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Cancer bacteria are bacteria infectious organisms that are known or suspected to cause cancer. [1] While cancer-associated bacteria have long been considered to be opportunistic (i.e., infecting healthy tissues after cancer has already established itself), there is some evidence that bacteria may be directly carcinogenic. Evidence has shown that a specific stage in cancer can be associated with bacteria that is pathogenic. [2] The strongest evidence to date involves the bacterium H. pylori and its role in gastric cancer. [1]
Oncoviruses are viral agents that are similarly suspected of causing cancer.
Helicobacter pylori colonizes the human stomach and duodenum. It is described as a Class 1 carcinogen. [2] In some cases it can cause stomach cancer [3] [4] and MALT lymphoma. [5] Animal models have demonstrated Koch's third and fourth postulates for the role of Helicobacter pylori in the causation of stomach cancer. [6] 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. [7] Another bacteria that is in this genus is Helicobacter hepaticus, which causes hepatitis and liver cancer in mice. [8]
Chronic inflammation contributes to the pathogenesis of several types of malignant diseases, but it is particularly important for H. pylori. [9] Following a H. pylori infection many circulating immune cells are recruited to the infection site including neutrophils. [10] To destroy the pathogens, neutrophils produce substances with antimicrobial activities such as oxidants like reactive oxygen species (ROS) and reactive nitrogen species (RNS). [11] H. pylori can survive the induced oxidative stress by producing antioxidant enzymes such as e.g., catalase. [12] However, the overproduction of ROS and RNS induces various types of DNA damage in the infected gastric cells. [12] At the same time H. pylori is known to down-regulate major DNA repair pathways. [13] As a result, genomic and mitochondrial mutations accumulate, leading to genomic instability - a well-known Hallmark of Cancer [14] - in the gastric cells. [13]
The virulence factor CagA in H. pylori has been linked to the development of gastric cancer. [15] Once CagA is injected into the cytoplasm it can change the gastric cell signaling in both a phosphorylation-dependent and -independent manner. [11] Phosphorylated CagA affects cell adhesion, spread and migration [16] but can also induce the release of the proinflammatory chemokine IL-8. [15] Additionally, interactions of the CRPIA motif in non-phosphorylated CagA were shown to lead to the persistent activation of the PI3K/Akt pathway, a pathway that is often overly active in many human cancers. [17] [18] This leads to the activation of the pro-inflammatory NF-κB and β-catenin pathways as well as increased gastric cell proliferation. [17] Furthermore, CagA has also been found to increase tumor suppressor gene hypermethylation and thereby inhibiting the tumor suppressor genes. [19] This is achieved by upregulating the methyltransferase DNMT1 via the AKT–NF-κB pathway. [19] [20] Lastly, CagA also induces the expression of the enzyme spermine oxidase (SMOX) that converts spermine to spermidine. [11] 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. [11]
A number of bacteria have associations with cancer, although their possible role in carcinogenesis is unclear.
Bacteria | Suggested link |
---|---|
Salmonella Typhi, Paratiphi A, Typhimurium | is associated with gallbladder cancer. [21] [22] |
Streptococcus bovis | is associated with colorectal cancer. [23] [24] |
Chlamydia pneumoniae | is associated with lung cancer. [23] [25] |
Mycoplasma | may also have a role in the formation of different types of cancer. [26] [27] |
Helicobacter pylori | has been linked with certainty to stomach cancer [28] and may be related to MALT lymphoma, and has also been associated to oral cancer. [2] but may also protect certain individuals from esophageal cancer. [23] |
Porphyromonas gingivalis | is associated with esophageal cancer, colorectal cancer, pancreatic cancer. [29] |
Fusobacterium nucleatum | is associated with esophageal cancer, colorectal cancer, pancreatic cancer. [29] |
Escherichia coli | is associated with colorectal cancer. [29] |
Salmonella spp. | is associated with colorectal cancer. [29] |
Enterotoxigenic Bacteroides fragilis | is associated with colorectal cancer. [29] |
Chlamydia trachomatis in concert with HPV infection | is associated with cervical cancer. [29] |
Streptococcus anginosus | is associated with esophageal cancer. [30] |
Streptococcus mitis | is associated with esophageal cancer. [30] |
Ruminococcus | is associated with colorectal cancer when under aerobic conditions. [31] |
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. [23] Bacteria found in the gut may be related to colon cancer but may be more complicated due to the role of chemoprotective probiotic cancers. [32] Microorganisms and their metabolic byproducts, or impact of chronic inflammation, may also be linked to oral cancers. [33]
The relationship between cancer and bacteria may be complicated by different individuals reacting in different ways to different cancers. [23]
In 1890, the Scottish pathologist William Russell reported circumstantial evidence for the bacterial cause of cancer. [34] In 1926, Canadian physician Thomas Glover reported that he could consistently isolate a specific bacterium from the neoplastic tissues of animals and humans. [35] One review summarized Glover's report as follows:
