Carbonate Ions and Gastric Cancer

Sammanfattning: Nearly one million new cases of gastric cancer are diagnosed annually throughout the world. Even though the incidence has fallen dramatically in recent decades, this disease is still the second leading cause of cancer death in a global perspective. The geographic distribution of gastric cancer varies markedly, with the highest rates in Asian countries such as Japan, Korea, and China. This variation is presumably associated with modifiable risk factors, primarily H. pylori infection and diet, which have dominated the debate on this topic for more than a decade. The incidence of spontaneous gastric cancer is extremely low in rats, which has led to testing of different experimental models in attempts to generate gastric tumors in these animals. In the first study underlying this thesis, rats were subjected to gastric resection to generate duodenogastric reflux (DGR) and subsequent development of gastric adenocarcinomas. The effects of various food supplements on the incidence of cancer were studied using a total of 256 male Wistar rats. Surprisingly, in the first set of experiments in the second study, ingestion of food supplemented with calcium carbonate more than tripled the incidence of carcinomas (61%) compared to controls (17%). In a second set of experiments, calcium ions were switched to sodium ions, which revealed that carbonate ions caused the remarkable increase in cancer in the rats given an altered diet (54%, compared to 12% for controls). Both experimental and clinical studies have shown that DGR is associated with the development of gastric cancer. It has also been found that pancreaticoduodenal juice is responsible for the neoplastic formation, and that such fluid is especially rich in carbonate ions. The final study examined non-transformed mucosa in a rat model of gastric cancer to determine expression of COX-2 and ODC as markers of tumor promotion and to measure production of Ki67 as an indication of cell proliferation. This was done to assess the effect of carbonate ions on gastric tumorigenesis. The results indicated that the gastric resection per se increased COX-2 expression and significantly augmented cell proliferation. Dietary supplementation of carbonate ions did not further enhance the levels of COX-2. However, in the resected animals, carbonate-supplemented food led to elevated expression of ODC and a further increase in cell proliferation in the non-transformed mucosa. In conclusion, an environment entailing persistent chronic inflammation and increased levels of COX-2, induced by either duodenogastric reflux or a factor such as H. pylori infection, increases the risk of malignant transformation. Moreover, extra carbonate intake raises the levels of ODC in the gastric mucosa in a COX-2-dependent manner, which magnifies the proliferative drive and results in an even higher risk of gastric carcinoma.