ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2011) 25 P173

Adenosine receptors modulate chromogranin A secretion and growth of neuroendocrine tumours: potential targets for therapy

Atul Kalhan1, Borzo Garibi1, Bharat Jasani1, Mark Kidd2, Irvin Modlin2, Roswitha Pfragner3, Aled Rees1 & Jack Ham1

1University Hospital of Wales, Cardiff, UK; 2Yale University School of Medicine, New Haven, Connecticut, USA; 3Institute of Pathophysiology, Graz, Austria.

Introduction: Neuroendocrine tumors of GI tract are a heterogeneous group of rare neoplasms that secrete peptides and amines. These tumors are highly vascular and their vascularity reflects increased tumour related angiogenesis. Adenosine, a major regulator of angiogenesis, is released by enhanced degradation of ATP, during cellular stress, damage and hypoxia.

Material and methods: The expression of adenosine receptors (AR) was investigated in two human neuroendocrine tumors cell lines BON-1 (pancreatic) and KRJ-1 (intestinal) and in archival material from neuroendocrine tumors patients.

Results: Adenosine (ED50 5–10×10−7 M) stimulated a 3–15 fold increase in cAMP levels (P<0.01) indicating a predominance of the A2a and A2b subtypes. The stable AR agonist NECA and the A2aR selective agonist CGS21680 stimulated cell proliferation by 20–30% at 10−5 M agonist (P<0.001) which was attenuated by A2bR (PSB603 and MRS1706) and by the A2aR (SCH442416) but not the A1R (PSB36) antagonists. In BON-1 cells, adenosine (ED50 5×10−6 M) and NECA (ED50 10−7 M) stimulated a 2-fold (P<0.05) secretion in Chromogranin A but had little effect on serotonin secretion. Eighteen archival human neuroendocrine tumors histopathological tissue samples were immunostained for AR. Strong labelling for the A2bR was seen in 4/4 appendiceal tumours, 4/4 pancreatic tumours and 4/9 intestinal tumours and all tumours were strongly positive for the A2aR. There was very weak or no staining for the A1R or A3R in any of the tumours.

Conclusions: Our data suggest that neuroendocrine tumors express predominantly the A2aR and A2bR and their activation leads to increased proliferation and secretion of Chromogranin A. Targeting adenosine signal pathways may thus be useful in the therapeutic management of neuroendocrine tumours.

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