Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Imidazoles/therapeutic use , Melanoma/drug therapy , Oximes/therapeutic use , Pyridones/therapeutic use , Pyrimidinones/therapeutic use , Skin Neoplasms/drug therapy , Aged , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Humans , Imidazoles/pharmacology , Male , Melanoma/genetics , Melanoma/pathology , Mice , Mutation , Oximes/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Pyridones/pharmacology , Pyrimidinones/pharmacology , Skin/pathology , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
The canonical Wnt signalling pathway induces the ß-catenin/lymphoid enhancer factor transcription factors. It is activated in various cancers, most characteristically carcinomas, in which it promotes metastatic spread by increasing migration and/or invasion. The Wnt/ß-catenin signalling pathway is frequently activated in melanoma, but the presence of ß-catenin in the nucleus does not seem to be a sign of aggressiveness in these tumours. We found that, unlike its positive role in stimulating migration and invasion of carcinoma cells, ß-catenin signalling decreased the migration of melanocytes and melanoma cell lines. In vivo, ß-catenin signalling in melanoblasts reduced the migration of these cells, causing a white belly-spot phenotype. The inhibition by ß-catenin of migration was dependent on MITF-M, a key transcription factor of the melanocyte lineage, and CSK, an Src-inhibitor. Despite reducing migration, ß-catenin signalling promoted lung metastasis in the NRAS-driven melanoma murine model. Thus, ß-catenin may have conflicting roles in the metastatic spread of melanoma, repressing migration while promoting metastasis. These results highlight that metastasis formation requires a series of successful cellular processes, any one of which may not be optimally efficient.
Subject(s)
Cell Movement , Lung Neoplasms/metabolism , Melanocytes/physiology , Melanoma/metabolism , beta Catenin/physiology , Animals , CSK Tyrosine-Protein Kinase , Cell Line, Tumor , GTP Phosphohydrolases/metabolism , Humans , Lung Neoplasms/secondary , Melanoma/secondary , Membrane Proteins/metabolism , Mice , Mice, Nude , Mice, Transgenic , Microphthalmia-Associated Transcription Factor/metabolism , Neoplasm Transplantation , Wnt Signaling Pathway , src-Family Kinases/metabolismABSTRACT
Partial and some few cases of complete spontaneous regression have been observed in cutaneous melanoma patients but little is known about the molecular mechanisms involved. The Melanoblastoma-bearing Libechov Minipig (MeLiM) is a suitable animal model to study the phenomenon of spontaneous regression because MeLiM pigs exhibit naturally occurring melanomas which regress completely 6 months after birth. In this study, we used suppression subtractive hybridization (SSH) to identify molecular determinants of melanoma regression within swine melanoma tissues and melanoma cell cultures. Several markers involved in cell-adhesion, -communication, -motility, signal transduction, negative regulation of cell proliferation, transport and immune response were identified that correlated with melanoma regression whereas the main genes involved in melanin synthesis showed a strong downregulation. For the most differentially expressed genes, we validated the results obtained by SSH with qRT-PCR and with immunohistochemistry for some of them (CD9, MITF, RARRES1). Most notable, for the first time in melanoma, we identified the retinoic acid responder 1 gene (RARRES1) as a main actor of the regression process in melanoma. This first gene expression study in swine melanoma regression, may contribute to the finding of new therapeutic targets for human melanoma treatment.