Rapamycin Prevents Early Onset of Tumorigenesis in an Oral-Specific K-ras and p53 Two-Hit Carcinogenesis Model

Autores
Raimondi, Ana Rosa; Molinolo, Alfredo; Gutkind, Jorge Silvio
Año de publicación
2009
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Head and neck squamous cell carcinomas (HNSCC), the majority of which occur in the oral cavity, remain a significant cause of morbidity and mortality worldwide. Amajor limitation in HNSCC research has been the paucity of animal models to test the validity of current genetic paradigms of tumorigenesis and to explore the effectiveness of new treatment modalities and chemopreventive strategies. Here, we have developed an inducible oral-specific animal tumor model system, which consists in the expression of a tamoxifeninducible Cre recombinase (CreERtam) under the control of the cytokeratin 14 (K14) promoter (K14-CreERtam) and mice in which the endogenous K-ras locus is targeted (LSLK-rasG12D), thereby causing the expression of endogenous levels of oncogenic K-rasG12D following removal of a stop element. Surprisingly, whereas K14-CreERtam can also target the skin, K14-CreERtam/LSL-K-rasG12D mice developed papillomas exclusively in the oral mucosa within 1 month after tamoxifen treatment. These lesions were highly proliferative but never progressed to carcinoma. However, when crossed with p53 conditional knockout (p53flox/flox) mice, mice developed SCCs exclusively on the tongue as early as 2 weeks after tamoxifen induction, concomitant with a remarkable activation of the mammalian target of rapamycin (mTOR) signaling pathway. The availability of this ras and p53 two-hit animal model system recapitulating HNSCC progression may provide a suitable platform for exploring novel molecular targeted approaches for the treatment of this devastating disease. Indeed, we show here that mTOR inhibition by the use of rapamycin is sufficient to halt tumor progression in this genetically defined oral cancer model system, thereby prolonging animal survival.
Fil: Raimondi, Ana Rosa. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Fil: Molinolo, Alfredo. National Institutes of Health; Estados Unidos
Fil: Gutkind, Jorge Silvio. National Institutes of Health; Estados Unidos
Materia
oral cancer
Kras
p53
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/113821
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/113821
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Rapamycin Prevents Early Onset of Tumorigenesis in an Oral-Specific K-ras and p53 Two-Hit Carcinogenesis ModelRaimondi, Ana RosaMolinolo, AlfredoGutkind, Jorge Silviooral cancerKrasp53https://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Head and neck squamous cell carcinomas (HNSCC), the majority of which occur in the oral cavity, remain a significant cause of morbidity and mortality worldwide. Amajor limitation in HNSCC research has been the paucity of animal models to test the validity of current genetic paradigms of tumorigenesis and to explore the effectiveness of new treatment modalities and chemopreventive strategies. Here, we have developed an inducible oral-specific animal tumor model system, which consists in the expression of a tamoxifeninducible Cre recombinase (CreERtam) under the control of the cytokeratin 14 (K14) promoter (K14-CreERtam) and mice in which the endogenous K-ras locus is targeted (LSLK-rasG12D), thereby causing the expression of endogenous levels of oncogenic K-rasG12D following removal of a stop element. Surprisingly, whereas K14-CreERtam can also target the skin, K14-CreERtam/LSL-K-rasG12D mice developed papillomas exclusively in the oral mucosa within 1 month after tamoxifen treatment. These lesions were highly proliferative but never progressed to carcinoma. However, when crossed with p53 conditional knockout (p53flox/flox) mice, mice developed SCCs exclusively on the tongue as early as 2 weeks after tamoxifen induction, concomitant with a remarkable activation of the mammalian target of rapamycin (mTOR) signaling pathway. The availability of this ras and p53 two-hit animal model system recapitulating HNSCC progression may provide a suitable platform for exploring novel molecular targeted approaches for the treatment of this devastating disease. Indeed, we show here that mTOR inhibition by the use of rapamycin is sufficient to halt tumor progression in this genetically defined oral cancer model system, thereby prolonging animal survival.Fil: Raimondi, Ana Rosa. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Molinolo, Alfredo. National Institutes of Health; Estados UnidosFil: Gutkind, Jorge Silvio. National Institutes of Health; Estados UnidosAmerican Association for Cancer Research2009-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/113821Raimondi, Ana Rosa; Molinolo, Alfredo; Gutkind, Jorge Silvio; Rapamycin Prevents Early Onset of Tumorigenesis in an Oral-Specific K-ras and p53 Two-Hit Carcinogenesis Model; American Association for Cancer Research; Cancer Research; 69; 10; 5-2009; 4159-41660008-5472CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-08-4645info:eu-repo/semantics/altIdentifier/url/https://cancerres.aacrjournals.org/content/69/10/4159info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:47:12Zoai:ri.conicet.gov.ar:11336/113821instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:47:13.086CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Rapamycin Prevents Early Onset of Tumorigenesis in an Oral-Specific K-ras and p53 Two-Hit Carcinogenesis Model
title Rapamycin Prevents Early Onset of Tumorigenesis in an Oral-Specific K-ras and p53 Two-Hit Carcinogenesis Model
spellingShingle Rapamycin Prevents Early Onset of Tumorigenesis in an Oral-Specific K-ras and p53 Two-Hit Carcinogenesis Model
Raimondi, Ana Rosa
oral cancer
Kras
p53
