RESUMO
Acral melanoma is one of the most aggressive and fast-growing forms of cutaneous melanoma and is characterized by a predominant location on the palms and feet. Primary tumors, metastases, and normal tissue samples from five acral melanoma patients were examined by massive parallel sequencing, focusing on the coding regions of 4100 genes involved in the origin and progression of hereditary and oncology diseases. Somatic mutations were found in genes related to cell division, proliferation, and apoptosis (BRAF, NRAS, VAV1, GATA1, and GCM2); cell adhesion (CTNND2 and ITGB4); angiogenesis (VEGFA); and the regulation of energy metabolism (BCS1L). Comparisons of target DNA sequences between morphologically normal and primary tumor tissues and between normal and metastatic tissues identified the candidate genes responsible for rapid metastasis in acral melanoma.
Assuntos
Melanoma/genética , Melanoma/patologia , Mutação , Metástase Neoplásica/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Humanos , Análise de Sequência de DNARESUMO
The oncolytic potential of the attenuated mumps virus (MV) vaccine strain Leningrad-3 (L-3) was evaluated in a panel of four human metastatic melanoma cell lines. The lines were shown to be susceptible and permissive to MV infection. Efficient MV replication led to death of melanoma cells, but the effect differed among the cell lines. Possible mechanisms mediating the selectivity of MV L-3 towards the cell lines were explored. Replicative and oncolytic activity of MV was found to depend on the expression pattern of type I interferon genes. None of the melanoma cell lines showed induction of expression of the total spectrum of genes required to inhibit virus replication. Based on the results, MV L-3 was assumed to be a promising oncolytic agent for human melanoma cells.
Assuntos
Melanoma/terapia , Vírus da Caxumba/genética , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/patologia , Melanoma/virologia , Camundongos , Proteínas de Neoplasias/genética , Replicação Viral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The discovery of B-RAF activating mutations in malignant melanoma cells has led to the development of a number of targeted drugs, which block exclusively the mutant B-RAF protein. Tumor cells often acquire resistance to B-RAF inhibitors via activation of alternative signaling pathways. One of the resistance mechanisms is activation of PDGF, VEGF, c-KIT, and certain other tyrosine kinases. The possibility of overcoming the resistance to the B-RAF inhibitor Vemurafenib by inactivating receptor tyrosine kinases (RTKs) was studied in metastatic melanoma cell lines differing in B-RAF mutations and RTK activity. It was found that RTK inactivation may help to overcome resistance to B-RAF inhibitors via inhibition of tyrosine kinase phosphorylation and a subsequent blocking of the PI3K-AKT-mTOR and MEK-ERK1/2 downstream signaling pathways. The changes eventually mitigated the cell growth and enhanced the Vemurafenib-dependent cell cycle arrest.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Sistema de Sinalização das MAP Quinases , Melanoma , Proteínas Proto-Oncogênicas B-raf , Receptores Proteína Tirosina Quinases , Vemurafenib/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Melanoma/tratamento farmacológico , Melanoma/enzimologia , Melanoma/genética , Melanoma/patologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
The possibility of using VEGF-R1 receptor for targeted therapy in oncology was investigated. Using the approach to measuring the protein content in intact nuclei of cells, which was developed by us, we showed the presence of this receptor in the nuclei of tumor, but not normal cells. A direct correlation between the level of VEGF-R1 expression in the nucleus and the degree of malignancy of tumor cells, indicating the prognostic value of this parameter, was found. The mechanisms of the functioning of this receptor and the pathways of inhibiting its activity are discussed, and the validity of the selection of VEGF-R1 as a molecular target for anticancer therapy is conformed.
Assuntos
Antineoplásicos/farmacologia , Terapia de Alvo Molecular/métodos , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , HumanosRESUMO
We continue analysis of the phenotype of human melanoma cell Mel Ibr subclone obtained previously by treatment of the parental cell line by chicken embryo extract. The present study is focused on detection of markers of epithelial-mesenchymal transition that determine enhanced metastatic and invasive potential of malignant tumors of various locations. Analysis of the expression of E-cadherin and vimentin genes in the subclone and parental cells detected activation of epithelial-mesenchymal transition in the subclone. Immunological markers CD90, CD271, and CD95 were present in the parental population, but were not detected on the subclone cells. In contrast to the parental line, cells of the analyzed subclone retain viability in serum-free medium and formed vessel-like structures characteristic of vasculogenic mimicry.
Assuntos
Antineoplásicos/farmacologia , Melanoma/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Embrião de Galinha , Galinhas , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Vimentina/metabolismoRESUMO
Alofanib is a potential allosteric inhibitor of FGFR2 used in oncology. The inhibitor blocks the extracellular part of the receptor and prevents its binding with the ligand. Alofanib suppressed proliferation of endothelial cells, their migration activity, and ability to form vessellike structures in vitro and significantly decreased the number of microvessels in Matrigel implant and in ovarian cancer (SKOV-3) xenograft in vivo. The results indicate that Alofanib can inhibit angiogenesis.