Histamine metabolism, peptide receptors and monoamine transporters in carcinoid tumors

Abstract

Carcinoid tumours originate from the neuroendocrine cell system and produce biogenic amines and peptide hormones. With excess secretion the patient will suffer from hormonal symptoms. In the present study the clinical behaviour and biochemical parameters have been studied in a consecutive series of patients with gastric carcinoids (developing from enterochromaffin-like, ECL cells) using a new classification system. The most frequent type of ECL cell carcinoid was associated with chronic atrophic gastritis type A (ACAG) and concomitant hypergastrinemia. These tumours were small, multiple and benign. ECL cell proliferations in the ACAG setting seemed not to be reversible after normalisation of hypergastrinemia by antrectomy. The solitary lesions without precursor ECL cell proliferation in adjacent mucosa were larger, malignant, associated with histamine over-production, and not related to hypergastrinemia. The importance of gastrin and CCK-B/gastrin receptors for histamine formation by the rate-limiting enzyme histidine decarboxylase (HDC) in gastric carcinoids was studied in the Mastomys model (formation of ECL cell tumours by long-term hypergastrinemia). HDC expression in normal and tumour-bearing gastric mucosa of Mastomys was controlled by plasma gastrin levels. The influence of CCK-B/gastrin receptors was analysed after specific receptor blockade (YM022). The gastrin stimulus was mediated via the CCK-B/gastrin receptor in normal mucosa in contrast to tumour-bearing mucosa, i.e. other receptors than CCK-B/gastrin receptors may be of importance for mediating the stimulation by gastrin.The expression of all 5 somatostatin receptor subtypes (sstr) was studied in human carcinoid tumours and correlated with scintigraphic tumour visualisation by radiolabelled somatostatin analogue (octreotide) and with the effect of octreotide treatment in vivo and in vitro. Human foregut and midgut carcinoid tumours expressed all sstr with few exceptions. These tumours were all visualised by octreotide scintigraphy, also in the absence of the high affinity receptor sstr2. The patients responded favourably to octreotide treatment with decreased urinary excretion of 5-hydroxyindoleacetic acid. Reduced secretion of serotonin after octreotide treatment was also demonstrated in primary tumour cell cultures.Due to the lack of suitable cell lines for studies of carcinoid tumours an attempt was made to develop a transplantable human midgut carcinoid model in nude mice. Tumours were propagated over 5 generations with well-preserved neuroendocrine differentiation, including expression of all sstr and the vesicular monoamine transporters (VMAT 1 & 2). This new tumour model will thus serve as a useful tool for studies of sstr- and VMAT-mediated uptake of radionuclides for diagnostic and radiotherapeutic purposes