Chondroitin sulfate proteoglycans potently inhibit invasion and serve as a central organizer of the brain tumor microenvironment.
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.
Department of Neurological Surgery, University of Florida, Gainesville, Florida 32611, Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida 32610, Department of Neuroscience, Temple University, Philadelphia, Pennsylvania 19140, Arnold Palmer Hospital for Children, MD Anderson Cancer Center, Orlando, Florida 32806, Institute of Reconstructive Neurobiology, University of Bonn Medical Center, D-53105 Bonn, Germany, and Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106.
Daniel J
DJ
Silver
Florian A
FA
Siebzehnrubl
Michela J
MJ
Schildts
Anthony T
AT
Yachnis
George M
GM
Smith
Amy A
AA
Smith
Bjorn
B
Scheffler
Brent A
BA
Reynolds
Jerry
J
Silver
Dennis A
DA
Steindler
D000328:Adult; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D002648:Child; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006031:Glycosylation; D006801:Humans; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000378:metabolism; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
D011508:Chondroitin Sulfate Proteoglycans; C516772:PTPRF protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2