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


METHODS
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 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.


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.
Department of Otolaryngology-Head and Neck, University of Iowa, Iowa City, Iowa 52242, USA. marlan-hansen@uiowa.edu
Marlan R
MR
Hansen
J Jason
JJ
Clark
Bruce J
BJ
Gantz
Prabhat C
PC
Goswami
D017209:Apoptosis; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division; D004249:DNA Damage; D004428:Ear Neoplasms / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D020890:Neuregulin-1 / Q000494:pharmacology; D009464:Neuroma, Acoustic / Q000473:pathology* / Q000532:radiotherapy; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology* / Q000528:radiation effects*; D015398:Signal Transduction / Q000502:physiology / Q000528:radiation effects; D014407:Tumor Cells, Cultured / Q000528:radiation effects; D015837:Vestibular Diseases / Q000473:pathology* / Q000532:radiotherapy
D001973:Bromodeoxyuridine; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases