Obesity-Linked Mouse Models of Liver Cancer
Jimmy Stauffer, Ph.D., and colleagues working with Robert Wiltrout, Ph.D., in CCR’s Cancer and Inflammation Program, along with collaborators in the Laboratory of Human Carcinogenesis, have developed a novel mouse model that demonstrates how fat-producing phenotypes can influence the development of hepatic cancer. The team recently reported their findings in Cancer Research.
Starting with several oncoproteins and signaling pathways frequently dysregulated in cancer—namely, MET, beta-catenin (CAT), and AKT—the team used transposon technology to codeliver combinations of these mutated genes to mouse livers to see if they could trigger the growth of liver tumors. Both AKT/CAT and MET/CAT combinations induced microscopic tumors by 4 weeks; whereas, no tumors resulted when AKT, MET, or CAT genes were delivered alone.
Primary AKT/CAT-driven tumor cells began as fatty hepatocellular adenomas that progressed to hepatocellular carcinomas (HCC) upon in vivo passage. By contrast, primary MET/CAT-driven tumors began as, and remained, hepatocellular carcinomas.
The conversion of AKT/CAT-driven tumor cells to HCC during passage was associated with induction of a biomarker called a-fetoprotein and the stem cell marker CD133, both of which are also present in human hepatic cancers.
Using hierarchical clustering and gene set enrichment analysis, they compared the
primary mouse AKT/CAT- and MET/CAT-driven tumors to a panel of 53 human HCCs and determined that these two mouse models could be considered two distinct subtypes, and both are associated with a poor clinical prognosis.
The chief molecular networks identified in primary and passaged AKT/CAT tumors were fat producing and metabolizing pathways, respectively. Since obesity’s ability to promote tumorigenesis has been molecularly linked to pathways activated by inflammatory cytokines, these new obesity-linked mouse models of HCCs should help unravel how precancerous hepatic cells perceive inflammatory mediators as tumorigenic growth signals. Such discoveries might even suggest new interventions for hepatocellular carcinomas.
By making additional genetic modifications, Stauffer and his colleagues can use their novel mouse models of hepatic cancer to discover the microenvironmental factors responsible for the malignant progression of liver adenomas into carcinomas.
Summary Posted: 6/2011
Reviewed by Donna Kerrigan
- Understanding Papillary Renal Cell Carcinoma
- Insight into Prostate Cancer Stem Cells
- Naïve-Derived T Cell Adoptive Immunotherapy is Impaired by Memory T Cells
- Identifying Stem-like Cells Using Mitochondrial Membrane Potential
- Noncoding RNA Shows Context-Dependent Function
- T Cells that Recognize HPV Protein Can Target Virus-Infected Cells
- Pancreatic Cancer Sensitive to Selective p38 Pathway Inhibition
- Mutations Allow JC Polyomaviruses to Elude Antibody Recognition
- Mitochondrial DNA Unwinding Enzyme Required for Liver Regeneration
- Regulatory RNA Key Player in p53-Mediated Apoptosis in Embryonic Stem Cells
- New Method for Producing Significant Amounts of RNA Labeled at Specific Sites
- Mutant HABP2 Causes Non-Medullary Thyroid Cancer
- Paradigm Shift in Thyroid Hormone Mechanism of Action
- Changes in Bacteria Induce Inflammatory Skin Diseases