Tumor microenvironment tenascin-C promotes glioblastoma invasion and negatively regulates tumor proliferation

Shuli Xia, Bachchu Lal, Brian Tung, Shervin Wang, C. Rory Goodwin, John Laterra

Research output: Contribution to journalArticle

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. Conclusion. 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.

Original languageEnglish (US)
Pages (from-to)507-517
Number of pages11
JournalNeuro-Oncology
Volume18
Issue number4
DOIs
StatePublished - Apr 1 2016

Fingerprint

Tenascin
Tumor Microenvironment
Glioblastoma
Neoplasms
Brain Neoplasms
In Vitro Techniques
Microglia
Vascular Tissue Neoplasms
Stromal Cells
Actin Cytoskeleton
Heterografts
Cell Adhesion
Glioma
Extracellular Matrix
Endothelial Cells
Brain

Keywords

  • glioblastoma
  • patient-derived GBM neurospheres
  • TNC
  • tumor microenvironment

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Cite this

Tumor microenvironment tenascin-C promotes glioblastoma invasion and negatively regulates tumor proliferation. / Xia, Shuli; Lal, Bachchu; Tung, Brian; Wang, Shervin; Goodwin, C. Rory; Laterra, John.

In: Neuro-Oncology, Vol. 18, No. 4, 01.04.2016, p. 507-517.

Research output: Contribution to journalArticle

Xia, Shuli; Lal, Bachchu; Tung, Brian; Wang, Shervin; Goodwin, C. Rory; Laterra, John / Tumor microenvironment tenascin-C promotes glioblastoma invasion and negatively regulates tumor proliferation.

In: Neuro-Oncology, Vol. 18, No. 4, 01.04.2016, p. 507-517.

Research output: Contribution to journalArticle

@article{69948d0f629c4f8888d0b802de30c55b,
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. Conclusion. 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.",
keywords = "glioblastoma, patient-derived GBM neurospheres, TNC, tumor microenvironment",
author = "Shuli Xia and Bachchu Lal and Brian Tung and Shervin Wang and Goodwin, {C. Rory} and John Laterra",
year = "2016",
month = "4",
doi = "10.1093/neuonc/nov171",
volume = "18",
pages = "507--517",
journal = "Neuro-Oncology",
issn = "1522-8517",
publisher = "Oxford University Press",
number = "4",

}

TY - JOUR

T1 - Tumor microenvironment tenascin-C promotes glioblastoma invasion and negatively regulates tumor proliferation

AU - Xia,Shuli

AU - Lal,Bachchu

AU - Tung,Brian

AU - Wang,Shervin

AU - Goodwin,C. Rory

AU - Laterra,John

PY - 2016/4/1

Y1 - 2016/4/1

N2 - 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. Conclusion. 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.

AB - 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. Conclusion. 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.

KW - glioblastoma

KW - patient-derived GBM neurospheres

KW - TNC

KW - tumor microenvironment

UR - http://www.scopus.com/inward/record.url?scp=84966642201&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84966642201&partnerID=8YFLogxK

U2 - 10.1093/neuonc/nov171

DO - 10.1093/neuonc/nov171

M3 - Article

VL - 18

SP - 507

EP - 517

JO - Neuro-Oncology

T2 - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

IS - 4

ER -