Abstract 1432: Potent inhibition of brain tumor invasion by CSPG-rich tumor ECM

Abstract

Glioblastoma (GBM) is the most prevalent and lethal of all adult human brain cancers. Beyond its aggressive growth rate, the cause for this poor clinical prognosis is arguably the highly invasive character of the malignancy. Not a focal mass of cells, GBM is characterized by diffuse infiltration of the tumor throughout the otherwise healthy brain. Research into glioma invasion has been greatly limited by the paucity of genuine, pathologically accurate models of the disease. Counter intuitively; the majority of the classic animal models of GBM do not invade. Our laboratory has developed a library of novel GBM cell lines, that each demonstrates a remarkably invasive phenotype in vivo. When transplanted into the brains of immune-compromised mice, the resulting gliomas circumscribe blood vessels, invade within the sub-pial space, and demonstrate a strong preference for long-distance migration along myelinated fiber tracts. Here we present a comparison between “classic,” non-invasive and novel, diffusely infiltrative glioma models. The former, well-circumscribed, focal lesions are associated with a rich, chondroitin sulfate proteoglycan (CSPG)-containing, tumor extracellular matrix (ECM), whereas no detectable CSPGs are associated with the latter. Further, the presence of these highly sulfated ECM proteins within the non-invading tumor appear to act as the main organizers for a series of cellular interactions that ultimately define the non-invasive phenotype. Specifically, astrocyte retraction and microglial activation appear to be the hallmark cellular responses to a CSPG-rich, non-invading tumor mass. The situation for diffusely infiltrative brain tumors is entirely the opposite. Here, astrocytes are marginally more hypertrophic than their counterparts in non-tumor bearing regions of the brain, however they are not physically displaced by the tumor mass and tumor-associated microglia remain at their lowest, ramified state. In the future, it will be important to understand how the interactions between CSPG-rich, non-invading tumors and the surrounding “healthy” brain cells relate to tumor invasion. For instance, our data suggests that CSPGs alone are sufficient to induce the repulsion of astrocytes away from a non-invading tumor. However, it is unclear whether the sphere of displaced astrocytes or the CSPGs within the tumor act as the constraint against invasion. Chondroitinase digestion will help reveal the function of the CSPGs. The issue of microglial activation and its relationship to tumor invasion also remains unresolved. Lastly, we are interested in the idea of confining an otherwise diffusely infiltrating tumor. Can we build a wall, so to speak, around or within an otherwise invasive tumor by modulating the levels of CSPGs within the tumor microenvironment? Effectively, we seek to apply lessons learned from studying non-invading “glioma” models to genuine, infiltrative gliomas in the hopes of constraining GBM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1432. doi:10.1158/1538-7445.AM2011-1432