Vesicle proteins as markers for neuroendocrine tumors

Abstract: The neuroendocrine (NE) tumours comprise a diversity of tumours which share commonproperties, e.g. the capacity to produce, store and release hormones. A prominent feature ofthe NE phenotype is the production of secretory granules with associated vescicle proteins,e.g. chromogranin A and synaptophysin. The aim of the present investigation was to examinethe expression of vesicle proteins in NE tumours in relation to tumour biology and function.The expression of synaptic vesicle protein 2 (SV2) was studied in gastric, ileal, appendicealand rectal carcinoids, endocrine pancreatic tumours (EPT), gastrointestinal carcinomas andgastrointestinal stromal tumours (GIST). SV2 was expressed in all NE tumours but also in allGIST. SV2 was expressed regardless of tumour type or malignant potential. All nonendocrinetumours were negative for SV2.The NE secretory protein 55 (NESP55), a novel chromogranin-like protein, was studied ingastrointestinal, pancreatic and adrenal tumours. NESP55 expression was only detected inpheochromocytomas, neuroblastomas and EPT, while ileal carcinoids were negative. Therewas no relation between NESP55 expression in tumours and their malignant potential. Allnon-endocrine tumours were negative for NESP55.The expression of vesicular monoamine transporters (VMAT) was studied in gastrointestinaland pancreatic tumours. VMAT1 was expressed in serotonin-producing (EC cell) NE tumoursof the small intestine and appendix, while VMAT2 was expressed in histamine-producing(ECL cell) NE tumours of the stomach. Peptide-producing tumours of the GI tract andpancreas only occasionally expressed VMAT. All non-endocrine tumours were negative forVMAT1 & 2.The importance of VMAT1 & 2 for the uptake of meta-iodobenzylguanidine (MIBG) in NEtumours was studied in nude mice, carrying an ileal carcinoid, and in cell cultures. Specificuptake of MIBG, was only detected in NE-tumours expressing VMAT1 and/or VMAT2.Reserpine, a specific inhibitor of VMAT, blocked the uptake of MIBG in tumour cells,indicating that VMAT is of primary importance for the uptake of MIBG in NE tumours.In conclusion, vesicle proteins are powerful tools in the diagnosis and classification of NEtumours. In the future, certain vesicle proteins may be used for targeted tumour therapy.