Developmental context determines latency of MYC-induced tumorigenesis.

Beer S, Zetterberg A, Ihrie RA, McTaggart RA, Yang Q, Bradon N, Arvanitis C, Attardi LD, Feng S, Ruebner B, Cardiff RD, Felsher DW
PLoS Biol. 2004 2 (11): e332

PMID: 15455033 · PMCID: PMC519000 · DOI:10.1371/journal.pbio.0020332

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.

MeSH Terms (28)

Alleles Animals Apoptosis Blotting, Northern Blotting, Western Cell Division Cell Nucleus Cell Proliferation Cell Separation DNA Replication Flow Cytometry Gene Expression Regulation, Developmental Gene Expression Regulation, Neoplastic Hepatocytes Heterozygote Ki-67 Antigen Liver Mice Mice, SCID Mice, Transgenic Microscopy, Fluorescence Molecular Sequence Data Neoplasm Invasiveness Neoplasms Neoplasm Transplantation Polymerase Chain Reaction Proto-Oncogene Proteins c-myc Tumor Suppressor Protein p53

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