Periostin is a novel therapeutic target that predicts and regulates glioma malignancy

Periostin is a secreted matricellular protein critical for epithelial-mesenchymal transition and carcinoma metastasis. In glioblastoma, it is highly upregulated compared with normal brain, and existing reports indicate potential prognostic and functional importance in glioma. However, the clinical i...

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Published in:Neuro-oncology (Charlottesville, Va.) Va.), 2015-03, Vol.17 (3), p.372-382
Main Authors: Mikheev, Andrei M, Mikheeva, Svetlana A, Trister, Andrew D, Tokita, Mari J, Emerson, Samuel N, Parada, Carolina A, Born, Donald E, Carnemolla, Barbara, Frankel, Sam, Kim, Deok-Ho, Oxford, Rob G, Kosai, Yoshito, Tozer-Fink, Kathleen R, Manning, Thomas C, Silber, John R, Rostomily, Robert C
Format: Article
Language:English
Subjects:
Basic and Translational Investigations
Biomarkers, Tumor - metabolism
Brain Neoplasms - metabolism
Brain Neoplasms - mortality
Brain Neoplasms - pathology
Brain Neoplasms - prevention & control
Cell Adhesion
Cell Adhesion Molecules - antagonists & inhibitors
Cell Adhesion Molecules - metabolism
Cell Line, Tumor
Glioma - metabolism
Glioma - mortality
Glioma - pathology
Glioma - prevention & control
Humans
Integrins - metabolism
Kaplan-Meier Estimate
Neoplasm Grading
Neoplasm Invasiveness
Up-Regulation
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Summary:Periostin is a secreted matricellular protein critical for epithelial-mesenchymal transition and carcinoma metastasis. In glioblastoma, it is highly upregulated compared with normal brain, and existing reports indicate potential prognostic and functional importance in glioma. However, the clinical implications of periostin expression and function related to its therapeutic potential have not been fully explored. Periostin expression levels and patterns were examined in human glioma cells and tissues by quantitative real-time PCR and immunohistochemistry and correlated with glioma grade, type, recurrence, and survival. Functional assays determined the impact of altering periostin expression and function on cell invasion, migration, adhesion, and glioma stem cell activity and tumorigenicity. The prognostic and functional relevance of periostin and its associated genes were analyzed using the TCGA and REMBRANDT databases and paired recurrent glioma samples. Periostin expression levels correlated directly with tumor grade and recurrence, and inversely with survival, in all grades of adult human glioma. Stromal deposition of periostin was detected only in grade IV gliomas. Secreted periostin promoted glioma cell invasion and adhesion, and periostin knockdown markedly impaired survival of xenografted glioma stem cells. Interactions with αvβ3 and αvβ5 integrins promoted adhesion and migration, and periostin abrogated cytotoxicity of the αvβ3/β5 specific inhibitor cilengitide. Periostin-associated gene signatures, predominated by matrix and secreted proteins, corresponded to patient prognosis and functional motifs related to increased malignancy. Periostin is a robust marker of glioma malignancy and potential tumor recurrence. Abrogation of glioma stem cell tumorigenicity after periostin inhibition provides support for exploring the therapeutic impact of targeting periostin.
ISSN:1522-8517
1523-5866
DOI:10.1093/neuonc/nou161