IS THE RETINOBLASTOMA MINUS MOUSE A USEFUL GENETICALLY ENGINEERED MODEL TO STUDY PANCREATIC CANCER?

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Genetic alterations in the retinoblastoma tumor suppressor (RB) locus have been found to be present in pancreatic adenocarcinoma. The RB gene product has been previously associated with both proliferation and apoptosis of pancreatic cancer cells. In the current study, we evaluated the effect of RB inactivation on pancreatic cell growth in vivo and its accompanying molecular phenotype. Targeted RB inactivation (RB−/−) to the acinar cells results in malignant tumors that kill at an early age (6 months median survival). These tumors are characterized by a pseudoductular transdifferentiation that range from well to poorly differentiated. Both the rate of cell proliferation and apoptosis decrease in acinar cells that readily transdifferentiate into ductular-like populations, explaining at least in part why these animals never develop ductular adenocarcinoma. Unfortunately, with the exception of few proteins, the molecular machinery responsible for the long-term changes by which RB induces neoplastic transformation in both human and experimental models is not well understood. In this study we have used a combination of microarray gene profiling and bioinformatics-based pathway reconstruction modeling to better define these molecular events that participate in carcinogenesis by RB−/−. The molecular changes observed in the RB−/− pancreata show more similarities with expression profiles described in non-pancreatic cells carrying alterations in the RB pathways than those displayed by human pancreatic cancer. Interestingly, while both an increase in cell proliferation and apoptosis is observed at similar levels in RB−/− animals, only proliferation-associated genes are upregulated under these conditions. Thus, at the cellular level, our results demonstrate that apoptosis observed by RB deficiency is secondary to the growth-promoting effects of this protein. Therefore, these data show that the RB−/− mice can serve to model a limited number of biochemical events associated with the human pancreatic cancer phenotype. These results, obtained in a controlled genetic animal model of RB−/−, expand our understanding of how the molecular machinery that participates in carcinogenesis specifically induced by this pathway becomes altered during experimental pancreatic cancer. The highly expressed genes will provide new information on the RB pathway and its implications as well as they will give new targets for therapeutic strategies for pancreatic cancer. RU is supported by the Mayo Cancer Center and the National Institute of Health Grants DK52913 and CA102701.