Central nervous system hemangioblastomas in von Hippel-Lindau disease: Total growth rate and risk of developing new lesions not associated with circulating VEGF levels.

BACKGROUND: Hemangioblastomas of the central nervous system are a prominent feature of von Hippel-Lindau-disease (vHL). Hemangioblastomas are known to secrete vascular endothelial growth factor (VEGF), suggesting a potential role of VEGF as a biomarker for tumor growth. METHODS: Plasma VEGF samples from 24 patients with von Hippel-Lindau disease were analyzed by solid-phase proximity ligation assay (PLA). Levels were monitored over time together with numeric and volumetric CNS tumor burden, and compared to plasma VEGF levels in healthy controls. RESULTS: The mean yearly progression in tumor volume was 65.5%. Yearly risk of developing one or several new CNS tumor(s) was 50%. No significant correlation between tumor burden and levels of VEGF was seen. VEGF levels in patients (31.55-92.04; mean 55.83, median 56.41) as measured by immunodetection in a solid-phase PLA did not differ significantly from controls (37.38-104.56; mean 58.89, median 54.12) (p = 0,266). CONCLUSION: The increase in total CNS tumor volume in vHL occurred in a saltatory manner. The risk of developing a new lesion was 50% per year. We found no evidence for VEGF secretion from CNS hemangioblastomas in vHL in circulating blood. Other potential biomarkers should be explored to assess progression of tumor burden in vHL.

Leukocyte Differentiation by Histidine-Rich Glycoprotein/Stanniocalcin-2 Complex Regulates Murine Glioma Growth through Modulation of Antitumor Immunity.

The plasma-protein histidine-rich glycoprotein (HRG) is implicated in phenotypic switching of tumor-associated macrophages, regulating cytokine production and phagocytotic activity, thereby promoting vessel normalization and antitumor immune responses. To assess the therapeutic effect of HRG gene delivery on CNS tumors, we used adenovirus-encoded HRG to treat mouse intracranial GL261 glioma. Delivery of Ad5-HRG to the tumor site resulted in a significant reduction in glioma growth, associated with increased vessel perfusion and increased CD45+ leukocyte and CD8+ T-cell accumulation in the tumor. Antibody-mediated neutralization of colony-stimulating factor-1 suppressed the effects of HRG on CD45+ and CD8+ infiltration. Using a novel protein interaction-decoding technology, TRICEPS-based ligand receptor capture (LRC), we identified Stanniocalcin-2 (STC2) as an interacting partner of HRG on the surface of inflammatory cells in vitro and colocalization of HRG and STC2 in gliomas. HRG reduced the suppressive effects of STC2 on monocyte CD14+ differentiation and STC2-regulated immune response pathways. In consequence, Ad5-HRG-treated gliomas displayed decreased numbers of IL35+ Treg cells, providing a mechanistic rationale for the reduction in GL261 growth in response to Ad5-HRG delivery. We conclude that HRG suppresses glioma growth by modulating tumor inflammation through monocyte infiltration and differentiation. Moreover, HRG acts to balance the regulatory effects of its partner, STC2, on inflammation and innate and/or acquired immunity. HRG gene delivery therefore offers a potential therapeutic strategy to control antitumor immunity. Mol Cancer Ther; 17(9); 1961-72. ©2018 AACR.