Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors.

Oncogene 2019 Jul

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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 (AipFlox/Flox;Hesx1Cre/+) 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.

Citation

Sayka Barry, Eivind Carlsen, Pedro Marques, Craig E Stiles, Emanuela Gadaleta, Dan M Berney, Federico Roncaroli, Claude Chelala, Antonia Solomou, Maria Herincs, Francisca Caimari, Ashley B Grossman, Tatjana Crnogorac-Jurcevic, Oliver Haworth, Carles Gaston-Massuet, Márta Korbonits. Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors. Oncogene. 2019 Jul;38(27):5381-5395