Prolonged inhibition of intratumoral mast cells enhances efficacy of low-dose antiangiogenic therapy.
antiangiogenic therapy
hypoxia
mast cell inhibition
therapy resistance
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
22 Aug 2024
22 Aug 2024
Historique:
revised:
28
06
2024
received:
26
01
2024
accepted:
18
07
2024
medline:
23
8
2024
pubmed:
23
8
2024
entrez:
22
8
2024
Statut:
aheadofprint
Résumé
Low-dose antiangiogenic therapies have demonstrated the ability to enhance normalization of tumor vessels, consequently improving hypoxia levels, drug delivery, and promoting anticancer immune responses. Mast cells have been identified as contributors to resistance against antiangiogenic therapy and facilitators of abnormal neoangiogenesis. In this study, we demonstrate that by simultaneously targeting intratumoral mast cells with Imatinib and administering low-dose anti-VEGFR2 therapy, antitumor efficacy can be enhanced in preclinical models. Thus, combinatory treatment overcomes therapy resistance, while concurrently promoting tumor vessel normalization. Notably, histomorphometric analysis of tumor sections revealed that vessel perfusion could be improved through mast cell inhibition and, despite a significantly reduced microvessel density, the combination treatment did not result in elevated tumor hypoxia levels compared to anti-VEGFR2 therapy alone. Short-term Imatinib application effectively increased antitumor efficacy, and by prolonging the application of Imatinib tumor vessel normalization was additionally improved. The combination of mast cell depletion and antiangiogenic treatments has not been investigated in detail and promises to help overcoming therapy resistance. Further studies will be required to explore their impact on other treatment approaches, and subsequently to validate these findings in a clinical setting.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Universität Hamburg
ID : LFF-FV 45
Organisme : H2020 European Research Council (ERC)
ID : 758713
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : 650338
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : 491582655
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : 429191104
Organisme : Hector Stiftung II
Informations de copyright
© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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