Glioblastoma (GBM) remains the most pervasive and lethal of all brain malignancies. One factor that contributes to this poor prognosis is the highly invasive character of the tumor. GBM is characterized by microscopic infiltration of tumor cells throughout the 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 noninvasion-is mediated through the tumor extracellular matrix. Specifically, noninvasive lesions are associated with a rich matrix containing substantial amounts of glycosylated chondroitin sulfate proteoglycans (CSPGs), whereas glycosylated CSPGs are essentially absent from diffusely infiltrating tumors. CSPGs, acting as central organizers of the tumor microenvironment, dramatically influence resident reactive astrocytes, inducing their exodus from the tumor mass and the resultant encapsulation of noninvasive lesions. Additionally, CSPGs induce activation of tumor-associated microglia. We demonstrate that the astrogliotic capsule can directly inhibit tumor invasion, and its absence from GBM presents an environment favorable to diffuse infiltration. We also identify the leukocyte common antigen-related phosphatase receptor (PTPRF) as a putative intermediary between extracellular glycosylated CSPGs and noninvasive tumor cells. 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.

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

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

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