The present proposal is in response to PA -08-208, 'Pilot Studies in Pancreatic Cancer (R21)'which seeks to 'promote innovative research across multiple disciplines for a better understanding of the biology, etiology, detection, prevention and treatment of pancreatic cancer.'A major problem in pancreatic cancer research is the lack of clinically relevant animal models that can more faithfully replicate human disease. Here we propose to undertake a detailed characterization of a robust animal model for pancreatic islet cell cancer that we have serendipitously created as a result of cell-specifically deleting floxed Rb and p53 loci within the renin-expressing cell compartment of pancreas. Preliminary assessments suggest the model has the hallmarks of a metastatic islet cell carcinoma that expresses high levels of glucagon. It arises with high penetrance and, just like its human equivalent, exhibits profound metastatic spread to clinically relevant sites resulting in death by 4-5 months. We believe it is important to characterize and validate this model further as it exhibits unique features which will foster better understanding of pancreatic islet cell development, the role of the renin- angiotensin system therein, islet cell carcinogenesis, and the associated metastatic process. In the current proposal we will seek, for the first time, to identify the spatial-temporal windows of renin expression during pancreas ontogeny, utilizing transgenic reporter constructs and direct immunohistochemical assays for renin and pancreatic islet markers;characterize the initiation and progression of neoplasia of the primary tumor(s) in pancreas by monitoring histological features, hyperplasia, vascularization characteristics and the tumor expression profile(s), while monitoring noninvasively via MRI and serum analysis tumor growth, liver enzyme perturbations and relevant physiological parameters;and characterize the timing and spectrum of metastatic spread using histopathology. A preliminary assessment will be made by comparative genome hybridization (CGH) of lineal descendents of the renin-expressing cell as found in normal pancreatic islet cells, the stochastically arising primary tumors, and liver metastases with the aim of identifying potential genetic signatures associated with these processes. An organizing hypothesis linking the expression of renin to the specific islet cell neoplasia is put forth. Overall, these data will result in a newly characterized model of metastatic pancreas cancer that can be used for testing of novel therapeutics and will contribute to a more complete understanding of islet cell cancers.
While endocrine tumors of the pancreas are relatively rare there remains considerable interest in these entities because of the complexity of the tumor spectrum and the uncertain histogenesis underlying their specific origins. Unfortunately, representative animal models that enable a more thorough investigation of the etiology of the disease process are few. Because of the tremendous need for clinically relevant models of various pancreatic cancers, particularly ones that metastasize to clinically relevant locations, we believe it is important to characterize and validate this model further.
|Glenn, S T; Jones, C A; Sexton, S et al. (2014) Conditional deletion of p53 and Rb in the renin-expressing compartment of the pancreas leads to a highly penetrant metastatic pancreatic neuroendocrine carcinoma. Oncogene 33:5706-15|