CB-12LIPID DROPLET ACCUMULATION IN VON HIPPEL-LINDAU CNS HEMANGIOBLASTOMAS IS A MANIFESTATION OF HIF OVEREXPRESSION

摘要

CNS hemangioblastomas (HBs) are a major manifestation of the Von Hippel-Lindau (VHL) inherited tumor syndrome. Loss of functional VHL protein results in constitutive upregulation of hypoxia-inducible factor (HIF) and its downstream targets (e.g. VEGF) in affected cell types. The HB tumor cell exhibits a characteristic histologic lipid-laden "foamy" appearance, the biological basis of which has not been examined. Lipid accumulation in cells is an organized process and involves specific proteins that assist in assembling newly synthesized lipids into protein-covered droplets. The most studied lipid droplet proteins belong to the PAT family, named for the first three members: perilipin, adipose differentiation-related protein, and 47-kDa tail-interacting protein, now referred to as perilipin (PLIN) 1, 2, and 3, respectively. Of these, only PLIN2 is a HIF target gene, consistent with our observation that PLIN2 in glioblastoma occurs only focally in perinecrotic/hypoxic areas. We hypothesized that PLIN2 would be strongly upregulated in HB tumor cells. Twenty-two VHL-associated hemangioblastomas were examined immunohistochemically for PLIN1, -2, and -3. PLIN1 was absent and PLIN3 was observed only occasionally in small focal patches. However, all 22 HBs stained positively and robustly for PLIN2, which clearly outlined the lipid droplets in almost all HB tumor cells. In many cases, these droplets had enlarged and appeared to occupy the entire cytoplasm of the tumor cell. Double immunofluorescence indicated PLIN2 presence in the tumor/stromal, but not endothelial, cell compartment of HBs, another observation consistent with PLIN2 upregulation via HIF. The widespread, intense, and selective expression of PLIN2 in HBs suggests that HIF, via PLIN2 overexpression, promotes the extensive lipid droplet accumulation characteristic of these tumors. The extent to which this distinctive upregulation of PLIN2 has ramifications for understanding the biology of these tumors, or might be exploited for diagnostic or therapeutic purposes, remains to be determined.