Collective cancer invasion forms an integrin-dependent radioresistant niche.
J Exp Med
; 217(1)2020 01 06.
Article
em En
| MEDLINE
| ID: mdl-31658985
ABSTRACT
Cancer fatalities result from metastatic dissemination and therapy resistance, both processes that depend on signals from the tumor microenvironment. To identify how invasion and resistance programs cooperate, we used intravital microscopy of orthotopic sarcoma and melanoma xenografts. We demonstrate that these tumors invade collectively and that, specifically, cells within the invasion zone acquire increased resistance to radiotherapy, rapidly normalize DNA damage, and preferentially survive. Using a candidate-based approach to identify effectors of invasion-associated resistance, we targeted ß1 and αVß3/ß5 integrins, essential extracellular matrix receptors in mesenchymal tumors, which mediate cancer progression and resistance. Combining radiotherapy with ß1 or αV integrin monotargeting in invading tumors led to relapse and metastasis in 40-60% of the cohort, in line with recently failed clinical trials individually targeting integrins. However, when combined, anti-ß1/αV integrin dual targeting achieved relapse-free radiosensitization and prevented metastatic escape. Collectively, invading cancer cells thus withstand radiotherapy and DNA damage by ß1/αVß3/ß5 integrin cross-talk, but efficient radiosensitization can be achieved by multiple integrin targeting.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Integrinas
/
Adesão Celular
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Invasividade Neoplásica
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Neoplasias
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Exp Med
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Holanda