Hepatocellular carcinoma is an aggressive cancer with poor prognosis. Fibroblast growth factor 19, a member of the fibroblast growth factor family, is a ligand for fibroblast growth factor receptor 4. Moreover, it plays a crucial role in the progression of hepatocellular carcinoma. ASP5878 is a novel inhibitor of fibroblast growth factor receptors 1, 2, 3, and 4 that is under development. It inhibits fibroblast growth factor receptor 4 kinase activity with an IC 50 of 3.5 nmol/L. ASP5878 potently suppressed the growth of the fibroblast growth factor 19-expressing hepatocellular carcinoma cell lines Hep3B2
While the activation of the proto-oncogenes has been implicated in the development and progression of cancer of many tissues, the role of oncogenes in the development of oesophageal adenocarcinoma has not been defined. Fifteen patients who had undergone resection for oesophageal adenocarcinoma and 15 who had undergone oesophagectomy or biopsy for Barrett's oesophagus were studied. The latter patients also had adjacent normal gastric mucosa biopsied for comparison with the metaplastic oesophageal mucosa. The mucosal samples were snap frozen and subsequently stained with monoclonal antibodies to the following oncogene associated proteins; c-erbB2 (neu and CE-1) (external domain), cerbB2 (NCL-CB11) (internal domain), c-src, c-ras, c-myc, c-fos, c-jun, and the oncosuppressor gene -p53. All tumours were well or moderately differentiated adenocarcinomas arising from the lower third of the oesophagus. Eleven specimens showed strong membraneous staining with both c-erbB2 (neu) and c-erbB2 (CBL-CBll). Seven specimens showed strong nuclear staining with p53 oncosuppressor gene. Three specimens were positive for c-ras and c-src, and two were positive for c-jun. In Barrett's epithelium, nine specimens were positive for c-erbB2 (neu and CBII), three were positive for c-src, two were positive for c-ras and c-jun, and one was positive for c-fos. Two of the gastric mucosal biopsy specimens expressed c-erbB2 weakly but no other oncogenes were found. The frequency of positive staining for c-erbB2 is very high, compared with the expression of these genes in other tumours. It is also concluded that errors in the onco-suppressor gene p53, and especialiy in the external and internal domains of c-erbB2, which is also often expressed in Barrett's mucosa, may be implicated in the development of adenocarcinoma of the oesophagus.
Repeated injections of cholecystokinin (CCK) during a period of up to 3 weeks significantly increased the weight of the pancreas in rats. This was associated with an increase in the amount of protein per unit weight of DNA, suggesting hypertrophy of the acinar cells, and with increase in the total amount of pancreatic DNA, indicating additional hyperplasia of the gland. CCK administration also increased the pancreatic content of amylase and trypsin, but the content of lipase remained unchanged. The rate of secretion of the two enzymes increased in the CCK-treated rats, although it appeared that the functional capacity of the individual pancreatic acinar cells was not increased. CCK injections had no effect on the insulin content of the pancreas or on the composition of the partoid glands. Repeated injections of secretin in the doses used in this study had no effect on the pancreas.
1. In order to assess potential abnormalities in the control of mucosal proliferation, 30 patients with Barrett's oesophagus were studied in order to evaluate the presence and distribution of epidermal growth factor, transforming growth factor-alpha and epidermal growth factor receptor to determine the Ki-67 labelling index in the affected oesophageal mucosa. Serial sections were analysed immunohistochemically. Ten of the patients had adenocarcinoma in the Barrett's mucosa and the other 20 had differing histological types of Barrett's mucosa (10, intestinal-type; 10, fundic- or cardiac-type). 2. The expression of transforming growth factor-alpha, epidermal growth factor and epidermal growth factor receptor was increased and the Ki-67 labelling index was higher in Barrett's mucosa compared with normal gastric mucosa. The 'intestinal-type' of Barrett's mucosa had the greatest expression of transforming growth factor-alpha, epidermal growth factor receptor and the highest Ki-67 labelling index compared with the other types of Barrett's metaplasia. Five cases of 'intestinal-type' Barrett's metaplasia had especially high Ki-67 labelling indices and these patients over-expressed both transforming growth factor-alpha and epidermal growth factor receptor. The patients with adenocarcinomas in the Barrett's mucosa also over-expressed transforming growth factor-alpha and epidermal growth factor receptor, but not epidermal growth factor, compared with normal gastric mucosa. 3. In conclusion, both normal gastric mucosa and Barrett's mucosa have potential autocrine growth regulatory mechanisms, but Barrett's mucosa has increased expression of both of the measured ligands and of the epidermal growth factor receptor.
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