The role of the tumour microenvironment in the angiogenesis of pituitary tumours
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ORIGINAL ARTICLE
The role of the tumour microenvironment in the angiogenesis of pituitary tumours Pedro Marques1 Sayka Barry1 Eivind Carlsen2 David Collier1 Amy Ronaldson1 Neil Dorward3 Joan Grieve3 Nigel Mendoza4 Ramesh Nair4 Samiul Muquit5 Ashley B. Grossman1 Márta Korbonits 1 ●
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Received: 25 June 2020 / Accepted: 23 August 2020 © The Author(s) 2020
Abstract Purpose Angiogenesis has been studied in pituitary neuroendocrine tumours (PitNETs), but the role of the tumour microenvironment (TME) in regulating PitNET angiogenesis remains unknown. We aimed to characterise the role of TME components in determining the angiogenetic PitNET profile, focusing on immune cells and tumour-derived cytokines. Methods Immune cells were studied by immunohistochemistry in 24 human PitNETs (16 non-functioning-PitNETs (NFPitNETs) and 8 somatotrophinomas): macrophages (CD68, CD163, HLA-DR), cytotoxic (CD8) and T helper (CD4) lymphocytes, regulatory T cells (FOXP3), B cells (CD20) and neutrophils (neutrophil elastase); endothelial cells were assessed with CD31. Five normal pituitaries (NP) were included for comparison. Microvessel density and vascular morphology were estimated with ImageJ. The cytokine secretome from these PitNETs were assessed on culture supernatants using a multiplex immunoassay panel. Results Microvessel density/area was higher in NP than PitNETs, which also had rounder and more regular vessels. NFPitNETs had vessels of increased calibre compared to somatotrophinomas. The M2:M1 macrophage ratio correlated with microvessel area. PitNETs with more CD4+ T cells had higher microvessel area, while tumours with more FOXP3+ cells were associated with lower microvessel density. PitNETs with more B cells had rounder vessels. Of the 42 PitNET-derived cytokines studied, CCL2, CXCL10 and CX3CL1 correlated with microvessel density and vessel architecture parameters. Conclusions M2 macrophages appear to play a role in PitNET neovascularisation, while B, CD4+ and FOXP3+ lymphocytes, as well as non-cellular TME elements such as CCL2, CXCL10 and CX3CL1, may also modulate the angiogenesis of PitNETs. Keywords Pituitary neuroendocrine tumour Pituitary adenoma Tumour microenvironment Cytokine Immune cell Angiogenesis ●
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Introduction Supplementary information The online version of this article (https:// doi.org/10.1007/s12020-020-02478-z) contains supplementary material, which is available to authorized users. * Márta Korbonits [email protected] 1
Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Department of Pathology, STHF, Skien, Norway
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The National Hospital for Neurology and Neurosurgery, UCLH, NHS Trust, London, UK
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Department of Neurosurgery, Charing Cross Hospital, Imperial College, London, UK
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Department of Neurosurgery, Derriford Hospital, Plymouth, UK
The great majority of pituitary neuroendocrine tumours (PitNETs) are ben
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