成纤维细胞
癌症研究
内分泌学
成纤维细胞生长因子
医学
受体
垂体
神经科学
生物
内科学
细胞培养
激素
遗传学
作者
Pedro Marques,Sayka Barry,Eivind Carlsen,David Collier,Amy Ronaldson,Sherine Awad,Neil Dorward,Joan Grieve,Nigel Mendoza,Samiul Muquit,Ashley Grossman,Frances R. Balkwill,Márta Korbonits
出处
期刊:Endocrine-related Cancer
[Bioscientifica]
日期:2019-12-01
卷期号:26 (12): 853-865
被引量:34
摘要
Tumour-associated fibroblasts (TAFs) are key elements of the tumour microenvironment, but their role in pituitary neuroendocrine tumours (PitNETs) has been little explored. We hypothesised that TAF-derived cytokines may play a role in tumour aggressiveness and that their release can be inhibited by somatostatin analogues. TAFs were isolated and cultured from 16 PitNETs (11 clinically non-functioning tumours and 5 somatotropinomas). The fibroblast secretome was assessed with a 42-plex cytokine array before and after multiligand somatostatin receptor agonist pasireotide treatment. Angiogenesis and epithelial-to-mesenchymal transition pathway assessment included CD31, E-cadherin and ZEB1 expression. GH3 cells treated with TAF- or skin fibroblast-conditioned medium were assessed for migration, invasion and cell morphology changes. PitNET TAFs secreted significant amounts of cytokines including CCL2, CCL11, VEGF-A, CCL22, IL-6, FGF-2 and IL-8. TAFs from PitNETs with cavernous sinus invasion secreted higher IL-6 levels compared to fibroblasts from non-invasive tumours ( P = 0.027). Higher CCL2 release from TAFs correlated with more capillaries ( r = 0.672, P = 0.004), and TAFs from PitNETs with a higher Ki-67 tended to secrete more CCL2 ( P = 0.058). SST1 is the predominant somatostatin receptor in TAFs, and pasireotide decreased TAF-derived IL-6 by 80% ( P < 0.001) and CCL2 by 35% ( P = 0.038). GH3 cells treated with TAF-conditioned medium showed increased migration and invasion compared to cells treated with skin fibroblast-conditioned medium, with morphological and E-cadherin and ZEB1 expression changes suggesting epithelial-to-mesenchymal transition. TAF-derived cytokines may increase PitNET aggressiveness, alter angiogenesis and induce epithelial-to-mesenchymal transition changes. Pasireotide’s inhibitory effect on TAF-derived cytokines suggest that this effect may play a role in its anti-tumour effects.
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