Hormones and Neuroendocrine Cells, Role in Gastric and Renal Tumourigenesis
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The role of the neuroendocrine (NE) cell in the stomach has been widely studied for decades. Particularly the enterochromaffin-like (ECL) cell and its role in carcinogenesis has been of interest (1, 2). Gastrin is found to be the main stimulator of the ECL cell function in terms of histamine release (3) as well as their growth (4). The functional and trophic effects of gastrin on the ECL cell has the same concentration dependency, indicating that these two effects are mediated by the same receptor (5). It has been discovered that long-term hypergastrinaemia both in rodents (6, 7) and man (8, 9) can induce neoplasia. Further studies have revealed that an important part of human gastric carcinomas display NE markers, and more specifically ECL cell markers (10-12), indicating that some of these carcinomas may originate from ECL cells. NE cells and neuroendocrine tumours (NETs) have been described in a variety of organs, including the lungs (13), breast (14), and prostate gland (15). Much less is known about the NE cells and NETs in the kidneys. Guy et al (16) were not able to detect any neuroendocrine cells in the kidneys of children and fetuses, and they were not able to validate their hypothesis that the origin of NETs are from entrapped/misplaced progenitor cells during organogenesis. Interestingly, primitive neural crest derived tumours have been described (17, 18). Likewise, primary NETs in the kidney are seldom, but well known (19, 20). Less than 100 cases have been reported in the literature till now (21). Clear cell renal cell carcinoma (CCRCC) has many similarities with NETs occurring in other places (22, 23). Clinically NETs and CCRCC grow rather slowly, but metastasize at an early stage. The occurrence of polycythaemia in approximately 5% of the patients with renal cancer may be regarded as a hormonal overproduction syndrome due to erythropoietin (EPO) similar to what is seen in patients with insulinomas and gastrinomas (24). Furthermore, markers for NE cells have been found in a proportion of CCRCCs, where neuron-specific enolase (NSE) was most often detected in CCRCCs compared to other subtypes of renal cell carcinoma (25, 26). By combining our knowledge from studying neuroendocrine neoplasms (NENs) in the stomach with the fact that there are similarities between CCRCCs and NETs occurring elsewhere in the body we wished to explore this further. In paper I and IV we sought to investigate whether there was an association between the expression of NE markers and the hormone erythropoietin (EPO) in CCRCCs, and whether expression of EPO in the tumour tissue was related to serum EPO. Moreover, we wanted to identify the cell responsible for producing EPO in man. In both studies we found that almost all CCRCCs expressed EPO and NSE. NSE is a marker normally expressed in neuronal cells, NE cells and tumours originating from these cell types, and was one of the first markers used in immunohistochemistry (IHC) for determining NE differentiation in a tumour. However, NSE was considered non-specific due to its ability to stain tumours considered not to be of NE origin. Many of the studies arriving to this conclusion are old, and with improvements in IHC many tumours previously considered not to be of NE origin, do in fact express specific markers such as chromogranin A (CgA) and synaptophysin. In paper II we explored this further by comparing the expression of NSE with the expression of other NE markers in tumour tissue from breast, lung, kidney, and stomach. We found that NSE as a marker for NE differentiation is more useful than perceived in the past. In paper III we set out to further explore NENs in the stomach, especially with regards to the cholecystokinin B receptor (CCKBR), also known as the gastrin receptor. There has been some controversy with regard to the association between hypergastrinaemia and gastric cancer, but both past and recent studies have found gastrin to be associated with increased risk of developing gastric cancer. By keeping this in mind, we set out to investigate the expression of CCKBR in various types of gastric cancers (paper III), and found that 89% of cases expressed CCKBR protein, whereas 54% of cases expressed CCKBR mRNA. This in turn may be useful information in terms of new treatment options in a group of patients with a dismal prognosis in the first place.