Developmental Context Determines Latency of MYC-Induced Tumorigenesis

Abstract

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.

Autochthonous liver tumors induce systemic T cell tolerance associated with T cell receptor down-modulation #

“…1B), similarly to c-myc ϫ LAPtTA mice (c-myc tgϩ). 18 Initial tumor foci were observed as early as 4 weeks after induction in some mice (data not shown). Macroscopic and microscopic findings (Fig.…”

CDK2 Is Required By MYC to Induce Apoptosis

“…24 Similarly, in vivo, MYC overexpression in vivo in adult murine hepatocytes induced a proliferative arrest, but in neonatal hepatocytes that were proliferating or in proliferating liver tumor cells, was apoptosis observed. 54 Hence, apoptosis was observed as mechanism of last resort for containing MYC overexpression.…”

Tumor Dormancy: Death and Resurrection of Cancer As Seen through Transgenic Mouse Models

“…1A). [11][12][13]14 In contrast, MYC inactivation in osteogenic sarcoma resulted in the differentiation of tumor cells into mature bone cell cells (Fig. 1B).…”