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Periostin is a novel therapeutic target that predicts and regulates glioma malignancy
Andrei M Mikheev1, Svetlana A Mikheeva1, Andrew D Trister1
1Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington (A.M.M., S.A.M, S.N.E., C.A.P., R.G.O., J.R.S., R.C.R.); Department of Radiation Oncology, University of Washington School of Medicine, Seattle, Washington (A.D.T.); Division of Medical Genetics, Department of Internal Medicine, University of Washington School of Medicine, Seattle, Washington (M.J.T); Department of Bioengineering, University of Washington School of Medicine, Seattle, Washington (S.F., D.-H.K.); Department of Radiology, University of Washington School of Medicine, Seattle, Washington (K.R.T.-F.); Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, Washington (A.M.M., S.A.M., S.F., D.-H.K., R.C.R.); Sage Bionetworks, Seattle, Washington (A.D.T.); Neuropathology Service, Department of Pathology, Stanford University School of Medicine, Stanford, California (D.E.B.); Laboratory of Immunology, IRCCS San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy (B.C.); Case Western Reserve School of Medicine, Cleveland, Ohio (Y.K.); Neuroscience Associates, Boise, Idaho (T.C.M.).
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
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