The mass of the different cell types is regulated according to the need or use of its function. This is easily recognized macroscopically in persons performing heavy muscular work. However, when changing to a sedentary life, the muscle mass returns gradually to a lower level. The increase in muscle mass secondary to heavy work or training may be due to neural factors parallel to the stimulation of muscle use. In the stomach it has been convincingly shown that the vagal nerves not only stimulate acid secretion, but also have a positive trophic effect ^[1][5]. Generally, there is a close correlation between regulation of function and proliferation as demonstrated for the enterochromaffin like (ECL) cell where gastrin stimulates histamine release as well as proliferation ^[2][6]. The hormones are the most important trophic factors. They change the “set-point” for their target cells, increasing it in cells where the hormone stimulates the function and reducing it when the stimulation is removed ^[3][7] or where the hormone has an inhibitory effect on function like somatostatin ^[4][8]. For at least peptide hormones the effects on function and proliferation are mediated via the same membrane receptor which is maximally stimulated when the actual hormone is bound to all its receptors. Thus, hormone concentrations exceeding the level where all receptors are saturated, will have no additional effect. Against this background it is strange that, as previously claimed, only very high gastrin values would play any role in tumorigenesis, and that gastrin elevation secondary to proton pump inhibitor (PPI) treatment would not reach values of concern if anacidity was avoided ^[5][9]. On the contrary, there is no lower limit for the trophic effect which is exerted through the normal range as well ^[6][7][10,11]. Similarly, removal of the antrum to reduce acid secretion via hypogastrinemia, which a period was used in the treatment of peptic ulcer disease, resulted in oxyntic atrophy, and at least in the rat a particular reduction in ECL cells ^[8][12]. Patients operated with an antrectomy have a risk of developing cancer in the remaining part of the stomach, so-called stump carcinoma. Since gastrin has a negative trophic effect on the D (somatostatin producing) cells at most locations, it wase hypothesized that the postoperative hypogastrinemia via reduction in growth inhibition of D cells could predispose to stump cancers. We found expression of the neuroendocrine marker neuron-specific enolase (NSE) in a third of the stump carcinomas, and among them one with somatostatin expression ^[9][13]. Otherwise, it iswe only known of one D cell-derived tumour, a highly malignant cancer localized to the oxyntic mucosa, expressing somatostatin ^[10][14]. A continuous trophic overstimulation will not lead to a steady increase in the density of hyper stimulated cells since the increase in cell mass necessarily will augment the release of substance(s) inhibiting their own proliferation (functional chalones), and a new set point will be established preventing further increases. Nevertheless, there will be hyperplasia of the target cell which through the forced and augmented proliferation is at increased risk of mutations and possibly other genetic changes. Mutations even where growth regulation is only slightly changed, may manifest themselves by forming polyps. Such polyps are apparently reversible as they often disappear when the hormonal overstimulation is removed ^[11][12][15,16]. Whether all the mutated cells are gone after regress of macroscopical polyps, is, however, uncertain. The long-term tumorigenic effect of hormones is thus due to the ability to induce genetic changes (initiation) and then stimulate the mutated cells further to proliferation (promotion and progression). Thereby hormones become complete carcinogens. This was shown more than 50 years ago for sex hormones when girls borne of mothers having been treated with oestrogens during pregnancy, developed cancers of the vagina at an early age ^[13][17]. Similarly, and more recently also for gastric cancer that developed from ECL cells in young adults due to hypergastrinemia caused by missense mutation of one of the genes coding for the proton pump (Figure 1) ^[14][18].

The central role of hormones in carcinogenesis is also clearly shown by the difference in prevalence of breast cancer between the two sexes.

Examinations of tumours to detect mutations to tailor treatment have given rise to great expectations during recent years. Although some individual improvement in treatment may be gained by such an approach, this will not be of much help for understanding the etiology and pathogenesis of the tumour since by definition “spontaneous” mutations occur by chance. Instead of going directly from tumour classification based just on the organ to individual genetic changes in tumours, the rational approach would be to determine the cell of origin. Based upon the knowledge of its regulation, new information of the tumour pathogenesis will be gained. Examination for receptors normally present on the cell of origin, will then give information on the possibility to use hormone antagonists or agonists in the treatment. For example, our demonstration of the central role of the erythropoietin producing cell in CCRCC (clear cell renal cancer cell) ^[16][20] explains the recently detected effect of HIF (hypoxia inducible factor) antagonist in the treatment of such carcinomas ^[17][21]. Cell of origin is most easily determined by immunohistochemistry or in-situ hybridization although also whole genome sequencing is a possibility. However, in the latter case selection of single actual candidate cells for comparison may be a problem.

Tumours with traits of epithelial cells and having developed from such cells are classified as carcinomas, whereas those without such features generally are called sarcomas. There have been two theories for the pathogenesis of malignant neoplasia, dedifferentiation of normal cells ^[18][22] and the other, stop in differentiation of a primitive cell like a stem cell ^[19][23]. It is, however, evident that only cells able to divide may give origin to a tumour. Probably, both dedifferentiation of mature cells and stop in differentiation of immature cells both give rise to tumours.

Neuroendocrine (NE) cells occur in most external surfaces, and they can divide ^[20][24], although some have claimed that NE cells do not divide in man ^[21][25]. 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][26]. 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][27,28]. 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, itwe could not detect E-cadherin on the ECL cell in the oxyntic mucosa ^[25][29] 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][30] develop into tumours although D cells may rarely give rise to tumours ^[27][31] and even more seldom A-like (ghrelin producing) cells ^[28][32]. 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][33]. 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][34]. 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][35,36]. 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][37]. 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][38]. 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][39] or in rats dosed long-term with serotonin ^[36][40]. 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.

Only a low percentage of tumours is due to congenital genetic changes ^[37][38][41,42]. However, tumours develop due to acquired changes in genes, most often mutations. Without mutations there would have been no evolution, but at the same time it is the principal mechanism in the development of neoplasia. Only a low proportion of mutations results in a functional improvement which is preserved and contributing to the evolution. Some mutations affect silent parts of the gene and have no functional impact. However, most mutations have negative effect on the function of the gene product. Therefore, the apparent gain of function in tumour cells like increased proliferation and invasiveness represent a loss of function of a regulatory mechanism. Thus, very few new molecules are expressed in cancer cells compared with the normal cell, but during carcinogenesis markers are gradually lost which may make cell of origin difficult to identify ^[39][43]. However, when a compound relatively selectively is produced in a cell or a cell type, assessment of this compound may be used as a marker for such cells. Chromogranin A is a typical example of such a compound being specific for NE cells as it is found only in secretory granules ^[40][44] and accordingly increased in persons with NE cell hyperplasia ^[41][45] and NE tumours of low malignancy ^[41][45]. With increased malignancy the tumour cells lose specific traits including expression of secretory granules, and chromogranin A in blood may fall despite increased mass of tumour cells. In a study from our group, it wase found blood chromogranin A elevation in six adenocarcinomas. Five of these tumours expressed chromogranin A in their tumour cells when examined with immunohistochemistry with increased sensitivity by using tyramide signal amplification, which may suggest misclassification of neuroendocrine carcinomas as adenocarcinomas ^[42][46].