Characterization And Pathogenesis Analysis Of Islet Cell Tumor In A Transgenic Mouse Model

Neuroendocrine neoplasms arising primarily from the pancreatic islets of Langerhans (also named islet cell tumors) are quite rare. Because of its complex clinical symptoms, the early diagnostic routine is still not available. Previous study has seldom reported that the early diagnosis and therapy of islet cell tumors, meanwhile the molecular mechanism has not been clearly defined.SV40 belongs to polyomavirus and epidemiology shows that the character of its tumorigenesis is mostly related to T antigen-early proten. Some rodent models injected with SV40Tag would develop primary pancreatic cancer, bone sarcoma, urinary bladder carcinoma and liver cancer.Linearized pTRE-SV40Tag DNA and pTet-on were co-microinjected into the male pronucleus of fertilized zygotes of FVB mice. Founder (GO) mice were identified by PCR and Southern blotting analysis. It has been investigated that SV40Tag was only expressed in brain and pancreas of double transgenic mice with exposing them to doxycycline (Dox) supplied as drinking water but not other organs. We also observed that SV40Tag was also expressed in pancreas of double transgenic mice without Dox. Most double transgenic mice were limply, belly-bulge and peaky as early as 20 weeks age. The diagnosis of the islet cell tumors was made by traditional secretin test. The blood glucose levels of these mice were measured for the early diagnosis. All mice tested were found to suffer from hypoglycemia. The tumors were found to be present in the pancreas in majority of the mice.In our study, we have generated a pTet-on/pTRE-SV40Tag double transgenic mice model of islet cell tumor. The pathological and immunohistochemical characterization further confirmed the tumors observed in the transgenic mice being islet cell tumors. We applied real-time PCR and Western blotting and Immunoprecipitation experiments to study the gene expression change in the islet cell tumors. Our results demonstrated that the expression levels of genes in IGFs/IGF-1R signaling pathway was altered significantly. In summary, a line of double transgenic mice that developed neoplasms arising primarily from the pancreas has been established. The transgenic animal model reported herein might have important implication in understanding the molecular mechanism, and hereby in helping the development of the clinical diagnosis of the disease.