One of the enigmas in
tumor biology is that different types of cancers are
prevalent in different age groups. One possible explanation is that the ability of a specific
oncogene to cause
tumorigenesis in a particular cell type depends on
epigenetic parameters such as the developmental context. To address this hypothesis, we have used the
tetracycline regulatory system to generate
transgenic mice in which the expression of a c-MYC human
transgene can be conditionally regulated in murine
hepatocytes. MYC's ability to induce
tumorigenesis was dependent upon developmental context. In
embryonic and neonatal
mice,
MYC overexpression in the
liver induced marked
cell proliferation and immediate onset of
neoplasia. In contrast, in adult
mice MYC overexpression induced
cell growth and
DNA replication without
mitotic cell division, and
mice succumbed to
neoplasia only after a prolonged latency. In adult
hepatocytes,
MYC activation failed to induce
cell division, which was at least in part mediated through the
activation of p53. Surprisingly,
apoptosis is not a barrier to
MYC inducing
tumorigenesis. The ability of
oncogenes to induce
tumorigenesis may be generally restrained by developmentally specific mechanisms. Adult
somatic cells have evolved mechanisms to prevent individual
oncogenes from initiating
cellular growth,
DNA replication, and
mitotic cellular division alone, thereby preventing any single
genetic event from inducing
tumorigenesis.
