Constitutive neuregulin-1/ErbB signaling contributes to human vestibular schwannoma proliferation.
Vestibular schwannomas (VSs) are benign tumors that arise from the Schwann cells (SCs) lining the vestibular nerve. VS cells survive and proliferate far from neurons and axonally derived growth factors. We have previously shown that VSs produce the glial growth factor, neuregulin-1 (NRG1), and its receptors, ErbB2 and ErbB3. In the present work, we explore the contribution of constitutive NRG1:ErbB signaling to human VS cell proliferation. We confirm that human VSs, which express markers of immature and denervated SCs, also express endogenous NRG1 and activated ErbB2. We find that a blocking anti-NRG1 antibody and trastuzumab (Herceptin, HCN), a humanized anti-ErbB2 inhibitory monoclonal antibody, effectively inhibit NRG1 induced SC proliferation. Treatment of primary VS cultures with anti-NRG1 or HCN reduces cell proliferation in the absence of exogenous NRG1. Furthermore, conditioned medium from VS cell cultures contains NRG1 and stimulates SC proliferation in SC cultures, an effect that is inhibited by anti-NRG1 and HCN. These data suggest an autocrine pathway of VS growth stimulation involving NRG and ErbB receptors. Inhibition of constitutive NRG:ErbB signaling reduces VS cell proliferation in vitro and may have therapeutic potential for patients with VSs.
Hansen
Marlan R
MR
Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, 52242, USA. marlan-hansen@uiowa.edu
Roehm
Pamela C
PC
Chatterjee
Papri
P
Green
Steven H
SH
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D020890:Neuregulin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009464:Neuroma, Acoustic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018739:Oncogene Proteins v-erbB / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D014725:Vestibular Nerve / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
D000906:Antibodies; D015415:Biomarkers; D017077:Culture Media, Conditioned; D006023:Glycoproteins; D020890:Neuregulin-1; D018739:Oncogene Proteins v-erbB; D018719:Erb-b2 Receptor Tyrosine Kinases; C483804:Erbb2 protein, rat