Pituitary tumour fibroblast-derived cytokines influence tumour aggressiveness

in Endocrine-Related Cancer
Authors:
Pedro Marques 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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Sayka Barry 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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Eivind Carlsen Department of Pathology, STHF, Skien, Norway

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David Collier 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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Amy Ronaldson 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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Sherine Awad 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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Neil Dorward The National Hospital for Neurology and Neurosurgery, UCLH, NHS Trust, London, UK

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Joan Grieve The National Hospital for Neurology and Neurosurgery, UCLH, NHS Trust, London, UK

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Nigel Mendoza Department of Neurosurgery, Charing Cross Hospital, Imperial College, London, UK

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Samiul Muquit Department of Neurosurgery, Derriford Hospital, Plymouth, UK

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Ashley B Grossman 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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Frances Balkwill Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK

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Márta Korbonits 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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Correspondence should be addressed to M Korbonits: m.korbonits@qmul.ac.uk
DOI:
https://doi.org/10.1530/ERC-19-0327
Volume/Issue:
Volume 26: Issue 12
Article Type:
Research Article
Page Range:
853–865
Online Publication Date:
Dec 2019
Copyright:
© 2019 Society for Endocrinology 2019
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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.

Supplementary Materials

    • Supplementary Table 1: Basal and pasireotide-treated cytokine secretome from tumour-associated fibroblasts isolated from PitNETs.
    • Supplementary Table 2: Correlations between the cytokine secretome from PitNET-derived tumour-associated fibroblasts and microvessel density, microvessel area, E-cadherin and ZEB1 immunoreactivities in PitNETs.

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Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© 2019 Society for Endocrinology 2019
Page(s):
13
Received Date:
16 Oct 2019
Accepted Date:
23 Oct 2019
Print Publication Date:
01 Dec 2019
Online Publication Date:
Dec 2019
Keywords:
pituitary neuroendocrine tumour; tumour microenvironment; tumour-associated fibroblasts; cytokine; pasireotide

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