Pituitary tumour fibroblast-derived cytokines influence tumour aggressiveness.
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.
['Marques|Pedro|P|', 'Barry|Sayka|S|', 'Carlsen|Eivind|E|', 'Collier|David|D|', 'Ronaldson|Amy|A|', 'Awad|Sherine|S|', 'Dorward|Neil|N|', 'Grieve|Joan|J|', 'Mendoza|Nigel|N|', 'Muquit|Samiul|S|', 'Grossman|Ashley B|AB|', 'Balkwill|Frances|F|', 'Korbonits|Márta|M|']
D000328:Adult D000368:Aged D000818:Animals D000072645:Cancer-Associated Fibroblasts D045744:Cell Line, Tumor D002465:Cell Movement D002478:Cells, Cultured D016207:Cytokines D058750:Epithelial-Mesenchymal Transition D005260:Female D006801:Humans D008297:Male D008875:Middle Aged D018358:Neuroendocrine Tumors D010911:Pituitary Neoplasms D051381:Rats
cytokine tumour-associated fibroblasts tumour microenvironment pituitary neuroendocrine tumour pasireotide