Targeting Ferroptosis-Elicited Inflammation Suppresses Hepatocellular Carcinoma Metastasis and Enhances Sorafenib Efficacy.
Cancer Res
; 84(6): 841-854, 2024 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-38231484
ABSTRACT
Triggering ferroptosis, an iron-dependent form of cell death, has recently emerged as an approach for treating cancer. A better understanding of the role and regulation of ferroptosis is needed to realize the potential of this therapeutic strategy. Here, we observed extensive activation of ferroptosis in hepatoma cells and human hepatocellular carcinoma (HCC) cases. Patients with low to moderate activation of ferroptosis in tumors had the highest risk of recurrence compared to patients with no or high ferroptosis. Upon encountering ferroptotic liver cancer cells, aggregated macrophages efficiently secreted proinflammatory IL1ß to trigger neutrophil-mediated sinusoidal vascular remodeling, thereby creating favorable conditions for aggressive tumor growth and lung metastasis. Mechanistically, hyaluronan fragments released by cancer cells acted via an NF-κB-dependent pathway to upregulate IL1ß precursors and the NLRP3 inflammasome in macrophages, and oxidized phospholipids secreted by ferroptotic cells activated the NLRP3 inflammasome to release functional IL1ß. Depleting either macrophages or neutrophils or neutralizing IL1ß in vivo effectively abrogated ferroptosis-mediated liver cancer growth and lung metastasis. More importantly, the ferroptosis-elicited inflammatory cellular network served as a negative feedback mechanism that led to therapeutic resistance to sorafenib in HCC. Targeting the ferroptosis-induced inflammatory axis significantly improved the therapeutic efficacy of sorafenib in vivo. Together, this study identified a role for ferroptosis in promoting HCC by triggering a macrophage/IL1ß/neutrophil/vasculature axis. SIGNIFICANCE:
Ferroptosis induces a favorable tumor microenvironment and supports liver cancer progression by stimulating an inflammatory cellular network that can be targeted to suppress metastasis and improve the efficacy of sorafenib.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carcinoma Hepatocelular
/
Ferroptose
/
Neoplasias Hepáticas
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Neoplasias Pulmonares
Limite:
Humans
Idioma:
En
Revista:
Cancer Res
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China
País de publicação:
Estados Unidos