Abstract
PurposeAngiogenesis 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.MethodsImmune cells were studied by immunohistochemistry in 24 human PitNETs (16 non-functioning-PitNETs (NF-PitNETs) 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.ResultsMicrovessel density/area was higher in NP than PitNETs, which also had rounder and more regular vessels. NF-PitNETs 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.ConclusionsM2 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.
Highlights
The great majority of pituitary neuroendocrine tumours (PitNETs) are benign, they can be associated with significant morbidity due to mass effects on surrounding tissues and/or excessive or low hormone secretion [1, 2]
We analysed a cohort of 24 PitNETs with clinico-pathological, cytokine and infiltrating immune cells data for microvessel density and vasculature architecture parameters, staining the vessels with CD31
In terms of vascular architecture parameters, there were no major differences between PitNETs and normal pituitaries (NP), except that vessels were less round in PitNETs than those seen in NP (0.47 (0.43–0.49) vs 0.56 (0.56–0.59); p = 0.001) (Fig. 1)
Summary
The great majority of pituitary neuroendocrine tumours (PitNETs) are benign, they can be associated with significant morbidity due to mass effects on surrounding tissues and/or excessive or low hormone secretion [1, 2]. Angiogenesis is the process by which new blood vessels are formed from pre-existing ones, and is essential for tumour development, growth, invasion and metastasis. Angiogenesis is regulated by different non-cellular TME components, such as cytokines, chemokines, growth factors or extracellular matrix-remodelling enzymes [11,12,13], as well as by different non-neoplastic cells such as macrophages [14] or tumour-associated fibroblasts [15]. The degree of tumour angiogenesis is commonly evaluated by assessment of microvessel density, i.e. the number of vessels per given area, other vascular morphological parameters are relevant [11], and studying angiogenesis often relies on the CD31 and CD34 endothelial cell antigens [16]
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