Developmental Context Determines Latency of MYC-Induced Tumorigenesis

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

Combined Analysis of Murine and Human Microarrays and ChIP Analysis Reveals Genes Associated with the Ability of MYC To Maintain Tumorigenesis

The MYC oncogene has been implicated in the regulation of up to thousands of genes involved in many cellular programs including proliferation, growth, differentiation, self-renewal, and apoptosis. MYC is thought to induce cancer through an exaggerated effect on these physiologic programs. Which of these genes are responsible for the ability of MYC to initiate and/or maintain tumorigenesis is not clear. Previously, we have shown that upon brief MYC inactivation, some tumors undergo sustained regression. Here we demonstrate that upon MYC inactivation there are global permanent changes in gene expression detected by microarray analysis. By applying StepMiner analysis, we identified genes whose expression most strongly correlated with the ability of MYC to induce a neoplastic state. Notably, genes were identified that exhibited permanent changes in mRNA expression upon MYC inactivation. Importantly, permanent changes in gene expression could be shown by chromatin immunoprecipitation (ChIP) to be associated with permanent changes in the ability of MYC to bind to the promoter regions. Our list of candidate genes associated with tumor maintenance was further refined by comparing our analysis with other published results to generate a gene signature associated with MYC-induced tumorigenesis in mice. To validate the role of gene signatures associated with MYC in human tumorigenesis, we examined the expression of human homologs in 273 published human lymphoma microarray datasets in Affymetrix U133A format. One large functional group of these genes included the ribosomal structural proteins. In addition, we identified a group of genes involved in a diverse array of cellular functions including: BZW2, H2AFY, SFRS3, NAP1L1, NOLA2, UBE2D2, CCNG1, LIFR, FABP3, and EDG1. Hence, through our analysis of gene expression in murine tumor models and human lymphomas, we have identified a novel gene signature correlated with the ability of MYC to maintain tumorigenesis

Developmental context determines latency of MYC-induced tumorigenesis.

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

MYC-Induced Hepatic Tumors Are Invasive and Metastatic

<div><p>(A) Adult mouse with <i>MYC</i>-induced liver tumor that has metastasized to the abdomen and the lungs.</p> <p>(B) Histology of an adult <i>MYC</i>-induced lung metastasis.</p> <p>(C) Histology of an adult <i>MYC</i>-induced liver tumor.</p> <p>(D) Gross pathology of a liver tumor from a neonatal host transplanted subcutaneously into a <i>scid</i> mouse.</p></div

<i>MYC</i> Activation in Adult Hepatocytes Causes Cellular Hypertrophy

<div><p>(A) Relative volumes of neonatal hepatocytes and nuclei after <i>MYC</i> activation. Data are expressed as normalized volume plus or minus the standard error of the mean. The volume was normalized by dividing each measurement by the mean volume of normal 1-d-old neonatal mice. Three livers were measured per time point. T, tumor.</p> <p>(B) Neonatal liver weights of normal and <i>MY</i>C-activated livers. Three to five livers were weighed per time point. Data are expressed as the mean weight (grams) plus or minus the standard error of the mean.</p> <p>(C) Relative volumes of adult hepatocytes and nuclei after <i>MYC</i> activation. Volumes of cells are expressed as the mean volume divided by the mean volume of hepatocytes from normal mice plus or minus the standard error of the mean. Cells from two to three livers were measured per time point.</p> <p>(D) Adult liver weights after <i>MYC</i> activation. A total of nine livers were measured per time point after <i>MYC</i> activation. Data are expressed as the mean weight (grams) plus or minus the standard error of the mean.</p></div

<i>MYC</i> Activation in Adult Hepatocytes Induces Increased Cell Size

<p>A histogram obtained by FACS forward versus light scatter analysis of adult hepatocytes from normal FVB/N livers (green), doxycycline-treated transgenic livers (red), and livers in which the <i>MYC</i> transgene was overexpressed for 3 months (blue). The <i>x</i>-axis represents cell size and the <i>y</i>-axis represents cell count. Adult mice were matched for age.</p