B
authors.initials: DS
authors.lastname: Hoon
authors.forename: Isaac P
authors.initials: IP
authors.lastname: Witz
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000556:secondary*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002465:Cell Movement; D062445:Claudin-1 / Q000502:physiology*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D061206:Neoplasm Micrometastasis; D010641:Phenotype; D012878:Skin Neoplasms / Q000473:pathology*; D059016:Tumor Microenvironment
chemical_list: C568108:CLDN1 protein, human; D062445:Claudin-1
keywords: brain metastasis; claudin-1; melanoma; micrometastasis