This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gilbertson, R. J. Articles by Ellison, D. W. Search for Related Content PubMed PubMed Citation Articles by Gilbertson, R. J. Articles by Ellison, D. W.

ERBB Receptor Signaling Promotes Ependymoma Cell Proliferation and Represents a Potential Novel Therapeutic Target for This Disease¹

Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105 [R. J. G., L. B., R. H., A. J. F., M. C., C. W., T. C.]; MediCity Research Laboratories and Department of Medical Biochemistry and Molecular Biology [T. T. J., K. E.] and Turku Graduate School of Biomedical Sciences [T. T. J.], University of Turku, FIN-20520 Turku, Finland; Department of Pathology, Tampere University Hospital, FIN-33521 Tampere, Finland [H. H.]; Northern Institute for Cancer Research, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom [D. W. E.]; and Department of Neuropathology, Newcastle General Hospital, Newcastle Upon Tyne NE4 6BE, United Kingdom [D. W. E.]

Purpose: This study was designed to investigate the biological and therapeutic significance of ERBB1, ERBB2, ERBB3, and ERBB4 in childhood ependymoma.

Experimental Design: The expression frequency and clinical significance of ERBB1–4 was analyzed in a large cohort of pediatric ependymoma (n = 121) using immunohistochemistry, Western blotting, and reverse transcription-PCR analysis. Histological markers of anaplasia (necrosis, microvascular proliferation, and Ki-67 proliferative index) were also determined. Functional assessment of ERBB-dependent cell signaling and proliferation, in addition to novel therapeutic inhibition of these processes, was conducted using short-term cultures of human ependymoma cells.

Results: Coexpression of ERBB2 and ERBB4 was identified in over 75% of tumors. High-level coexpression of these receptors was significantly related to tumor proliferative activity [P < 0.05; Ki-67 labeling index (LI)] and, in combined survival analysis of clinical (degree of surgical resection) and molecular (ERBB2/ERBB4 expression status and Ki-67 LI) factors, enabled a greater resolution of patient prognosis than any individual variable alone. Ligand-dependent activation of ERBB receptor-signaling in cultured ependymoma cells resulted in AKT phosphorylation and cellular proliferation that was significantly blocked in a dose-dependent manner using WAY-177820, a novel inhibitor of ERBB2 tyrosine kinase activity.

Conclusions: This study suggests that ERBB receptor signaling results in aggressive disease behavior in ependymoma by promoting tumor cell proliferation. An analysis of ERBB2 and ERBB4 expression, in association with Ki-67 LI and the degree of surgical resection, may provide an accurate tool for assessing disease risk in children with this disease. In addition, these receptors may serve as a target for novel therapeutic approaches in ependymoma.

This article has been cited by other articles:

				P. Modena, E. Lualdi, F. Facchinetti, J. Veltman, J. F. Reid, S. Minardi, I. Janssen, F. Giangaspero, M. Forni, G. Finocchiaro, et al. Identification of Tumor-Specific Molecular Signatures in Intracranial Ependymoma and Association With Clinical Characteristics J. Clin. Oncol., November 20, 2006; 24(33): 5223 - 5233. [Abstract] [Full Text] [PDF]

				U. Tabori, J. Ma, M. Carter, M. Zielenska, J. Rutka, E. Bouffet, U. Bartels, D. Malkin, and C. Hawkins Human Telomere Reverse Transcriptase Expression Predicts Progression and Survival in Pediatric Intracranial Ependymoma J. Clin. Oncol., April 1, 2006; 24(10): 1522 - 1528. [Abstract] [Full Text] [PDF]

				F. Mendrzyk, A. Korshunov, A. Benner, G. Toedt, S. Pfister, B. Radlwimmer, and P. Lichter Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markers in intracranial ependymoma. Clin. Cancer Res., April 1, 2006; 12(7): 2070 - 2079. [Abstract] [Full Text] [PDF]

				J. A. Maatta, M. Sundvall, T. T. Junttila, L. Peri, V. J. O. Laine, J. Isola, M. Egeblad, and K. Elenius Proteolytic Cleavage and Phosphorylation of a Tumor-associated ErbB4 Isoform Promote Ligand-independent Survival and Cancer Cell Growth Mol. Biol. Cell, January 1, 2006; 17(1): 67 - 79. [Abstract] [Full Text] [PDF]

				R. Ho, J. E. Minturn, T. Hishiki, H. Zhao, Q. Wang, A. Cnaan, J. Maris, A. E. Evans, and G. M. Brodeur Proliferation of Human Neuroblastomas Mediated by the Epidermal Growth Factor Receptor Cancer Res., November 1, 2005; 65(21): 9868 - 9875. [Abstract] [Full Text] [PDF]

				R. J. Gilbertson ERBB2 in Pediatric Cancer: Innocent Until Proven Guilty Oncologist, August 1, 2005; 10(7): 508 - 517. [Abstract] [Full Text] [PDF]

				B. Suarez-Merino, M. Hubank, T. Revesz, W. Harkness, R. Hayward, D. Thompson, J. L. Darling, D. G.T. Thomas, and T. J. Warr Microarray analysis of pediatric ependymoma identifies a cluster of 112 candidate genes including four transcripts at 22q12.1-q13.3 Neuro-oncol, January 1, 2005; 7(1): 20 - 31. [Abstract] [PDF]

				O. Cooper and O. Isacson Intrastriatal Transforming Growth Factor {alpha} Delivery to a Model of Parkinson's Disease Induces Proliferation and Migration of Endogenous Adult Neural Progenitor Cells without Differentiation into Dopaminergic Neurons J. Neurosci., October 13, 2004; 24(41): 8924 - 8931. [Abstract] [Full Text] [PDF]

				A. Gajjar, R. Hernan, M. Kocak, C. Fuller, Y. Lee, P. J. McKinnon, D. Wallace, C. Lau, M. Chintagumpala, D. M. Ashley, et al. Clinical, Histopathologic, and Molecular Markers of Prognosis: Toward a New Disease Risk Stratification System for Medulloblastoma J. Clin. Oncol., March 15, 2004; 22(6): 984 - 993. [Abstract] [Full Text] [PDF]

				T. T. Junttila, M. Laato, T. Vahlberg, K.-O. Soderstrom, T. Visakorpi, J. Isola, and K. Elenius Identification of Patients with Transitional Cell Carcinoma of the Bladder Overexpressing ErbB2, ErbB3, or Specific ErbB4 Isoforms: Real-Time Reverse Transcription-PCR Analysis in Estimation of ErbB Receptor Status from Cancer Patients Clin. Cancer Res., November 1, 2003; 9(14): 5346 - 5357. [Abstract] [Full Text] [PDF]

				C. Calabrese, A. Frank, K. Maclean, and R. Gilbertson Medulloblastoma Sensitivity to 17-Allylamino-17-demethoxygeldanamycin Requires MEK/ERK J. Biol. Chem., July 4, 2003; 278(27): 24951 - 24959. [Abstract] [Full Text] [PDF]