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Title: The role of the tumour microenvironment in the phenotype of pituitary adenomas
Author: Marques, Pedro Miguel Pereira de S.
ISNI:       0000 0004 9355 4888
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2020
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Non-neoplastic cells in the tumour microenvironment (TME) influence tumoural aggressiveness and oncogenic mechanisms. Little is known about the TME in pituitary adenomas (PAs). This work aimed to characterise the TME of PAs and its effects in tumour aggressiveness and oncogenic mechanisms, focusing on the cytokine network, infiltrating immune cells and PA-associated fibroblasts (TAFs). To study the cytokine secretion of tumour/non-tumoural cells, cytokine bead arrays were performed on culture supernatants. PA-infiltrating immune cells, angiogenesis, epithelial-to-mesenchymal transition (EMT) and matrix metalloproteinases were assessed by immunohistochemistry. In vitro pituitary tumour–macrophage/TAF interactions were assessed by conditioned medium (CM) of GH3 (pituitary tumour) and RAW264.7 (macrophage) cell lines, as well as primary TAFs, in terms of morphology, migration, invasion and EMT activation. IL-8, CCL2, CCL3, CCL4, CXCL10, CCL22 and CXCL1 were the main PA-derived cytokines, which facilitate macrophage, neutrophil and T lymphocyte recruitment. More FOXP3+ T cells, lower CD8:CD4 or CD8:FOXP3 ratios and deleterious immune phenotype (CD68hiCD4hiFOXP3hiCD20hi) correlated with tumour proliferation, whereas M2:M1 ratio correlated with microvessel density and area. Invasive PAs had higher TAF-derived IL-6 levels, whereas TAFs from PA with more vessels and increased proliferation secreted more CCL2, both inhibited by pasireotide. GH3 cell-CM increased macrophage chemotaxis, while macrophage-CM/TAF-CM changed morphology, migration, invasion and EMT in GH3 cells. These data support that different TME elements affect PA tumourigenesis and aggressiveness. Data from different in vitro cell models suggest that AIP deficiency may not lead to differential cytokine secretion, and thus unlike to play a crucial role in the cytokine secretory function. The clinical study revealed that AIPmut and MEN1mut PA phenotypes are variable, including highly aggressive but also indolent cases such as prospectively-diagnosed AIPmut PAs, which are less aggressive and associated with more favourable clinical outcomes comparing to clinically-presenting AIPmut PAs, highlighting the benefits of AIP genetic and clinical screenings.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available