Carcinogenic bacteria

Known to cause cancer

Helicobacter pylori colonizes the human stomach and duodenum. It is described as a Class 1 carcinogen. In some cases it can cause stomach cancer and MALT lymphoma. Animal models have demonstrated Koch's third and fourth postulates for the role of Helicobacter pylori in the causation of stomach cancer. The mechanism by which H. pylori causes cancer may involve chronic inflammation, or the direct action of some of its virulence factors, for example, CagA has been implicated in carcinogenesis. Another bacteria that is in this genus is Helicobacter hepaticus, which causes hepatitis and liver cancer in mice.

Chronic inflammation

Chronic inflammation contributes to the pathogenesis of several types of malignant diseases, but it is particularly important for H. pylori. Following a H. pylori infection many circulating immune cells are recruited to the infection site including neutrophils. To destroy the pathogens, neutrophils produce substances with antimicrobial activities such as oxidants like reactive oxygen species (ROS) and reactive nitrogen species (RNS). H. pylori can survive the induced oxidative stress by producing antioxidant enzymes such as e.g., catalase. However, the overproduction of ROS and RNS induces various types of DNA damage in the infected gastric cells.At the same time H. pylori is known to down-regulate major DNA repair pathways. As a result, genomic and mitochondrial mutations accumulate, leading to genomic instability - a well-known hallmark of Cancer - in the gastric cells.

CagA

The virulence factor CagA in H. pylori has been linked to the development of gastric cancer. Once CagA is injected into the cytoplasm it can change the gastric cell signaling in both a phosphorylation-dependent and -independent manner. Phosphorylated CagA affects cell adhesion, spread and migration but can also induce the release of the proinflammatory chemokine IL-8. This leads to the activation of the pro-inflammatory NF-κB and β-catenin pathways as well as increased gastric cell proliferation. Furthermore, CagA has also been found to increase tumor suppressor gene hypermethylation and thereby inhibiting the tumor suppressor genes. This is achieved by upregulating the methyltransferase DNMT1 via the AKT–NF-κB pathway. Lastly, CagA also induces the expression of the enzyme spermine oxidase (SMOX) that converts spermine to spermidine. As a by-product H2O2 is produced which causes ROS accumulation and contributes to the oxidative stress that the gastric cells experience during chronic inflammation.

Speculative links

A number of bacteria have associations with cancer, although their possible role in carcinogenesis is unclear.

Salmonella Typhi has been linked to gallbladder cancer but may also be useful in delivering chemotherapeutic agents for the treatment of melanoma, colon and bladder cancer. Microorganisms and their metabolic byproducts, or impact of chronic inflammation, may also be linked to oral cancers.

The relationship between cancer and bacteria may be complicated by different individuals reacting in different ways to different cancers.

History

In 1890, the Scottish pathologist William Russell reported circumstantial evidence for the bacterial cause of cancer. In 1926, Canadian physician Thomas Glover reported that he could consistently isolate a specific bacterium from the neoplastic tissues of animals and humans. One review summarized Glover's report as follows:

Glover was asked to continue his work at the Public Health Service (later incorporated into the National Institutes of Health) completing his studies in 1929 and publishing his findings in 1930. He asserted that a vaccine or anti-serum manufactured from his bacterium could be used to treat cancer patients with varying degrees of success. According to historical accounts, scientists from the Public Health Service challenged Glover's claims and asked him to repeat his research to better establish quality control. Glover refused and opted to continue his research independently; not seeking consensus, Glover's claims and results led to controversy and are today not given serious merit.

In 1950, a Newark-based physician named Virginia Livingston published a paper claiming that a specific Mycobacterium was associated with neoplasia. Livingston continued to research the alleged bacterium throughout the 1950s and eventually proposed the name Progenitor cryptocides as well as developed a treatment protocol. Ultimately, her claim of a universal cancer bacterium was not supported in follow up studies. In 1990 the National Cancer Institute published a review of Livingston's theories, concluding that her methods of classifying the cancer bacterium contained "remarkable errors" and it was actually a case of misclassification - the bacterium was actually Staphylococcus epidermidis.

Other researchers and clinicians who worked with the theory that bacteria could cause cancer, especially from the 1930s to the 1960s, included Eleanor Alexander-Jackson, William Coley, William Crofton, Gunther Enderlein, Franz Gerlach, Josef Issels, Elise L'Esperance, Milbank Johnson, Arthur Kendall, Royal Rife, Florence Seibert, Wilhelm von Brehmer, and Ernest Villequez. Alexander-Jackson and Seibert worked with Virginia Livingston. Some of the researchers published reports that also claimed to have found bacteria associated with different types of cancers.

