ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor
In this work, we have analyzed the expression of different members of the ErbB family in human samples of testicular germ cell tumors (GCTs). We observed expression of ErbB1 or ErbB2 in different tumor subtypes, but we also found high expression of ErbB3 in all GCTs tested. This pattern of expressio...
| Autores: | , , , , , , , , , , , , , |
|---|---|
| Formato: | artículo |
| Estado: | Versión aceptada para publicación |
| Fecha de publicación: | 2013 |
| País: | España |
| Recursos: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2445/120253 |
| Acesso em linha: | https://hdl.handle.net/2445/120253 |
| Access Level: | acceso abierto |
| Palavra-chave: | Receptors cel·lulars Medicaments antineoplàstics Malalties del testicle Tumors Càncer Cell receptors Antineoplastic agents Testis diseases Cancer |
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ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumorJuliachs Milà, MercèCastillo-Ávila, WilmarVidal-Bel, AugustPiulats, Josep M.García del Muro Solans, XavierCondom i Mundó, EnricHernández-Losa, JavierTeixidó, C.Pandiella, AtanasioGraupera i Garcia-Milà, MarionaCasanovas i Casanovas, OriolGermà Lluch, José RamónVillanueva Garatachea, AlbertoViñals Canals, FrancescReceptors cel·lularsMedicaments antineoplàsticsMalalties del testicleTumorsCàncerCell receptorsAntineoplastic agentsTestis diseasesTumorsCancerIn this work, we have analyzed the expression of different members of the ErbB family in human samples of testicular germ cell tumors (GCTs). We observed expression of ErbB1 or ErbB2 in different tumor subtypes, but we also found high expression of ErbB3 in all GCTs tested. This pattern of expression was maintained when primary tumors were orthotopically implanted in nude mice. We have chosen a choriocarcinoma model characterized by high levels of ErbB1, but also of ErbB2 and ErbB3, to assay the in vivo effect of ErbB inhibitors on tumoral growth. Our results showed a complete lack of effect (refractoriness) to the pure ErbB1 receptor inhibitors cetuximab and gefitinib. While these inhibitors blocked ErbB1 phosphorylation, ErbB2 phosphorylation was not affected, suggesting an ErbB1-independent activation of this receptor. To confirm the importance of ErbB2 activation, animals were treated with lapatinib, a dual ErbB1 and ErbB2 inhibitor. Lapatinib treatment caused a 50% inhibition in tumor growth, an effect correlated with a blockade of both ErbB1 and ErbB2 phosphorylation levels, and of downstream signaling pathways (Akt, ERKs and Stat3). ErbB2 activation could still occur due to the formation of ErbB2/ErbB3 heterodimers, and ErbB3 activation was completely inhibited by lapatinib. Finally, combined inhibition of ErbB1 (gefitinib) and ErbB3 activities (knockdown expression by shRNA) inhibited tumoral testicular cells proliferation in a similar way to lapatinib. Our results explain why lapatinib but not anti-ErbB1 agents might be effective for treatment of testicular GCT patients.Wiley2018201820132018info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion12 p.application/pdfhttps://hdl.handle.net/2445/120253Articles publicats en revistes (Ciències Fisiològiques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1002/ijc.28009International Journal of Cancer, 2013, vol. 133, num. 1, p. 235-246https://doi.org/10.1002/ijc.28009(c) Union for International Cancer Control (UICC), 2013info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1202532026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor |
| title |
ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor |
| spellingShingle |
ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor Juliachs Milà, Mercè Receptors cel·lulars Medicaments antineoplàstics Malalties del testicle Tumors Càncer Cell receptors Antineoplastic agents Testis diseases Tumors Cancer |
| title_short |
ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor |
| title_full |
ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor |
| title_fullStr |
ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor |
| title_full_unstemmed |
ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor |
| title_sort |
ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor |
