A dynamic switch in Rb+/- mediated neuroendocrine tumorigenesis.

Rb+/- mice develop a complex spectrum of neuroendocrine tumors on a mixed genetic (129Sv x C57BL/6) background. To understand how the 129Sv and C57BL/6 contributions affect Rb+/- tumorigenesis, we serially backcrossed Rb+/- animals to the 129Sv or C57BL/6 strain, and analysed their pathological profiles. Strikingly, the length of survival and the penetrance, severity and multiplicity of neuroendocrine tumors switch dramatically between Rb+/- animals from the two genetic backgrounds. In fact, the 129Sv background significantly enhances both the initiation and progression of tumorigenesis in the intermediate lobe of the pituitary (ILP) in Rb+/- animals. This is due to the surprising fact that ILPs from wild-type 129Sv animals are inherently abnormal, and thus greatly predisposed to neoplasia. This is likely to explain the high incidence of ILP tumors, an otherwise rare tumor type in wild-type mice, in numerous knockout studies performed on the 129Sv strain, and raises the intriguing possibility that the classic Rb+/- neuroendocrine tumors may fade away in another as of yet unidentified inbred strain. Finally, we have increased the utility of the Rb+/- tumor model, since Rb+/- animals on the C57BL/6 background develop high-penetrance tumors of the anterior lobe of the pituitary, a class of tumors estimated to occur in 20-25% of humans.