Neuroendocrine (NE) cells occur in most external surfaces, and they can divide
[20], although some have claimed that NE cells do not divide in man
[21]. However, they do proliferate very slowly, which might explain the disputes about their ability to divide. The slow normal proliferation is also reflected in the NETs, although being malignant with the ability to metastasize, they grow slowly which explains the often long-survival of NET patients. Moreover, no chromogranin A positive cells were shown to divide in gastric carcinomas, and therefore chromogranin A positive tumour cells were claimed to be quiescent cells without any role in tumorigenesis
[22]. Alternatively, this phenomenon may be explained by lack of chromogranin A expression during mitoses. The tumour cells in NETs are phenotypically very similar to the normal NE cell of origin, which probably reflects the low mutation rate in these tumours
[23][24]. In contrast to other epithelial cells, normal NE cells do not adhere to each other, possibly due to reduced expression of adherence molecules. In fact, it could not detect E-cadherin on the ECL cell in the oxyntic mucosa
[25] suggesting that this cell was prone to develop into a tumour. Another consequence of accepting that differentiated cells may degenerate into a tumour is the possible role of normal signal substances in tumorigenesis. Thus, there are about 20 different NE cells in the gastrointestinal tract, but mainly enterochromaffin (EC) and ECL cells
[26] develop into tumours although D cells may rarely give rise to tumours
[27] and even more seldom A-like (ghrelin producing) cells
[28]. The different NE cell types are very similar both anatomically and functionally, why then this great discrepancy in tumorigenesis? The high prevalence of atrophic oxyntic gastritis leading to reduced gastric acidity and hypergastrinemia, is of course an important factor for ECL cell tumorigenesis. The knowledge of the functional and proliferative regulation of the EC cell is much less
[29]. However, the EC and ECL cell have another property in common, the production of vasoactive signal substances, serotonin, and histamine, respectively. Histamine through its vascular dilatation and permeation may facilitate the spread of tumour cells, and together with another ECL cell mediator, REG(regenerating) protein, have a trophic effect on another cell, the stem cell
[30]. Serotonin has also profound vascular effects, but probably more importantly, a stimulatory effect on fibrosis which manifests itself in the proximity of EC cell NETs as tumour desmoplasia
[31][32]. The effects of serotonin are mediated by multiple different receptors and its main functions seem to be as neurotransmitter. Outside the central nervous system, the EC cell is the main producer of serotonin
[33]. It is taken up by megakaryocytes and platelets and transported by the latter to the place of need. As other platelet constituents, serotonin is released from the platelets upon blood sampling as well as separation of blood corpuscles from plasma. This makes assessment of serotonin in blood very difficult, and it is possible that free serotonin does not circulate in blood during normal conditions although it is detectable in patients with EC cell NETs
[34]. In other words, is serotonin a real hormone, or just a neurotransmitter and a signal substance transported by the platelets? In any way, serotonin alone can induce valvular heart disease as exemplified in patients with EC cell NETs metastasized to the liver
[35] or in rats dosed long-term with serotonin
[36]. NETs are often divided into those giving hormonal overproduction syndrome like serotonin or histamine flush, and those without such syndromes. It has, however, to be realized that this does not necessarily reflect important differences between the tumour cells. The presence of hormonal overproduction syndromes depends on the acute effects of the signal substance, for instance insulin, and the site of release as EC cell NETs give rise to serotonin flush even before liver metastasis when the primary is localized to the lungs. The peculiarities of NETs are summarized in
Table 1.