Effects of ErbB2 signaling on the response of vestibular schwannoma cells to gamma-irradiation

Marlan R Hansen; J Jason Clark; Bruce J Gantz; Prabhat C Goswami

doi:10.1097/MLG.0b013e318163f920

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Effects of ErbB2 signaling on the response of vestibular schwannoma cells to gamma-irradiation

Journal article

Peer reviewed

Effects of ErbB2 signaling on the response of vestibular schwannoma cells to gamma-irradiation

Marlan R Hansen, J Jason Clark, Bruce J Gantz and Prabhat C Goswami

The Laryngoscope, Vol.118(6), pp.1023-1030

06/2008

DOI: 10.1097/MLG.0b013e318163f920

PMID: 18520822

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Abstract

For vestibular schwannomas (VSs) that require treatment, options are limited to microsurgery or irradiation (IR). Development of alternative therapies that augment or replace microsurgery or IR would benefit patients not suitable for current therapies. This study explored the ability of ErbB2 inhibitors to modulate the effects of IR on VS cells. Prospective study using primary cultures derived from human VSs. Primary cultures of VS cells were derived from acutely resected tumors. Cultures received single escalating doses (15-40 Gy) of gamma-irradiation from a Cs gamma-irradiation source. Cell proliferation was determined by BrdU uptake and apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Trastuzumab (Herceptin) and PD158780 were independently used to inhibit ErbB2 signaling while neuregulin-1beta (NRG-1) was used to activate ErbB2. IR induces VS cell cycle arrest and apoptosis in doses greater than 20 Gy, demonstrating that VS cells are relatively radioresistant. This radioresistance likely arises from their low proliferative capacity as a sublethal dose of IR (10 Gy) strongly induces deoxyribonucleic acid (DNA) damage evidenced by histone H2AX phosphorylation. Inhibition of ErbB2, which decreases VS cell proliferation, protects VS cells from radiation-induced apoptosis, while NRG-1, an ErbB2 ligand and VS cell mitogen, increases radiation-induced VS cell apoptosis. Compared with many neoplastic conditions, VS cells are relatively radioresistant. The radio-protective effect of ErbB2 inhibitors implies that the sensitivity of VS cells to IR depends on their proliferative capacity. These results hold important implications for current and future treatment strategies.

Immunohistochemistry

Apoptosis

In Situ Nick-End Labeling

Vestibular Diseases - radiotherapy

Neuroma, Acoustic - radiotherapy

Ear Neoplasms - pathology

Prospective Studies

Humans

Neuregulin-1 - pharmacology

Receptor, ErbB-2 - physiology

Vestibular Diseases - pathology

Ear Neoplasms - radiotherapy

Cell Division

Receptor, ErbB-2 - radiation effects

Neuroma, Acoustic - pathology

Signal Transduction - physiology

Tumor Cells, Cultured - radiation effects

Receptor, ErbB-2 - antagonists & inhibitors

Bromodeoxyuridine - metabolism

DNA Damage

Signal Transduction - radiation effects

Details

Title: Subtitle: Effects of ErbB2 signaling on the response of vestibular schwannoma cells to gamma-irradiation
Creators: Marlan R Hansen - Department of Otolaryngology-Head and Neck, University of Iowa, Iowa City, Iowa 52242, USA. marlan-hansen@uiowa.edu
J Jason Clark
Bruce J Gantz
Prabhat C Goswami
Resource Type: Journal article
Publication Details: The Laryngoscope, Vol.118(6), pp.1023-1030
DOI: 10.1097/MLG.0b013e318163f920
PMID: 18520822
NLM abbreviation: Laryngoscope
eISSN: 1531-4995
Publisher: United States
Grant note: K08 DC006211 / NIDCD NIH HHS
Language: English
Date published: 06/2008
Academic Unit: Molecular Physiology and Biophysics; Radiation Oncology; Neurosurgery; Otolaryngology
Record Identifier: 9984006450902771

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