Recapitulation of pancreatic neuroendocrine tumors in human multiple endocrine neoplasia type I syndrome via Pdx1-directed inactivation of men 1

Multiple endocrine neoplasia type 1 (MENl) is an autosomal syndrome caused by mutations in the MENl tumor suppressor gene. Whereas the protein product of MENl, menin, is ubiquitously expressed, somatic loss of the remaining wild-type MENl allele results in tumors primarily in parathyroid, pituitary, and endocrine pancreas. To understand the endo-crine specificity of the MENl syndrome, we evaluated biallelic loss of Menl by inactivating Menl in pancreatic progenitor cells using the Cre-lox system. Menl deletion in progenitor cells that differentiate into exocrine and endocrine pancreas did not affect normal pancreas morphogenesis and develop-ment. However, mice having homozygous inactivation of the Menl in pancreas developed endocrine tumors with no exocrine tumor manifestation, recapitulating phenotypes seen in the MENl patients. In the absence of menin, the endocrine pancreas showed increase in cell proliferation, vascularity, and abnormal vascular structures; such changes were lacking in exocrine pancreas. Further analysis revealed that these endocrine manifestations were associated with up-regulation in vascular endothelial growth factor expression in both human and mouse MENl pancreatic endocrine tumors. Together, these data suggest the presence of cell-specific factors for menin and a permissive endocrine environment for MENl tumorigenesis in endocrine pancreas. Based on our analysis, we propose that menin's ability to maintain cellular and microenvironment integrity might explain the endocrine-restrictive nature of the MENl syndrome.