Chondroitin Sulfate Proteoglycans Potently Inhibit Invasion and Serve as a Central Organizer of the Brain Tumor Microenvironment

Abstract

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.

Astrocytes promote glioma invasion via the gap junction protein connexin43

“…80 Indeed, astrocytes are well positioned to regulate tumor cell invasion and are believed to enhance the invasiveness of glioma cells through the action of paracrine factors, 81 such as matrix metalloproteases, 15,17 connective tissue growth factor 16 and chondroitin sulfate proteoglycans. 73 Here we demonstrate for the first time that the absence of a gap junction channel protein Cx43, normally upregulated in activated astrocytes, 19,20 reduces the ability of glioma cells to invade into the brain parenchyma. This is supported by our findings from two independent immunecompetent conditional knockout mouse lines in which Cx43 has been eliminated in the astrocytes.…”

“…19 Some evidence suggests that the glial scar acts as a barrier to constrain invasive tumor cells. 73 To determine whether there is a correlation between the extent of astrogliosis and glioma invasiveness, we examined the degree of gliosis by measuring the distance from the tumor periphery to a region of brain parenchyma with no detectable level of GFAP immunoreactivity. 19,74 Tumor-induced astrogliosis was significantly increased in Cx43-null mice (589.6 ± 57.0 μm; n = 9) when compared with wild-type mice (437.3 ± 29.5 μm; n = 9) (Figure 7a).…”

Stereotaxic administrations of allogeneic human Vγ9Vδ2 T cells efficiently control the development of human glioblastoma brain tumors

“…26 GBM-10 primary cells, isolated from a fresh biopsy and cultured in defined media maintain the cellular heterogeneity and especially the presence of CSC, 24 have been used for establishing new and robust human GBM xenograft mouse model. In contrary to U-87MG cell line triggering a compact and homogenous tumor mass, primary GBM-10 cells are highly infiltrative and exhibiting typical morphological features of human GBM, 27 representing new tools for establishing the next-generation animal models of human GBM tumors.…”

CD44-Mediated Adhesion to Hyaluronic Acid Contributes to Mechanosensing and Invasive Motility

“…This dire prognosis is in large part attributed to the aggressively invasive nature of glioma cells, which in turn has fueled interest in exploring new strategies for slowing invasion, including identifying and limiting interactions between tumor cells and pro-invasive components of the tumor extracellular matrix (ECM) (1). In addition to invading brain tissue along vascular structures, GBM tumors are characterized by a diffuse single-cell invasion pattern of glioma cells into brain parenchyma (2, 3), which contains ECM characteristically devoid of the fibrillar adhesive proteins found in connective tissue, but rich in HA (3, 4).…”