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.Malignant melanoma has a high tendency to develop brain metastasis. Almost 40% of melanoma patients are treated for complications due to brain metastasis, and in additional 30-40% of patients CNS lesions are detected at autopsy. 1,2 Treatment options for melanoma patients with cerebral metastasis are limited and depend on the number and size of the lesions. In view of the poor survival rates of these patients, it is necessary to develop novel treatment strategies for the therapy of melanoma brain metastasis.

Identification of Epigenetically Inactivated Genes in Human Hepatocellular Carcinoma by Integrative Analyses of Methylation Profiling and Pharmacological Unmasking

“…More importantly, our analysis identified FRZB as a potential TSG in HCC as indicated by its inactivation through DNA methylation. Another gene, claudin 11 (CLDN11) - an epigenetic biomarker of melanoma [19,20] - was found having a hypermethylated promoter in our study. We have also identified the cyclin-dependent kinase inhibitor 1C ( CDKN1C) as an epigenetically inactivated gene in HCCs.…”

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“…Human embryonic kidney 293T cells were maintained as described previously [10]. Immortalized human brain microvascular endothelial cells (hCMEC/D3) were kindly provided by Dr. Clara Nahmias and Prof. Pierre-Olivier Couraud (Inserm, U1016, Institut Cochin, Paris, France) and were maintained as described by Weksler et al [59].…”

“…Our functional studies indicated that claudin-1 (CLDN1) is a MBM suppressor [10] and recently that CCR4 is a MBM promoter [11].…”

Clinical significance of serum claudin-1 levels in melanoma patients

“…Loss of cell-to-cell adhesion is one of the most important steps in the progression of cancer to metastasis. Claudins with at least 24 members are the most important structural and functional components of tightjunction integral membrane proteins [1][2][3][4][5][6][7][8][9][10]. Therefore, they have significant roles in regulating paracellular permeability and maintaining cell polarity in epithelial and endothelial cell sheets.…”

“…Tight junctions are involved in cell-to-cell adhesion and serve the barrier and the fence functions in epithelial cell layers [1][2][3][4][5][6][7][8][9][10]. Loss of cell-to-cell adhesion is one of the most important steps in the progression of cancer to metastasis.…”