PubMed · 11774965
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K Hornbuckle, J Scheiman. 2001. EUS--predicting the future?. https://doi.org/10.1016/s0002-9270(01)03934-x
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Mutational alterations of PTEN and PIK3CA, which negatively and positively regulate PI3-kinase activity, respectively, have been observed in many types of human cancer. To explore the implication of PTEN and PIK3CA mutations in gastric tumorigenesis, we characterized the expression and mutation status of the genes in 126 gastric tissues and 15 cell lines. Expression of PTEN transcript was abnormally low in 5 of 15 (33%) cell lines and 20 of 55 (36%) primary carcinomas, whereas 0 of 71 noncancerous tissues including 16 benign tumors showed altered expression. Allelotyping analysis using an intragenic polymorphism (IVS4+109) revealed that 14 of 30 (47%) informative cases carried LOH of the gene, which is closely linked to low expression. The LOH rate was significantly higher in advanced tumors [12 of 19 (63%)] compared to early-stage tumors [2 of 11 (18%)] and more frequent in poorly differentiated tumors [9 of 13 (69%)] than well- or moderately differentiated tumors [5 of 17 (29%)]. Interestingly, however, none of the LOH tumors carried mutational disruption of the remaining allele, suggesting haploinsufficiency of PTEN in gastric tumorigenesis. Methylation studies revealed that PTEN pseudogene, but not PTEN, is methylated in cell lines and primary tumors, indicating that PTEN is not a target of epigenetic silencing in gastric cancers and that the pseudogene should be considered more carefully in methylation analysis of the PTEN promoter. Genomic amplification of PIK3CA was found in 9 of 15 (60%) cell lines and 20 of 55 (36.4%) primary tumors but in no noncancerous tissues. Furthermore, PIK3CA amplification was predominantly detected in tumors with no PTEN alterations, suggesting that mutations of PTEN and PIK3CA are mutually exclusive events in gastric tumorigenesis. Amplification of PIK3CA was strongly associated with increased expression of PIK3CA transcript and elevated levels of phospho-AKT. Collectively, our data reveal that 13 of 15 (87%) gastric cell lines and 31 of 55 (56%) primary carcinomas harbored either amplification of PIK3CA or abnormal reduction of PTEN. Mutually exclusive alterations of PTEN and PIK3CA also suggest that mutations of either gene could activate the PI3-kinase/AKT signaling pathway, which is directly linked to the malignant progression of gastric tumor cells.
The modification effects of nimesulide, a cyclooxygenase (COX)-2 inhibitor, administration during the postinitiation phase of pancreatic carcinogenesis were investigated in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Male Syrian hamsters were given 4 weekly s.c. injections of BOP at a dose of 10 mg/kg and thereafter administered 0, 100 or 400 ppm nimesulide in the diet for 36 weeks. Additional groups of hamsters were fed 400 ppm nimesulide without prior BOP initiation or nontreated. At week 40, all surviving animals were killed and development of neoplastic and preneoplastic lesions was assessed histopathologically. The incidence of pancreatic adenocarcinomas was significantly (p < 0.05) decreased in the BOP/400 ppm nimesulide group compared to the BOP alone group. The multiplicity of total lesions of pancreatic adenocarcinoma plus atypical hyperplasia was also significantly (p < 0.05) lowered. Immunohistochemically, COX-2 was clearly expressed in pancreatic and lung tumor cells, whereas expression was not remarkably affected by the 400 ppm nimesulide treatment. Proliferating cell nuclear antigen labeling indices of pancreatic ducts were significantly (p < 0.01) reduced by nimesulide. The incidence and multiplicity of neoplastic lesions in other organs did not significantly differ among the BOP-treated groups, though only the multiplicity of lung tumors showed a tendency to decrease. No neoplastic lesions were detected in animals receiving nimesulide alone. Our results clearly indicate that nimesulide protects against BOP-induced pancreatic tumors in hamsters.
A rat colonic adenocarcinoma was implanted subcutaneously in female nude (C57BL/6JBom-nu) mice. After 7 days, the animals were divided into different groups. One group received triple therapy with octreotide, galanin, and serotonin, 10 microg/kg body weight of each, twice daily. The second group served as controls and received only saline solution. Three groups received 10 microg/kg body weight twice daily of octreotide, galanin, or serotonin. The last group consisted of controls that received only saline solution. The treatment lasted for 5 days. The tumour volume, wet weight, and relative volume density of blood vessels were significantly decreased after the triple treatment, as compared to controls. Apoptotic index was significantly increased, but the proliferation index was not affected in the group of mice that received triple therapy. There was no significant difference between controls and mice treated with octreotide, galanin, or serotonin regarding tumour volume or weight. The relative volume density of blood vessels was decreased in tumours treated with galanin, but not with octreotide or serotonin. There was no statistical difference in the proliferation index between controls and animals treated with octreotide, galanin, or serotonin, as compared with controls. Tumour necrosis and increased apoptosis may be responsible for the reduction in the volume and weight of the tumour after triple therapy. Tumour necrosis may be caused by the induction of tumour ischemia due to a reduction in tumour blood flow, which is caused by decreased incidence of tumour-feeding blood vessels, and by constriction of tumour-feeding arterioles. These results are promising and may offer treatment for colon cancer.