title_short Rapamycin Prevents Early Onset of Tumorigenesis in an Oral-Specific K-ras and p53 Two-Hit Carcinogenesis Model
title_full Rapamycin Prevents Early Onset of Tumorigenesis in an Oral-Specific K-ras and p53 Two-Hit Carcinogenesis Model
title_fullStr Rapamycin Prevents Early Onset of Tumorigenesis in an Oral-Specific K-ras and p53 Two-Hit Carcinogenesis Model
title_full_unstemmed Rapamycin Prevents Early Onset of Tumorigenesis in an Oral-Specific K-ras and p53 Two-Hit Carcinogenesis Model
title_sort Rapamycin Prevents Early Onset of Tumorigenesis in an Oral-Specific K-ras and p53 Two-Hit Carcinogenesis Model
dc.creator.none.fl_str_mv Raimondi, Ana Rosa
Molinolo, Alfredo
Gutkind, Jorge Silvio
author Raimondi, Ana Rosa
author_facet Raimondi, Ana Rosa
Molinolo, Alfredo
Gutkind, Jorge Silvio
author_role author
author2 Molinolo, Alfredo
Gutkind, Jorge Silvio
author2_role author
author
dc.subject.none.fl_str_mv oral cancer
Kras
p53
topic oral cancer
Kras
p53
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Head and neck squamous cell carcinomas (HNSCC), the majority of which occur in the oral cavity, remain a significant cause of morbidity and mortality worldwide. Amajor limitation in HNSCC research has been the paucity of animal models to test the validity of current genetic paradigms of tumorigenesis and to explore the effectiveness of new treatment modalities and chemopreventive strategies. Here, we have developed an inducible oral-specific animal tumor model system, which consists in the expression of a tamoxifeninducible Cre recombinase (CreERtam) under the control of the cytokeratin 14 (K14) promoter (K14-CreERtam) and mice in which the endogenous K-ras locus is targeted (LSLK-rasG12D), thereby causing the expression of endogenous levels of oncogenic K-rasG12D following removal of a stop element. Surprisingly, whereas K14-CreERtam can also target the skin, K14-CreERtam/LSL-K-rasG12D mice developed papillomas exclusively in the oral mucosa within 1 month after tamoxifen treatment. These lesions were highly proliferative but never progressed to carcinoma. However, when crossed with p53 conditional knockout (p53flox/flox) mice, mice developed SCCs exclusively on the tongue as early as 2 weeks after tamoxifen induction, concomitant with a remarkable activation of the mammalian target of rapamycin (mTOR) signaling pathway. The availability of this ras and p53 two-hit animal model system recapitulating HNSCC progression may provide a suitable platform for exploring novel molecular targeted approaches for the treatment of this devastating disease. Indeed, we show here that mTOR inhibition by the use of rapamycin is sufficient to halt tumor progression in this genetically defined oral cancer model system, thereby prolonging animal survival.
Fil: Raimondi, Ana Rosa. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Fil: Molinolo, Alfredo. National Institutes of Health; Estados Unidos
Fil: Gutkind, Jorge Silvio. National Institutes of Health; Estados Unidos
description Head and neck squamous cell carcinomas (HNSCC), the majority of which occur in the oral cavity, remain a significant cause of morbidity and mortality worldwide. Amajor limitation in HNSCC research has been the paucity of animal models to test the validity of current genetic paradigms of tumorigenesis and to explore the effectiveness of new treatment modalities and chemopreventive strategies. Here, we have developed an inducible oral-specific animal tumor model system, which consists in the expression of a tamoxifeninducible Cre recombinase (CreERtam) under the control of the cytokeratin 14 (K14) promoter (K14-CreERtam) and mice in which the endogenous K-ras locus is targeted (LSLK-rasG12D), thereby causing the expression of endogenous levels of oncogenic K-rasG12D following removal of a stop element. Surprisingly, whereas K14-CreERtam can also target the skin, K14-CreERtam/LSL-K-rasG12D mice developed papillomas exclusively in the oral mucosa within 1 month after tamoxifen treatment. These lesions were highly proliferative but never progressed to carcinoma. However, when crossed with p53 conditional knockout (p53flox/flox) mice, mice developed SCCs exclusively on the tongue as early as 2 weeks after tamoxifen induction, concomitant with a remarkable activation of the mammalian target of rapamycin (mTOR) signaling pathway. The availability of this ras and p53 two-hit animal model system recapitulating HNSCC progression may provide a suitable platform for exploring novel molecular targeted approaches for the treatment of this devastating disease. Indeed, we show here that mTOR inhibition by the use of rapamycin is sufficient to halt tumor progression in this genetically defined oral cancer model system, thereby prolonging animal survival.
publishDate 2009
dc.date.none.fl_str_mv 2009-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/113821
Raimondi, Ana Rosa; Molinolo, Alfredo; Gutkind, Jorge Silvio; Rapamycin Prevents Early Onset of Tumorigenesis in an Oral-Specific K-ras and p53 Two-Hit Carcinogenesis Model; American Association for Cancer Research; Cancer Research; 69; 10; 5-2009; 4159-4166
0008-5472
CONICET Digital
CONICET
url http://hdl.handle.net/11336/113821
identifier_str_mv Raimondi, Ana Rosa; Molinolo, Alfredo; Gutkind, Jorge Silvio; Rapamycin Prevents Early Onset of Tumorigenesis in an Oral-Specific K-ras and p53 Two-Hit Carcinogenesis Model; American Association for Cancer Research; Cancer Research; 69; 10; 5-2009; 4159-4166
0008-5472
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-08-4645
info:eu-repo/semantics/altIdentifier/url/https://cancerres.aacrjournals.org/content/69/10/4159
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Association for Cancer Research
publisher.none.fl_str_mv American Association for Cancer Research
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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