Multiple endocrine neoplasia type 1 (MEN1) is an autosomal syndrome caused by mutations in the MEN1 tumor suppressor gene. While the protein product of MEN1, menin, is ubiquitously expressed, somatic loss of the remaining wildtype MEN1 allele results in tumors primarily in parathyroid, pituitary, and endocrine pancreas. To understand the endocrine specificity of the MEN1 syndrome, we evaluated biallelic loss of Men1 by inactivating Men1 in pancreatic progenitor cells utilizing the Cre-lox system. Men1 deletion in progenitor cells that differentiate into exocrine and endocrine pancreas did not affect normal pancreas morphogenesis and development. However, mice having homozygous inactivation of the Men1 in pancreas developed endocrine tumors with no exocrine tumor manifestation, recapitulating phenotypes seen in the MEN1 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 upregulation in VEGF expression in both human and mouse MEN1 pancreatic endocrine tumors. Together these data suggest the presence of cell-specific factors for menin and a permissive endocrine environment for MEN1 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 MEN1 syndrome.
Since their initial description in 1857, gold nanoparticles have been used extensively in the fields of diagnostics and therapeutics. Now, gold nanoparticles are engineered to target the delivery of potent anti-cancer therapeutics to solid tumors to improve either their safety or efficacy or both. Described in this chapter is the development of one such nanotherapeutic, termed CYT-6091, that targets the delivery of tumor necrosis factor alpha (TNF) to solid tumors. Outlined in the presentation is a discussion of nanoparticles and specifically colloidal gold, an historical review on the biology of TNF and its limited use in the clinic when administered systemically, and finally, how gold nanoparticles bound with TNF may improve the safety and efficacy profiles of TNF.
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