# Bacterial Therapy of Cancer: A Way to the Dustbin of History or to the Medicine of the Future?
## 3 Tumor Microbiome: Peaceful Inhabitants or Malicious Instigators?
The classification of carcinogenic agents was developed by the International Agency for Research on Cancer based on a set of precise and strict criteria, including the genotoxicity of the potential carcinogenic agent, its electrophilicity and immunosuppressive, the ability to alter DNA repair or cause genomic instability, induce epigenetic alterations, oxidative stress, or chronic inflammation, to modulate receptor-mediated effects, cause immortalization, and alter cell proliferation, cell death, or the nutrient supply [39; 40]. According to these criteria, only one bacterial pathogen is defined to date by the IARC as a human carcinogenic agent--_Helicobacter pylori_, which is considered as the strongest known risk factor for gastric cancer [41; 42; 43; 44]. The researchers who showed its role in inducing stomach ulcers were awarded the Nobel prize in 2005. According to estimations, more than half the world's population is infected with _H. pylori_; however, to be fair, only a small minority (1-2%) of those infected develop gastric cancer or precancerous gastric lesions. By colonizing the stomach, _H. pylori_ can cause chronic inflammation and induce high levels of expression of proinflammatory cytokines, which cause oxidative stress and oxidative DNA damage in the infected mucosa. On the other hand, increased production of free radicals--reactive oxygen/nitrogen species (ROS/RNS)--near _H. pylori_ takes place, leading to an increase in the mutation rate of host cells. Altogether, this leads to the genomic instability and activates oncogenic pathways. The more or less virulent strains of _H. pylori_ were described: those strains that produce high levels of proteins such as vacuolating cytotoxin A (VacA), cytotoxin-associated gene A protein (CagA), and neutrophil-activating protein A (NapA) appear to cause more tissue damage than those that produce lower levels or are completely devoid of these proteins. Another effect of the CagA protein is suggested to prevent the human immune system from recognizing and killing bacterial cells, which is a critical factor in the long-term survival of this bacterium inside the stomach. _H. pylori_ also causes a variety of epigenetic changes which can be associated with the development of cancer. These epigenetic changes occur due to the _H. pylori_-induced methylation of CpG sites in gene promoters and the altered expression of multiple microRNAs. Epigenetic changes lead in particular to a decrease in the effectiveness of the DNA repair mechanism, contributing to the accumulation of mutations and genomic instability. The development of gastric carcinoma is a step-by-step process, and is typically preceded by the development of chronic gastritis, intestinal metaplasia, and dysplasia [45]. In addition to _H. pylori_, there are several other bacterial species that are commonly discussed as associated or even being causative agents (triggering factors?) of cancer (Table 1). Among them are _Salmonella typhi_, which is considered as linked to hepatobiliary carcinoma and gallbladder cancer, _Campylobacter jejuni_ (small intestinal lymphomas), _Chlamydia pstitaci_ (ocular lymphomas), _Mycobacterium tuberculosis_ and _Chlamydia pneumonia_ (lung cancer), _Fusobacterium nucleatum_, _Bacteroides fragilis_, _Streptococcus bovis_ and _Citrobacter rodentium_ (human colorectal cancer), _Chlamydia trachomatis_ (cervical cancer), _Porphyromonas gingivalis_ (pancreatic and oral cancer), and some others (Figure 1). These bacteria are usually found in the altered microbiota of the damaged tissues of cancer patients. There are many investigations demonstrating that these bacteria secrete virulence factors resulting in oxidative stress, chronic inflammation, and host DNA damage that can promote carcinogenesis.