The role of bacterial pathogens in cancer Roger Vogelmann 1 and Manuel R Amieva 2 The association of Helicobacter pylori with gastric cancer is the best-studied relationship between a bacterial infection and cancer. Other bacterial pathogens in humans and rodents are now being recognized as potentially having a direct role in carcinogenesis. Thus, it might be possible to understand the pathogenesis and prevention of certain cancers by studying the bacterial infections associated with them, and their effects on the host. However, the mechanisms by which bacteria contribute to cancer formation are complex, and recent investigations show that they involve the interplay between chronic inflammation, direct microbial effects on host cell physiology and, ultimately, changes in tissue stem cell homeostasis. Addresses 1 Klinikum rechts der Isar, II Medizinische Klinik, Technical University Munich, Ismaninger Street 22, D-81675 Munich, Germany 2 Department of Microbiology and Immunology, Fairchild D035, Stanford University School of Medicine, 299 Campus Drive, Stanford, CA 94305– 5124, USA Corresponding author: Amieva, Manuel R (amieva@stanford.edu) Current Opinion in Microbiology 2007, 10:76–81 This review comes from a themed issue on Host-microbe interactions: bacteria Edited by Pamela Small and Gisou van der Goot Available online 8th January 2007 1369-5274/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.mib.2006.12.004 Introduction The discovery of penicillin in 1929 by Alexander Fleming and its introduction to the public in 1942 after a fire catastrophe in a Boston nightclub dramatically changed the course of human history. The long-time search for drugs that would kill disease-causing bacteria without toxicity to the patient was beginning to bear fruit [1]. Less than a century later, cancer-related diseases have overtaken most bacterial-associated diseases with regards to the need to find non-toxic strategies to treat them. We realize now that less toxic treatments for cancer, as well as cancer prevention strategies will evolve from an under- standing of the biological principles that govern cancer formation. Despite the tremendous impact antibiotics have had in fighting infectious diseases, pathogenic bac- teria are still with us. In fact, we are beginning to learn that some chronic bacterial infections are associated with tumor formation, and thus that it might even be possible to prevent or treat some forms of cancer if we address the infectious source [2]. Although antibiotic therapy is com- mon practice for one type of gastric cancer (mucosa- associated lymphoid tissue [MALT] lymphoma) [3], the complexity of ‘cause and effect’ between bacterial infection and cancer formation lies at the crux of the relationship between microbes and humans as their hosts. The best-studied relationship between a bacterial infec- tion and cancer is that of Helicobacter pylori and two different forms of gastric cancer: MALT lymphoma and the more common gastric adenocarcinoma [4]. It is estimated that H. pylori is causally related to 60–90% of all gastric cancers [2]. Other known associations between bacterial infections and human cancer are that of Salmo- nella typhi infection and gallbladder cancer in people that develop chronic carriage after typhoid fever, Streptococcus bovis and colon cancer, Chlamydia pneumonia and lung cancer, and Bartonella species and vascular tumor for- mation [5–8]. Causality between infection and tumor formation has been shown for Bartonella [8,9] and has also been established in various animal model systems for H. pylori [10,11]; however, for most other associations it is still not known whether the bacterial infection is a marker of disease or is causally related to tumor formation. The idea that certain bacteria are capable of causing cancer is further supported by studies of animal-specific patho- gens that promote tumor formation in rodents. For example, Helicobacter hepaticus was discovered in 1992 as a cause of chronic active hepatitis that progressed to hepatocellular carcinoma in A/JCr mice [12]. Furthermore, formation of colon cancer in genetically altered mice is also promoted by H. hepaticus infection, either on its own, [13,14] or in conjunction with Helicobacter bilis [15]. Also, chronic infection with Citrobacter rodentium, a mouse pathogen that is genetically similar to enteropathogenic Escherichia coli, can result in colon cancer [16]. In a recent study, Rao et al.[17  ] were able to show that H. hepaticus indirectly promotes cancer formation in the mammary gland of mice, which is not directly exposed to the bacteria. In general, these studies suggest that bacteria often are not sufficient to induce cancer on their own, that the process is accompanied by chronic inflammation, and that tumor formation might require independent mutations in oncogenic signaling pathways. Bacteria-induced cancer: effects on the immune system Chronic inflammatory conditions have been known to promote and modulate tumor formation with or without Current Opinion in Microbiology 2007, 10:76–81 www.sciencedirect.com