| dc.creator.none.fl_str_mv |
Juliachs Milà, Mercè Castillo-Ávila, Wilmar Vidal-Bel, August Piulats, Josep M. García del Muro Solans, Xavier Condom i Mundó, Enric Hernández-Losa, Javier Teixidó, C. Pandiella, Atanasio Graupera i Garcia-Milà, Mariona Casanovas i Casanovas, Oriol Germà Lluch, José Ramón Villanueva Garatachea, Alberto Viñals Canals, Francesc |
| author |
Juliachs Milà, Mercè |
| author_facet |
Juliachs Milà, Mercè Castillo-Ávila, Wilmar Vidal-Bel, August Piulats, Josep M. García del Muro Solans, Xavier Condom i Mundó, Enric Hernández-Losa, Javier Teixidó, C. Pandiella, Atanasio Graupera i Garcia-Milà, Mariona Casanovas i Casanovas, Oriol Germà Lluch, José Ramón Villanueva Garatachea, Alberto Viñals Canals, Francesc |
| author_role |
author |
| author2 |
Castillo-Ávila, Wilmar Vidal-Bel, August Piulats, Josep M. García del Muro Solans, Xavier Condom i Mundó, Enric Hernández-Losa, Javier Teixidó, C. Pandiella, Atanasio Graupera i Garcia-Milà, Mariona Casanovas i Casanovas, Oriol Germà Lluch, José Ramón Villanueva Garatachea, Alberto Viñals Canals, Francesc |
| author2_role |
author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Receptors cel·lulars Medicaments antineoplàstics Malalties del testicle Tumors Càncer Cell receptors Antineoplastic agents Testis diseases Tumors Cancer |
| topic |
Receptors cel·lulars Medicaments antineoplàstics Malalties del testicle Tumors Càncer Cell receptors Antineoplastic agents Testis diseases Tumors Cancer |
| description |
In this work, we have analyzed the expression of different members of the ErbB family in human samples of testicular germ cell tumors (GCTs). We observed expression of ErbB1 or ErbB2 in different tumor subtypes, but we also found high expression of ErbB3 in all GCTs tested. This pattern of expression was maintained when primary tumors were orthotopically implanted in nude mice. We have chosen a choriocarcinoma model characterized by high levels of ErbB1, but also of ErbB2 and ErbB3, to assay the in vivo effect of ErbB inhibitors on tumoral growth. Our results showed a complete lack of effect (refractoriness) to the pure ErbB1 receptor inhibitors cetuximab and gefitinib. While these inhibitors blocked ErbB1 phosphorylation, ErbB2 phosphorylation was not affected, suggesting an ErbB1-independent activation of this receptor. To confirm the importance of ErbB2 activation, animals were treated with lapatinib, a dual ErbB1 and ErbB2 inhibitor. Lapatinib treatment caused a 50% inhibition in tumor growth, an effect correlated with a blockade of both ErbB1 and ErbB2 phosphorylation levels, and of downstream signaling pathways (Akt, ERKs and Stat3). ErbB2 activation could still occur due to the formation of ErbB2/ErbB3 heterodimers, and ErbB3 activation was completely inhibited by lapatinib. Finally, combined inhibition of ErbB1 (gefitinib) and ErbB3 activities (knockdown expression by shRNA) inhibited tumoral testicular cells proliferation in a similar way to lapatinib. Our results explain why lapatinib but not anti-ErbB1 agents might be effective for treatment of testicular GCT patients. |
| publishDate |
2013 |
| dc.date.none.fl_str_mv |
2013 2018 2018 2018 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion |
| format |
article |
| status_str |
acceptedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/120253 |
| url |
https://hdl.handle.net/2445/120253 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Versió postprint del document publicat a: https://doi.org/10.1002/ijc.28009 International Journal of Cancer, 2013, vol. 133, num. 1, p. 235-246 https://doi.org/10.1002/ijc.28009 |
| dc.rights.none.fl_str_mv |
(c) Union for International Cancer Control (UICC), 2013 info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
(c) Union for International Cancer Control (UICC), 2013 |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
12 p. application/pdf |
| dc.publisher.none.fl_str_mv |
Wiley |
| publisher.none.fl_str_mv |
Wiley |
| dc.source.none.fl_str_mv |
Articles publicats en revistes (Ciències Fisiològiques) reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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Recercat. Dipósit de la Recerca de Catalunya |
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15,811543 |