Neuroendocrine tumours (NETs) occur in multiple tissues and vary widely in clinical behaviour. Up to 70% of diagnosed patients have elevated circulating levels of chromogranin A, the only serum marker commonly used in clinical practice. However, its low sensitivity and the identification of confounding factors that compromise specificity have raised the need for additional or alternative markers for disease detection and management. Here we aimed to discover candidate NET markers by comparing low molecular weight proteins secreted by BON1, NCI-H727, and SHP-77 NET cells. We identified 316 proteins, 42 of which were secreted by all three lines. One of these proteins, thymosin beta-4 (TMSB4X), was found to be elevated in 50% of gastroenteropancreatic NET patient serum samples compared with healthy controls. Half of the samples with elevated TMSB4X had no elevation of chromogranin A. TMSB4X is a small 43-amino acid intracellular peptide that was first isolated from bovine thymus tissue. Studies have shown that TMSB4X plays an important role in a wide range of processes. These processes include apoptosis, inflammation, tumour invasion and metastasis. We then investigated the mitogenic activity of TMSB4X and its naturally occurring oxidized form. Both forms stimulated BON1 cell ERK1/2 phosphorylation, and increased cell proliferation. Moreover, increases in proliferation were dependent on ERK activity as they were abolished by an ERK1/2 inhibitor. The experimental findings support the idea and role that TMSB4X is a suitable GEP-NET marker and also plays an important role as an autocrine mitogen. Moreover, TMSB4X signalling is potentially a therapeutic target for NETs.
02 Dec 2019
UK and Ireland Neuroendocrine Tumour Society