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Fowler Award Presentation: Effects of ErbB2 Signaling on the Response of Vestibular Schwannoma Cells to γ‐Irradiation
Author(s) -
Hansen Marlan R.,
Clark J Jason,
Gantz Bruce J.,
Goswami Prabhat C.
Publication year - 2008
Publication title -
the laryngoscope
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.181
H-Index - 148
eISSN - 1531-4995
pISSN - 0023-852X
DOI - 10.1097/mlg.0b013e318163f920
Subject(s) - radioresistance , apoptosis , tunel assay , terminal deoxynucleotidyl transferase , cancer research , dna damage , cell growth , cell cycle , biology , medicine , microbiology and biotechnology , radiation therapy , biochemistry , dna
Abstract Objective: 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. Study Design: Prospective study using primary cultures derived from human VSs. Methods: Primary cultures of VS cells were derived from acutely resected tumors. Cultures received single escalating doses (15–40 Gy) of γ‐irradiation from a 137 Cs γ‐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‐1β (NRG‐1) was used to activate ErbB2. Results: 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. Conclusions: 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.