In the last few years, animal models have been developed that more accurately recapitulate human cancer. Scott Lowe and his coworkers have developed a new animal model for hepatocellular carcinoma, the fifth most frequent neoplasm worldwide. Liver progenitor cells (stem cells) taken from one mouse can be transplanted into the liver of a second mouse and be reconstituted in the liver alongside host liver cells. Before transplantation, the stem cells can be genetically manipulated so that effects of different genes or combinations of genes on cancer development can be evaluated. If tumors arise, lesions derived from the transplanted cells can be examined to see what, if any, additional genetic changes occurred during the development of the tumor. Using this approach, the Lowe lab identified a region that was amplified in the resulting tumor.
In an independent series of experiments, Scott Powers had been looking at DNA from human liver tumors and found amplification of a human genomic region. Drs. Lowe and Powers compared the results in the mouse model to the human data and found they had identified homologous regions. This correlation suggested that the same genes may contribute to cancer in both mice and humans. Further analysis narrowed the candidate genes to cIAP and YAP. To confirm that these two genes were the ones responsible for cancer, liver progenitor cells were engineered to specifically overexpress CIAP and YAP. When transplanted into the mouse, liver tumors developed at a high frequency, confirming that cancer developed was accelerated when the cIAP and Yap were overexpressed.
This study demonstrated that novel animal models for cancer can be used to rapidly identify new cancer genes. Results in mice can be compared to human genomic data to confirm relevance to humans. And finally, once candidate genes are identified, the role of the candidate genes can be confirmed in the mouse models by reintroducing the specific genetic lesion. The types of studies can be used to identify potential targets for drug discovery as well as providing a means for testing efficacy of potential new therapies.
