Helicobacter pylori infection and colorectal carcinoma: is there a causal association?

Abstract

To the Editor, We would like to thank Dr. Kapetanakis and his colleagues for their interest in our article (1). We specifically appreciate the attention they brought to the importance of environmental factors, particularly Helicobacter pylori (H. pylori) infection, in the development of sporadic colorectal carcinoma (CRC). While the focus of our article was on the pathologic aspects (2), we would like to take this opportunity to extend our discussion to H. pylori as a potential etiopathogenetic factor in colorectal tumorigenesis. As mentioned by Dr. Kapetanakis and his colleagues, the development of sporadic CRC is associated with a variety of environmental factors including diet and lifestyle. Given that the colon harbors the largest number of microorganisms in the body, it is natural to assume that certain microbial species may play a role in colorectal tumorigenesis. The first reports connecting intestinal microflora with CRC were published back in the early 1950s. Streptococcus bovis septicemia was reported to be associated with carcinoma of the sigmoid colon (3). This association was subsequently supported by several publications (4-6). Animal studies have shown that S. bovis or its cell wall antigens promote the formation of hyperproliferative aberrant colonic crypts, enhance the expression of proliferation markers, and increase IL-8 production in the colonic mucosa (7). IL-8 is a proinflammatory cytokine that has been shown to promote the growth, angiogenesis and metastasis of colon cancer cells (8-11). Taken together, these observations suggest that S. bovis acts as a promoter of colorectal tumorigenesis. Later on in the mid-1970s, experiments with germ-free rats further showed that intestinal microflora played a modifying role in colorectal tumorigenesis. Germ-free rats developed much fewer colonic tumors compared to conventional rats when challenged with carcinogens (12,13). Since then, a number of commensal bacteria have been linked to CRC, including Escherichia coli, Enterococcus faecalis, Bacteroides spp. (B. fragilis, B. vulgatus, B. stercoris), Eubacterium limosum, and Clostridium septicum (14-22). Ever since the oncogenic properties of H. pylori were firmly established in the stomach, studies on its oncogenicity have extended to other parts of the gastrointestinal tract, particularly the colon (23). To date, the link between H. pylori infection and CRC remains inconclusive, with some reports showing an association (24-32) while others none (33-37). The results of two meta-analyses published in 2006 and 2008 both suggested a possible small increased risk of CRC in association with H. pylori infection (38,39). Several hypotheses have been proposed to explain the possible link between H. pylori infection and CRC. These include: (I) hypergastrinemia, (II) change in colorectal microflora, (III) toxin production, and (IV) chronic inflammation secondary to direct H. pylori colonization in the colon.