The Role of Apoptosis and Apoptosis Regulatory Genes in Stem Cell Homeostasis and Carcinogenic Risk in the Gastrointestinal Tract

摘要

The gastrointestinal tract is one of the major organs of the body, and the small intestine makes up a major component of the gastrointestinal tract. In humans, the small intestine is between 5 and 6 m in length (about 20 cm in the mouse), in contrast to the large bowel, which has a length of about 11/2 m in humans (6-7 cm in the mouse). In both regions, cell proliferation is high to compensate for the extensive cell loss that occurs when cells reach the end of their functional differentiated life and are extruded into the lumen of the gut. Cell cycle times are short, particularly in the mouse, where in the small intestine the majority of cells in the crypts divide twice a day. The transit time through the tissue of a newborn cell in the crypt to the time that it is lost at the end of its life from the villus tip or the intercrypt table is short. In the mouse small intestine this transit time is of the order of 2-5 days (the time depending on whether the cell being considered is at the top of the crypt or closer to the bottom of the crypt). As a consequence of the rapid cell cycle activity and the short transit time, the small intestine is extremely sensitive to cytotoxic agents including radiation and expresses the damage rapidly. Clinically it is well known that the gastrointestinal tract is one of the major limiting tissues in cancer therapy, with gastrointestinal mucositis and the radiation or drug cytotoxic syndrome being an unpleasant side effect of cancer therapy. Colorectal cancer is the third commonest cancer in the Western world, in both males and females. The incidence and mortality levels between the sexes are almost equal. There have been many attempts to address the question as to why the colorectum is so prone to cancer development, but an interesting corollary question is why is it that the small intestine, which represents a much larger mass of tissue and is generally proliferating faster by a factor of about 2 than the large intestine, so rarely develops cancer? The incidence or mortality figures for small intestinal cancer are about 1.5% of those for the colorectum. An insight into the answers to these questions may be found in studies comparing the response of the small and large bowel to cytotoxic insults, the activation and effectiveness of the early response genes, and the relative levels of apoptosis and cell survival that are determined by the genes involved in apoptosis and cell survival.