期刊
ONCOGENE
卷 38, 期 27, 页码 5381-5395出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-019-0779-5
关键词
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资金
- Medical Research Council [MR/M018539/1]
- Wellcome Trust [097970/Z/11/Z]
- Fundacion Alfonso Martin Escudero Fellowship
- Rosetrees Trust [M505]
- Barts and the London Charity
- Pfizer UK [WS 733753]
- Wellcome Trust [097970/Z/11/Z] Funding Source: Wellcome Trust
- MRC [MR/M018539/1] Funding Source: UKRI
The molecular mechanisms leading to aryl hydrocarbon receptor interacting protein (AIP) mutation-induced aggressive, young-onset growth hormone-secreting pituitary tumors are not fully understood. In this study, we have identified that AIP-mutation-positive tumors are infiltrated by a large number of macrophages compared to sporadic tumors. Tissue from pituitary-specific Aip-knockout (Aip(Flox/Flox) ; Hesx1(cre/+)) mice recapitulated this phenotype. Our human pituitary tumor transcriptome data revealed the epithelial-to-mesenchymal transition (EMT) pathway as one of the most significantly altered pathways in AIP(pos) tumors. Our in vitro data suggest that bone marrow-derived macrophage-conditioned media induces more prominent EMT-like phenotype and enhanced migratory and invasive properties in Aip-knockdown somatomammotroph cells compared to non-targeting controls. We identified that tumor-derived cytokine CCL5 is upregulated in AIP-mutation-positive human adenomas. Aip-knockdown GH3 cell-conditioned media increases macrophage migration, which is inhibited by the CCL5/CCR5 antagonist maraviroc. Our results suggest that a crosstalk between the tumor and its microenvironment plays a key role in the invasive nature of AIP-mutation-positive tumors and the CCL5/CCR5 pathway is a novel potential therapeutic target.
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