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

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.

The CCL5/CCR5 Axis in Cancer Progression

“…Inhibited tumor cell growth and intracellular Ca 2+ flux [138] shRNA-CCL5 silencing, anti-CCR5 antibody Inhibited the invasive capacity of CSLCs, inhibited invasion of ovarian cancer stem-like cells in vitro and in tumor xenografts [59] Anti-CCL5 antibody Decreased tumor growth and invasion induced by CAFs [139] Reduced epithelial-mesenchymal transition-like process of non-stem ovarian cancer cells, metastasis in xenografts [140] Anti-CCL5 antibody, shRNA-CCL5 silencing Inhibited endothelial cell differentiation and tube formation of cancer stem-like cells in vitro and in xenografts [141] Pancreatic cancer Maraviroc Decreased tumor cell growth and invasion [51] Decreased tumor cell Inhibited, induced apoptosis in vitro, reduced liver metastasis from xenografts [142] Pituitary tumor Maraviroc Decreased macrophage migration induced by tumor cells [143] Prostate cancer…”

“…Pituitary tumors with mutated-aryl hydrocarbon receptor interacting protein have an aggressive phenotype [186]. This tumor is characterized by an intratumoral accumulation of macrophages and high levels of CCL5 expression compared to sporadic adenomas or normal pituitary [143]. Macrophages secrete molecules that induce EMT and enhance the invasiveness of mutated cancer cells.…”

Pituitary Adenomas and Invasiveness from Anatomo-Surgical, Radiological, and Histological Perspectives: A Systematic Literature Review

“…Finally, since familial cases of pituitary germline mutations responsible for the pathogenesis of PitNETs have been described, such as those in MEN1 or AIP, and such mutations may be present in a sporadic setting and correlate with tumor aggressiveness since tumors with MEN1 or AIP mutations have been reported to be resistant to conventional treatment [178]. Of note, a recent report indicated that MMP2 and MMP9 are upregulated in AIP-positive PitNETs and may confer a more aggressive phenotype [179]. In AIP-positive tumors, a significant number of altered mesenchymal-to-epithelial transition (EMT) associated genes, including epithelial markers (CDH1, CTNNB1, ERSP1, and EPCAM) and transcriptional (ZEB1) and post-transcriptional regulators (ESRP1) has been identified, suggesting that disruption of the EMT pathway may be responsible for a more aggressive phenotype.…”

Hypoxia and the hypoxia inducible factor 1α activate protein kinase A by repressing RII beta subunit transcription

“…While germline and somatic mutations in the genes encoding for PKA regulatory subunits have been characterized, they are infrequent and little is known about nongenomic effectors of aberrant PKA activity in human tumors [7,8,25]. The role of the tumor microenvironment in shaping the phenotype of AIP-mutation-positive somatotroph tumors recently been highlighted [26]. We therefore hypothesized that the decreased vascular density observed in acromegalic pituitary tumors may contribute to the activated PKA found in the absence of stimulating gsp mutations.…”