Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors
| Autor: | Barry, Sayka, Carlsen, Eivind, Marques, Pedro, Stiles, Craig E., Gadaleta, Emanuela, Berney, Dan M., Roncaroli, Federico, Chelala, Claude, Solomou, Antonia, Herincs, Maria, Caimari, Francisca, Grossman, Ashley B., Crnogorac-Jurcevic, Tatjana, Haworth, Oliver, Gaston-Massuet, Carles, Korbonits, Márta |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Mice
Knockout Epithelial-Mesenchymal Transition Lydia Becker Institute Receptors CCR5 Intracellular Signaling Peptides and Proteins Article Prognostic markers Mice ResearchInstitutes_Networks_Beacons/lydia_becker_institute_of_immunology_and_inflammation Mutation Biomarkers Tumor Tumor Microenvironment Animals Humans Extracellular signalling molecules Neoplasm Invasiveness Pituitary Neoplasms Chemokine CCL5 |
| Zdroj: | Oncogene Barry, S, Carlsen, E, Marques, P, Stiles, C E, Gadaleta, E, Berney, D M, Roncaroli, F, Chelala, C, Solomou, A, Herincs, M, Caimari, F, Grossman, A B, Crnogorac-Jurcevic, T, Haworth, O, Gaston-Massuet, C & Korbonits, M 2019, ' Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors ', Oncogene . https://doi.org/10.1038/s41388-019-0779-5 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/s41388-019-0779-5 |
| Popis: | 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 AIPpos 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. |
| Databáze: | OpenAIRE |
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