The role of bacterial pathogens in cancer
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 understanding of the biological principles that govern cancer formation. Despite the tremendous impact antibiotics have had in fighting infectious diseases, pathogenic bacteria 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 common 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 infection 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 Salmonella 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 formation [5, 6, 7, 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 pathogens 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.
Section snippets
Bacteria-induced cancer: effects on the immune system
Chronic inflammatory conditions have been known to promote and modulate tumor formation with or without infection [18]. Host genetic polymorphisms of the adaptive and innate immune response play an important role in bacteria-induced cancer formation [19, 20]. Therefore, studying the immunological responses to chronic bacterial infections is likely to yield important clues on both the mechanisms of persistent infection and the relationship between inflammation and cancer formation [21, 22].
Bacterial virulence factors and cancer
Bacterial pathogens have evolved several sophisticated effector molecules that are used to interact specifically with host eukaryotic cells for various purposes. Some are involved in adhesion to cell surfaces, in activating or inhibiting entry into host cells, others modulate cytoskeletal or junctional functions, and yet others activate specific eukaryotic signaling pathways. Some bacterial effectors have been shown to directly affect cellular processes involved in cancer formation [35], and in
Bacteria and stem cells
The gastrointestinal epithelium, where many of the bacteria-induced tumors originate, is a highly dynamic tissue with a high turnover rate of about 2 × 108 epithelial cells per day. The differentiated epithelium is regenerated by tissue-specific stem cells. In order to secure the vast supply of differentiated cells, stem-cell homeostasis is tightly regulated to avoid uncontrolled proliferation and hence cancer formation [58]. Findings in Drosophila suggest that the stem cell niche regulates
Conclusion
The discovery of H. pylori and its association with gastric cancer has fueled the idea that bacteria can cause cancer. Studies in animal models convincingly support a causative role for several bacterial pathogens in cancer formation. The pathogenesis of this process is complex, and involves interplay between the effects of chronic inflammation, bacterial products that affect cell signaling and cell biology, and stem-cell homeostasis (Figure 1). Not every bacteria-induced chronic infection, not
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Because of space constraints we have included examples of a limited number of pathogens and their targets rather than attempting to be complete. We apologize to the many investigators whose work we were unable to cite. Work from the Vogelmann and Amieva laboratories is supported by a Max-Eder Nachwuchsgruppe, Deutsche Krebshilfe (RV); RO1–CA92229, PO3 DK56339 and MedImmune Career Development Award.
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