title: Tumor microenvironment tenascin-C promotes glioblastoma invasion and negatively regulates tumor proliferation.
abstract: BACKGROUND
  Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor in adults. Recent research on cancer stroma indicates that the brain microenvironment plays a substantial role in tumor malignancy and treatment responses to current antitumor therapy. In this work, we have investigated the effect of alterations in brain tumor extracellular matrix tenascin-C (TNC) on brain tumor growth patterns including proliferation and invasion.
  
  
  METHODS
  Since intracranial xenografts from patient-derived GBM neurospheres form highly invasive tumors that recapitulate the invasive features demonstrated in human patients diagnosed with GBM, we studied TNC gain-of-function and loss-of function in these GBM neurospheres in vitro and in vivo.
  
  
  RESULTS
  TNC loss-of-function promoted GBM neurosphere cell adhesion and actin cytoskeleton organization. Yet, TNC loss-of-function or exogenous TNC had no effect on GBM neurosphere cell growth in vitro. In animal models, decreased TNC in the tumor microenvironment was accompanied by decreased tumor invasion and increased tumor proliferation, suggesting that TNC regulates the "go-or-grow" phenotypic switch of glioma in vivo. We demonstrated that decreased TNC in the tumor microenvironment modulated behaviors of stromal cells including endothelial cells and microglia, resulting in enlarged tumor blood vessels and activated microglia in tumors. We further demonstrated that tumor cells with decreased TNC expression are sensitive to anti-proliferative treatment in vitro.
  
  
  CONCLUSIONS
  Our findings suggest that detailed understanding of how TNC in the tumor microenvironment influences tumor behavior and the interactions between tumor cells and surrounding nontumor cells will benefit novel combinatory antitumor strategies to treat malignant brain tumors.
authors: Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland (S.X., B.L., B.T., S.W., C.R.G., J.L.); Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland (S.X., B.L., C.R.G., J.L.); Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, Maryland (C.R.G., J.L.); Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland (J.L.).
authors: Shuli
authors: S
authors: Xia
authors: Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland (S.X., B.L., B.T., S.W., C.R.G., J.L.); Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland (S.X., B.L., C.R.G., J.L.); Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, Maryland (C.R.G., J.L.); Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland (J.L.).
authors: Bachchu
authors: B
authors: Lal
authors: Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland (S.X., B.L., B.T., S.W., C.R.G., J.L.); Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland (S.X., B.L., C.R.G., J.L.); Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, Maryland (C.R.G., J.L.); Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland (J.L.).
authors: Brian
authors: B
authors: Tung
authors: Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland (S.X., B.L., B.T., S.W., C.R.G., J.L.); Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland (S.X., B.L., C.R.G., J.L.); Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, Maryland (C.R.G., J.L.); Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland (J.L.).
authors: Shervin
authors: S
authors: Wang
authors: Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland (S.X., B.L., B.T., S.W., C.R.G., J.L.); Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland (S.X., B.L., C.R.G., J.L.); Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, Maryland (C.R.G., J.L.); Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland (J.L.).
authors: C Rory
authors: CR
authors: Goodwin
authors: Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland (S.X., B.L., B.T., S.W., C.R.G., J.L.); Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland (S.X., B.L., C.R.G., J.L.); Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, Maryland (C.R.G., J.L.); Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland (J.L.).
authors: John
authors: J
authors: Laterra
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011917:Rats, Inbred Lew; D019063:Tenascin / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D019063:Tenascin
keywords: TNC; glioblastoma; patient-derived GBM neurospheres; tumor microenvironment