Abstract
Although there is a wide range of accepted models of tumorigenesis involving genetic lesions, the timing and hierarchy of epigenetic alterations associated with tumor progression and metastasis are still poorly understood. In this regard, the best characterized mouse carcinogenesis system, the multistage skin cancer progression model, has recently been used to identify epigenetic alterations during tumor progression and to provide decisive information about how epigenetic lesions precede metastasis. This model reveals a progressive global loss of genomic methylcytosine that is associated with the degree of tumor aggressiveness and that occurs in the context of increasing numbers of hypermethylated CpG islands of tumor-suppressor genes during the most malignant stages of carcinogenesis. DNA microarrays coupled with demethylating drug treatments confirm the progressive establishment of hypermethylation events from the early stages to the most aggressive phenotypes. It is of particular interest that the transition from epithelial to spindle cell morphology with metastatic potential is associated with prominent epigenetic alterations: E-cadherin methylation, demethylation of the Snail promoter, and a profound decrease of global DNA methylation.
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Fraga, M.F., Esteller, M. (2005). A Mouse Skin Multistage Carcinogenesis Model That Unmasks Epigenetic Lesions Responsible for Metastasis. In: Esteller, M. (eds) DNA Methylation, Epigenetics and Metastasis. Cancer Metastasis — Biology and Treatment, vol 7. Springer, Dordrecht. https://doi.org/10.1007/1-4020-3642-6_2
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DOI: https://doi.org/10.1007/1-4020-3642-6_2
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