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.2007 Aug 15;67(16):7589-96.
doi: 10.1158/0008-5472.CAN-07-0381.

Loss of p53 and Ink4a/Arf cooperate in a cell autonomous fashion to induce metastasis of hepatocellular carcinoma cells

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Loss of p53 and Ink4a/Arf cooperate in a cell autonomous fashion to induce metastasis of hepatocellular carcinoma cells

Ya-Wen Chen et al. Cancer Res..

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. HCC patients frequently present with disease that has metastasized to other regions of the liver, the portal vein, lymph nodes, or lungs, leading to poor prognoses. Therefore, model systems that allow exploration of the molecular mechanisms underlying metastasis in this disease are greatly needed. We describe here a metastatic HCC model generated after the somatic introduction of the mouse polyoma virus middle T antigen to mice with liver-specific deletion of the Trp53 tumor suppressor locus and show the cell autonomous effect of p53 loss of function on HCC metastasis. We additionally find that cholangiocarcinoma also develops in these mice, and some tumors display features of both HCC and cholangiocarcinoma, suggestive of origin from liver progenitor cells. Concomitant loss of the Ink4a/Arf tumor suppressor locus accelerates tumor formation and metastasis, suggesting potential roles for the p16 and p19 tumor suppressors in this process. Significantly, tumor cell lines isolated from tumors lacking both Trp53 and Ink4a/Arf display enhanced invasion activity in vitro relative to those lacking Trp53 alone. Thus, our data illustrate a new model system amenable for the analysis of HCC metastasis.

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Figures

Figure 1
Figure 1
(A) Histologic features of liver tumors induced by RCAS-PyMT inTrp53 null livers. Tumors with features of large cell dysplasia (left panel), hepatocellular carcinoma (center panel), and cholangiocarcinoma (right panel) are present. (B) Metastatic lung lesions derived from a hepatocellular carcinoma (left) and a cholangiocarcinoma (right). (C) Histology of a liver from an age-matched animal injected with RCAS-GFP.
Figure 2
Figure 2
(A) Reduced expression of E-cadherin and β-catenin in an HCC-derived lung metastasis (middle panels) and retention of E-cadherin and β-catenin expression in a CC-derived lung metastasis (bottom panels) relative to a primary HCC (top panels). (B) RT-PCR analysis of wild-type,Trp53 null, andTrp53 plusInk4a/Arf null primary liver tumors. Lanes 1-5,Trp53 null tumors; lane 6Trp53 null GFP-infected non-tumorous liver; lanes 7-11,Trp53 plusInk4a/Arf null tumors; lane 12,Trp53 plusInk4a/Arf null GFP-infected non-tumorous liver; lanes 15-17, wild-type tumors; lane 13,Trp53 plusInk4a/Arf null HCC cell line MM189; lane 14Trp53 null cell line BL185.
Figure 3
Figure 3
(A) Histologic findings in RCAS-PyMT injectedTrp53 plusInk4a/Arf null livers. Left panel - Hepatocellular carcinoma; 2nd panel - cholangiocarcinoma (arrow) growing adjacent to a hepatocellular carcinoma (asterisk); 3rd panel – aggressive cholangiocarcinoma (arrow) within a hepatocellular carcinoma; right panel – hepatocellular carcinoma cells with giant nuclei (arrowheads). (B) Metastatic lesions fromTrp53 plusInk4a/Arf null tumors found in the lung (left panel) and diaphragm (right panel). M denotes metastatic lesion, D denotes diaphragm. (C) Immunoblots demonstrating levels of phosphorylated and total Erk 1/2 and Akt inTrp53 null andTrp53 plusInk4a/Arf null liver tumors. T= tumor and N= normal liver.
Figure 4
Figure 4
(A) Immunostaining demonstrating expression of PyMT and the epithelial marker keratin 8 in cell lines derived from PyMT-induced liver tumors. Mouse embryo fibroblasts (MEFs) are used as a negative control. (B) RT-PCR analysis for TVA and p16/19 in the HCC cell lines. β-actin serves as a control. Measurement of the proliferation (performed in quadruplicate) (C), and soft agar colony formation potential (performed in triplicate) (D) of these cell lines. Data are from representative experiments. Error bars represent standard deviation.
Figure 5
Figure 5
(A) Measurement of the migration (blue) and invasion (red) capabilities of the BL185 and MM189 cell lines (left panel). Error is standard deviation from the mean. The number of invading cells is plotted as a percentage of the number of migrating cells (right panel). (B) Migration and invasion activity of MM189 cells in response to increasing concentrations of the mTOR antagonist rapamycin (left panel). Error is standard deviation from the mean. The number of invading cells is plotted as a percentage of the number of migrating cells (right panel). (C) H&E stained images of lung lesions induced after tail vein injection of the BL185 (left panel) and MM189 (right panel) cell lines. (D) Quantification of lung colony formation in the tail vein injection assay. * p<0.001. Error bars are standard error of the mean.
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