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A bacterial driverpassenger model for colorectal cancer: beyond the usual suspects
Harold Tjalsma, Annemarie Boleij, Julian R.Marchesi and Bas E.Dutilh
Abstract | Cancer has long been considered a genetic disease. However, accumulating evidence supports the involvement of infectious agents in the development of cancer, especially in those organs that are continuously exposed to microorganisms, such as the large intestine. Recent next-generation sequencing studies of the intestinal microbiota now offer an unprecedented view of the aetiology of sporadic colorectal cancer and have revealed that the microbiota associated with colorectal cancer contains bacterial species that differ in their temporal associations with developing tumours. Here, we propose a bacterial driverpassenger model for microbial involvement in the development of colorectal cancer and suggest that this model be incorporated into the genetic paradigm of cancer progression.
Cancer is defined as uncontrolled, malignant cell proliferation caused by accumulated genetic and epigenetic mutations1,2. The triggers for these mutations can be multifactorial in origin and remain elusive in many cases. Several types of cancer are associated with infectious agents, and many of these cancers occur in tissues with a high exposure to the microbiota3. It has been estimated that about 20% of the global cancer burden can be linked to infectious agents4.
Wellknown examples include cervicaland gastric cancer, which can be caused by human papilloma viruses and the bacterium Helicobacter pylori, respectively4,5.
Bacteria constitute about 90% of all cells in the human body, and it has been estimated that the total number of microbial genes exceeds the number of human genes by two orders of magnitude or more6. The majority of these bacteria, an estimated1014 cells comprising >103 different species, colonize the large intestine69. Interestingly, the bacterial density in the large intestine (~1012cells per ml) is much greater than that in the small intestine (~102 cells per ml), and this is paralleled by an approximately 12fold
increase in cancer risk for the large intestine compared with the small intestine10,11.
Moreover, mutant mice that are genetically susceptible to colorectal cancer (CRC) develop significantly fewer tumours under germfree conditions than when they have a conventional microbiota1214. Despite this knowledge, the possibility that intestinal microorganisms have a direct effect on the initiation and progression of sporadic CRC has...