Abstract 1639: Chondroitin sulfate proteoglycans potently inhibit invasion and serve as a central organizer of the brain tumor microenvironment.

Abstract

Despite tremendous effort, glioblastoma (GBM) remains the most pervasive and lethal of all brain malignancies. One factor that contributes to this exceedingly poor prognosis is the highly invasive character of the tumor. GBM is characterized by microscopic infiltration of tumor cells throughout the otherwise healthy brain, whereas non-neural metastases, as well as select lower-grade gliomas develop as self-contained and clearly delineated lesions. Illustrated by rodent xenograft tumor models as well as pathological human patient specimens, we present evidence that one fundamental switch between these two distinct pathologies - invasion and non-invasion - is mediated through the tumor extracellular matrix (ECM). Specifically, non-invasive lesions are associated with a rich matrix containing substantial amounts of glycosylated chondroitin sulfate proteoglycans (CSPGs), whereas glycosylated CSPGs are essentially absent from diffusely infiltrative tumors. CSPGs, acting as a central organizer of the tumor microenvironment, dramatically influence resident reactive astrocytes, inducing their exodus from the tumor mass and the resultant encapsulation of non-invasive lesions. Additionally, CSPGs induce activation of tumor-associated microglia. We demonstrate that the astrogliotic barrier can directly inhibit tumor invasion, and its absence from GBM presents an environment favorable to diffuse infiltration. We also identify the LAR phosphatase receptor as a putative intermediary between extracellular CSPGs and the tumor cells themselves. In all, we present CSPGs as critical regulators of brain tumor histopathology and help to clarify the role of the tumor microenvironment in brain tumor invasion. Citation Format: Daniel J. Silver, Florian A. Siebzehnrubl, Michela J. Schildts, Anthony T. Yachnis, George M. Smith, Amy A. Smith, Bjorn Scheffler, Brent A. Reynolds, Jerry Silver, Dennis A. Steindler. Chondroitin sulfate proteoglycans potently inhibit invasion and serve as a central organizer of the brain tumor microenvironment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1639. doi:10.1158/1538-7445.AM2013-1639