RESUMO
Melanoma probably is the most aggressive cancer in humans and remains one of the leading causes of cancer death in developed countries. This review summarizes the most important alterations in protooncogenes and tumor suppressor genes that contribute to the pathogenesis of malignant melanoma, with a special emphasis on the involved signaling pathways. Our knowledge of the molecular biology of melanoma has been benefited from recent advances on high-throughput technologies analyzing wide genomic and gene expression profiles that have uncovered unknown candidate genes. To test the interactions between distinct pathways and of those with the environment a wealth of genetically modified animal models has been generated over the past years. Other studies have focused on the isolation of melanoma stem cells and on the characterization of signaling pathways that contribute to their survival and maintenance. A consequence of all these studies is the emergence of potential new strategies that could improve the still inadequate arsenal of therapeutic tools to fight against this fatal disease.
Assuntos
Melanoma/genética , Animais , Inibidor p16 de Quinase Dependente de Ciclina/genética , Modelos Animais de Doenças , Genes ras , Engenharia Genética , Predisposição Genética para Doença , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Transdução de Sinais , Células-Tronco/fisiologia , Quinases raf/genéticaRESUMO
The incidence of melanoma has increased more rapidly than any other type of cancer. In this review, we summarize the most important genetic alterations that contribute to the development of malignant melanoma. Our knowledge of the genetic and biological events involved in the genesis and progression of this disease has been benefited from the evolvement of a wealth of genetically engineered animal models. Hopefully, the understanding generated by all these studies will contribute to develop new therapeutic strategies to handle this fatal malignancy.
Assuntos
Melanoma/genética , Biologia Molecular , Neoplasias Cutâneas/genética , Animais , Modelos Animais de Doenças , Predisposição Genética para Doença/genética , Humanos , CamundongosRESUMO
No disponible
Skin cancer is the most common cancer worldwide.Its incidence is doubling every 15-20 years likely becauseof an aging population, changes in behaviourtowards sun exposure, and increased UV light fluencyat the earth surface due to ozone depletion. Inthis review, we summarize the most important geneticchanges contributing to the development ofmalignant melanoma, basal cell carcinoma andsquamous cell carcinoma, the main tumor entitiesarising in the skin. While our understanding of theoncogenes and tumor suppressor genes involved inthe development and progression of skin tumors isstill fragmentary, recent advances have shown alterationsaffecting conserved signalling pathwaysthat control cellular proliferation and viability. Thesepathways include INK4a/Rb, ARF/p53, RAS/MAPKs,and sonic hedgehog/Gli
Assuntos
Humanos , Biologia Molecular/tendências , Melanoma/genética , Marcadores Genéticos , Neoplasias Cutâneas/genética , Radiação Solar , Raios Ultravioleta/efeitos adversos , Predisposição Genética para Doença , Carcinoma de Células Escamosas/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasia de Células Basais/genéticaRESUMO
In mouse epidermal carcinogenesis, the latest stage of malignant progression involves the transition from squamous cell carcinoma to a highly aggressive type of tumor with spindle morphology. In this work, we have isolated a minor epithelial cell subpopulation (CarC-R) contained in the highly malignant spindle carcinoma cell line CarC. CarC-R exhibited a drastic reduction in tumorigenicity when compared with CarC, but CarC-R-induced tumors were mainly sarcomatoid, although they subsequently reverted to the epithelial phenotype when tumor explants were recultured in vitro. Several single-cell clones with either stable epithelial or fibroblastic phenotypes were isolated from an explanted CarC-R tumor (CarC-RT). All these cell lines contained the same specific point mutation in H-Ras codon 61, but while CarC spindle cells had lost the normal H-Ras allele, it was retained in CarC-R- and CarC-RT-derived cell lines. Furthermore, CarC cells have inactivated p16INK4a and p19INK4a/ARF transcription, while CarC-R and CarC-RT clones expressed p19 mRNA and protein but not p16. Altogether, these results suggest that CarC-R represents a precursor stage to CarC in malignant progression. Spectral karyotyping analysis revealed that CarC-R was highly aneuploid and contained many chromosomal abnormalities. In contrast, CarC had a diploid or tetraploid modal chromosome number and contained a specific T(14;15) translocation in all of the analysed metaphases. The T(14;15) translocation was present in only a minority (1.9%) of CarC-R cells, but it was widely spread in CarC-RT and its derived cell clones, regardless of their epithelial or fibroblastic phenotype, indicating that T(14;15) segregates with malignancy.
