| Oncogenes may cause tumorigenesis most readily in contexts that provide a genetic or epigenetic program permissive to tumorigenesis. To interrogate the role of context, defined as state of liver development or liver injury, on the ability of the MYC oncogene to induce liver tumorigenesis, we used the Tetracycline Regulatory System to generate transgenic mice in which the expression of a c-MYC human transgene (MYC) can be conditionally regulated in murine hepatocytes. We found that MYC was capable of inducing mitotic division and tumorigenesis in the liver only in specific liver contexts. In embryonic, neonatal, and hepatotoxin-treated adult livers, MYC overexpression caused marked hepatocyte proliferation, associated with increased Cyclin B1 mRNA expression, and a rapid onset of neoplasia. In contrast, in adult murine livers, MYC overexpression resulted in hepatocyte growth and DNA replication, without mitotic division, and mice succumbed to neoplasia only after a prolonged latency. MYC overexpression failed to induce mitotic division of adult hepatocytes, at least in part, through the activation of p53. Mechanisms that regulate mitotic division may play a critical role in preventing potent oncogenes, such as MYC from inducing cancer in adult somatic hepatocytes. These findings have important implications for tumorigenesis in humans. First, they suggest that the time during development of tissue exposure to an oncogenic insult is decisive in determining if this mutation will contribute to proliferation and tumorigenesis. Second, they imply that oncogenic events, such as MYC overexpression, may generally be silent in somatic cells until the host is exposed to a toxin (or additional event), that stimulates mitotic division. |
