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

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.]

Abstract

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.

Footnotes

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵1 Supported in part by the United Kingdom Medical Research Council, Wessex Cancer Trust, Cancer Center (CORE) Support Grant CA 21765, American Lebanese Syrian Associated Charities (ALSAC), Academy of Finland, Sigrid Juselius Foundation, Turku University Central Hospital, University Foundation of Turku, and the Aurator Biomed Fund.
↵2 To whom requests for reprints should be addressed, at Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105. Phone: (901) 495-3913; Fax: (901) 495-2270; E-mail: Richard.Gilbertson{at}stjude.org
↵3 The abbreviations used are: RTK I, receptor tyrosine kinase type 1; LI, labeling index; MVP, microvascular proliferation; EGF, epidermal growth factor; EGFR, EGF receptor; IHC, immunohistochemical; FBS, fetal bovine serum; NRG, neuregulin; GFAP, glial fibrillary acidic protein; RT-PCR, reverse transcription-PCR.
↵4 T. T. Junttila et al., manuscript in preparation.
- Accepted June 18, 1902.
- Received March 11, 1902.
- Revision received June 5, 1902.