References

References

1. (22 February 2019). "The Possible Role of Helicobacter pylori in Gastric Cancer and Its Management". Frontiers in Oncology.
2. (May 2007). "Role of Helicobacter pylori infection and chronic inflammation in gastric cancer in the cardia". Japanese Journal of Clinical Oncology.
3. (2007). "Helicobacter pylori and gastric cancer: the causal relationship". Digestion.
4. (March 2000). "Gastric MALT lymphoma and its relationship to Helicobacter pylori infection: management and pathogenesis of the disease". Microscopy Research and Technique.
5. (September 1998). "Helicobacter pylori infection induces gastric cancer in mongolian gerbils". Gastroenterology.
6. (December 2005). "Helicobacter pylori CagA: a new paradigm for bacterial carcinogenesis". Cancer Science.
7. (June 2003). "The complete genome sequence of the carcinogenic bacterium Helicobacter hepaticus". Proceedings of the National Academy of Sciences of the United States of America.
8. (December 2002). "Inflammation and cancer". Nature.
9. (May 2015). "Differential inflammatory response to Helicobacter pylori infection: etiology and clinical outcomes". Journal of Inflammation Research.
10. (February 2023). "Helicobacter pylori and Gastric Cancer: Pathogenetic Mechanisms". International Journal of Molecular Sciences.
11. (2017-02-27). "Inflammation, DNA Damage, Helicobacter pylori and Gastric Tumorigenesis". Frontiers in Genetics.
12. (August 2010). "Helicobacter pylori infection generates genetic instability in gastric cells". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer.
13. (March 2011). "Hallmarks of cancer: the next generation". Cell.
14. (March 2014). "Helicobacter pylori CagA and gastric cancer: a paradigm for hit-and-run carcinogenesis". Cell Host & Microbe.
15. (October 2002). "Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites". Proceedings of the National Academy of Sciences of the United States of America.
16. (January 2009). "Helicobacter pylori CagA phosphorylation-independent function in epithelial proliferation and inflammation". Cell Host & Microbe.
17. (August 2021). "The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review". Cancers.
18. (December 2017). "DNA methyltransferases and their roles in tumorigenesis". Biomarker Research.
19. (March 2016). "Helicobacter pylori CagA induces tumor suppressor gene hypermethylation by upregulating DNMT1 via AKT-NFκB pathway in gastric cancer development". Oncotarget.
20. (June 2015). "Bacteria Moving into Focus of Human Cancer". Cell Host & Microbe.
21. (June 2015). "Salmonella Manipulation of Host Signaling Pathways Provokes Cellular Transformation Associated with Gallbladder Carcinoma". Cell Host & Microbe.
22. (March 2006). "Bacteria and cancer: cause, coincidence or cure? A review". Journal of Translational Medicine.
23. (July 2004). "Association of Streptococcus bovis bacteremia with colonic neoplasia and extracolonic malignancy". Archives of Surgery.
24. (August 2003). "Chronic Chlamydophila pneumoniae infection in lung cancer, a risk factor: a case-control study". Journal of Medical Microbiology.
25. (May 2004). "[Mycoplasma infection and cancer]". AI Zheng = Aizheng = Chinese Journal of Cancer.
26. (September 2009). "Persistent exposure to Mycoplasma induces malignant transformation of human prostate cells". PLOS ONE.
27. (2021-03-01). "Molecular modelling of the gastric barrier response, from infection to carcinogenesis". Best Practice & Research. Clinical Gastroenterology.
28. (2015). "Role of bacteria in oral carcinogenesis". Indian Journal of Dentistry.
29. (February 2023). "Bacterial Infections and Cancer: Exploring This Association And Its Implications for Cancer Patients". International Journal of Molecular Sciences.
30. (July 2004). "Frequent and preferential infection of Treponema denticola, Streptococcus mitis, and Streptococcus anginosus in esophageal cancers". Cancer Science.
31. (July 2016). "Major Anaerobic Bacteria Responsible for the Production of Carcinogenic Acetaldehyde from Ethanol in the Colon and Rectum". Alcohol and Alcoholism.
32. (February 2005). "Diet, anaerobic bacterial metabolism, and colon cancer: a review of the literature". Journal of Clinical Gastroenterology.
33. (September 2009). "Exploring the link between microorganisms and oral cancer: a systematic review of the literature". Head & Neck.
34. (December 1890). "An Address on a Characteristic Organism of Cancer". British Medical Journal.
35. (1926). "Progress in Cancer Research". Canada Lancet and Practitioner.
36. (1926). "A selected public health bibliography with annotations". American Journal of Public Health.
37. Glover TJ. (1930). "The bacteriology of cancer". Canada Lancet and Practitioner.
38. (1938). "Studies in Malignancy". Murdock Foundation.
39. (1990). "Livingston-Wheeler therapy". CA.
40. (December 1950). "Cultural properties and pathogenicity of certain microorganisms obtained from various proliferative and neoplastic diseases". The American Journal of the Medical Sciences.
41. (September 1965). "An experimental biologic approach to the treatment of neoplastic disease; determination of actinomycin in urine and cultures as an aid to diagnosis and prognosis". Journal of the American Medical Women's Association.
42. (1997). "Can Bacteria Cause Cancer?". NYU Press.
43. (January 1931). "Studies in Hodgkins Disease". Annals of Surgery.
44. (June–August 1941). "Etude bacteriolgigue sur la maladie d'Hodgkin". Montpellier Medicine.
45. "Siphonosopra polymorpha n. sp.: ein neuer microorganismus des blutes, seine beziehung zur tumorgenese". Med Welt.
46. (1936). "The True Nature of Viruses.". Staples Press Ltd..
47. (1955). "Le Parasitisme Latent des Cellules du Sang chez l' Homme, en Particulier dans le Sang des Cancreeux.". Librarie Maloine.
48. (1958). "Eziopatogenese del Cancro". Amadeo Nicola.& c..