Stroma-derived HGF drives metabolic adaptation of colorectal cancer to angiogenesis inhibitors

The role of paracrine Hepatocyte Growth Factor (HGF) in the resistance to angiogenesis inhibitors (AIs) is hidden in xenograft models because mouse HGF fails to fully activate human MET. To uncover it, we compared the efficacy of AIs in wild-type and human HGF knock-in SCID mice bearing orthotopic h...

ver descrição completa

Detalhes bibliográficos
Autores: Mira, A, Morello, V, Cespedes, MV, Perera, T, Comoglio, PM, Mangues, R, Michieli, P
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Recursos:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p6362
Acesso em linha:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=6362
Access Level:acceso abierto
Palavra-chave:colorectal cancer
HGF
anti-angiogenic therapy
resistance
tumor metabolism
id ES_f163cdb3c4b6868c4b6bf8116a3539a0
oai_identifier_str oai:iibsantpau.fundanetsuite.com:p6362
network_acronym_str ES
network_name_str España
repository_id_str
spelling Stroma-derived HGF drives metabolic adaptation of colorectal cancer to angiogenesis inhibitorsMira, AMorello, VCespedes, MVPerera, TComoglio, PMMangues, RMichieli, Pcolorectal cancerHGFanti-angiogenic therapyresistancetumor metabolismThe role of paracrine Hepatocyte Growth Factor (HGF) in the resistance to angiogenesis inhibitors (AIs) is hidden in xenograft models because mouse HGF fails to fully activate human MET. To uncover it, we compared the efficacy of AIs in wild-type and human HGF knock-in SCID mice bearing orthotopic human colorectal tumors. Species-specific HGF/MET signaling dramatically impaired the response to anti-angiogenic agents and boosted metastatic dissemination. In cell-based assays mimicking the consequences of anti-angiogenic therapy, colorectal cancer cells were completely resistant to hypoxia but extremely sensitive to nutrient deprivation. Starvation-induced apoptosis could be prevented by HGF, which promoted GLUT1-mediated glucose uptake, sustained glycolysis and activated autophagy. Pharmacological inhibition of GLUT1 in the presence of glucose killed tumor cells as effectively as glucose deprivation, and this effect was antagonized by HGF. Concomitant targeting of GLUT1 and HGF potently suppressed growth and dissemination of AI-resistant human tumors in human HGF knock-in SCID mice without exacerbating tumor hypoxia. These data suggest that stroma-derived HGF protects CRC cells against glucose starvation-induced apoptosis, promoting resistance to both AIs and anti-glycolytic agents. Combined inhibition of glucose metabolism and HGF/MET signaling ('anti-METabolic therapy') may represent a more effective CRC treatment compared to utterly blocking tumor blood supply.IMPACT JOURNALS LLC2017info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=6362OncotargetISSN: 19492553reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p63622026-06-14T12:41:47Z
dc.title.none.fl_str_mv Stroma-derived HGF drives metabolic adaptation of colorectal cancer to angiogenesis inhibitors
title Stroma-derived HGF drives metabolic adaptation of colorectal cancer to angiogenesis inhibitors
spellingShingle Stroma-derived HGF drives metabolic adaptation of colorectal cancer to angiogenesis inhibitors
Mira, A
colorectal cancer
HGF
anti-angiogenic therapy
resistance
tumor metabolism
title_short Stroma-derived HGF drives metabolic adaptation of colorectal cancer to angiogenesis inhibitors
title_full Stroma-derived HGF drives metabolic adaptation of colorectal cancer to angiogenesis inhibitors
title_fullStr Stroma-derived HGF drives metabolic adaptation of colorectal cancer to angiogenesis inhibitors
title_full_unstemmed Stroma-derived HGF drives metabolic adaptation of colorectal cancer to angiogenesis inhibitors
title_sort Stroma-derived HGF drives metabolic adaptation of colorectal cancer to angiogenesis inhibitors
dc.creator.none.fl_str_mv Mira, A
Morello, V
Cespedes, MV
Perera, T
Comoglio, PM
Mangues, R
Michieli, P
author Mira, A
author_facet Mira, A
Morello, V
Cespedes, MV
Perera, T
Comoglio, PM
Mangues, R
Michieli, P
author_role author
author2 Morello, V
Cespedes, MV
Perera, T
Comoglio, PM
Mangues, R
Michieli, P
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv colorectal cancer
HGF
anti-angiogenic therapy
resistance
tumor metabolism
topic colorectal cancer
HGF
anti-angiogenic therapy
resistance
tumor metabolism
description The role of paracrine Hepatocyte Growth Factor (HGF) in the resistance to angiogenesis inhibitors (AIs) is hidden in xenograft models because mouse HGF fails to fully activate human MET. To uncover it, we compared the efficacy of AIs in wild-type and human HGF knock-in SCID mice bearing orthotopic human colorectal tumors. Species-specific HGF/MET signaling dramatically impaired the response to anti-angiogenic agents and boosted metastatic dissemination. In cell-based assays mimicking the consequences of anti-angiogenic therapy, colorectal cancer cells were completely resistant to hypoxia but extremely sensitive to nutrient deprivation. Starvation-induced apoptosis could be prevented by HGF, which promoted GLUT1-mediated glucose uptake, sustained glycolysis and activated autophagy. Pharmacological inhibition of GLUT1 in the presence of glucose killed tumor cells as effectively as glucose deprivation, and this effect was antagonized by HGF. Concomitant targeting of GLUT1 and HGF potently suppressed growth and dissemination of AI-resistant human tumors in human HGF knock-in SCID mice without exacerbating tumor hypoxia. These data suggest that stroma-derived HGF protects CRC cells against glucose starvation-induced apoptosis, promoting resistance to both AIs and anti-glycolytic agents. Combined inhibition of glucose metabolism and HGF/MET signaling ('anti-METabolic therapy') may represent a more effective CRC treatment compared to utterly blocking tumor blood supply.
publishDate 2017
dc.date.none.fl_str_mv 2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=6362
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=6362
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv IMPACT JOURNALS LLC
publisher.none.fl_str_mv IMPACT JOURNALS LLC
dc.source.none.fl_str_mv Oncotarget
ISSN: 19492553
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869424151023845376
score 15,812429

Registos relacionados