Abstract
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.
Highlights
Heterozygous mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene are present in about fifth of both familial isolated pituitary adenoma and childhood
The tumor microenvironment plays a crucial role in the growth and invasion of tumors [7, 8, 10], but this has not been previously studied in aggressive pituitary tumors associated with AIP mutations
Using gene expression profiling of AIPpos human pituitary tumor samples, as well as in vitro and in vivo models, we established that AIPpos tumors have a unique microenvironment strikingly different from that of sporadic pituitary tumors
Summary
Heterozygous mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene are present in about fifth of both familial isolated pituitary adenoma and childhood-. Patients with germline AIP mutations (AIPpos) have distinct clinical features, such as young age at diagnosis, large, invasive, sparsely-granulated adenomas with poor response to somatostatin analogs [1,2,3,4,5,6]. Sparse data are available on the tumor microenvironment of pituitary adenomas. Previous studies found low level of macrophage [11] or lymphocyte [12] infiltration, while a more recent study showed that the presence of hematopoietic CD45+ cells was associated with poor clinical outcome [13] or invasiveness in sparsely granulated somatotroph adenomas [14]. In our in vitro experiments, supernatant of a stable Aip-knockdown somatomammotroph cell line stimulated macrophage migration via CCL5/CCR5 pathway, while macrophage-derived factors lead to epithelial-to-mesenchymal transition (EMT), increased migration, and invasion in pituitary somatotroph cells
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