The author reports the isolation of a pleomorphic organism from various types of cancer which can be grown in pure cultures in its several phases. He produced a serum from it which has given remarkable results in a series of 50 reported cases. This is very important, if true. We suppose the Cancer Society will give an opinion later on the reliability of the findings." [36]
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. [37] He asserted that a vaccine or anti-serum manufactured from his bacterium could be used to treat cancer patients with varying degrees of success. [37] 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. [38] 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. [39]
In 1950, a Newark-based physician named Virginia Livingston published a paper claiming that a specific Mycobacterium was associated with neoplasia. [40] Livingston continued to research the alleged bacterium throughout the 1950s and eventually proposed the name Progenitor cryptocides as well as developed a treatment protocol. [41] 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 . [39]
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. [42] 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. [43] [44] [45] [46] [47] [48]
Peptic ulcer disease is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines is a duodenal ulcer. The most common symptoms of a duodenal ulcer are waking at night with upper abdominal pain, and upper abdominal pain that improves with eating. With a gastric ulcer, the pain may worsen with eating. The pain is often described as a burning or dull ache. Other symptoms include belching, vomiting, weight loss, or poor appetite. About a third of older people with peptic ulcers have no symptoms. Complications may include bleeding, perforation, and blockage of the stomach. Bleeding occurs in as many as 15% of cases.
Helicobacter pylori, previously known as Campylobacter pylori, is a gram-negative, flagellated, helical bacterium. Mutants can have a rod or curved rod shape, and these are less effective. Its helical body is thought to have evolved in order to penetrate the mucous lining of the stomach, helped by its flagella, and thereby establish infection. The bacterium was first identified as the causal agent of gastric ulcers in 1983 by the Australian doctors Barry Marshall and Robin Warren, who obtained the Nobel prize in Medicine for this discovery.
Helicobacter is a genus of gram-negative bacteria possessing a characteristic helical shape. They were initially considered to be members of the genus Campylobacter, but in 1989, Goodwin et al. published sufficient reasons to justify the new genus name Helicobacter. The genus Helicobacter contains about 35 species.
Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lymphomas and mesenchymal tumors may also develop in the stomach. Early symptoms may include heartburn, upper abdominal pain, nausea, and loss of appetite. Later signs and symptoms may include weight loss, yellowing of the skin and whites of the eyes, vomiting, difficulty swallowing, and blood in the stool, among others. The cancer may spread from the stomach to other parts of the body, particularly the liver, lungs, bones, lining of the abdomen, and lymph nodes.
Gastritis is the inflammation of the lining of the stomach. It may occur as a short episode or may be of a long duration. There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain. Other possible symptoms include nausea and vomiting, bloating, loss of appetite and heartburn. Complications may include stomach bleeding, stomach ulcers, and stomach tumors. When due to autoimmune problems, low red blood cells due to not enough vitamin B12 may occur, a condition known as pernicious anemia.
Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor.
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in almost all tissues and under a variety of circumstances. Normally, the balance between proliferation and programmed cell death, in the form of apoptosis, is maintained to ensure the integrity of tissues and organs. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by interfering with the programming regulating the processes, upsetting the normal balance between proliferation and cell death. This results in uncontrolled cell division and the evolution of those cells by natural selection in the body. Only certain mutations lead to cancer whereas the majority of mutations do not.
MALT lymphoma is a form of lymphoma involving the mucosa-associated lymphoid tissue (MALT), frequently of the stomach, but virtually any mucosal site can be affected. It is a cancer originating from B cells in the marginal zone of the MALT.
Martin J. Blaser is an American physician who is the director of the Center for Advanced Biotechnology and Medicine at Rutgers (NJ) Biomedical and Health Sciences and the Henry Rutgers Chair of the Human Microbiome and Professor of Medicine and Pathology and Laboratory Medicine at the Rutgers Robert Wood Johnson Medical School in New Jersey.
This is a timeline of the events relating to the discovery that peptic ulcer disease and some cancers are caused by H. pylori. In 2005, Barry Marshall and Robin Warren were awarded the Nobel Prize in Physiology or Medicine for their discovery that peptic ulcer disease (PUD) was primarily caused by Helicobacter pylori, a bacterium with affinity for acidic environments, such as the stomach. As a result, PUD that is associated with H. pylori is currently treated with antibiotics used to eradicate the infection. For decades prior to their discovery, it was widely believed that PUD was caused by excess acid in the stomach. During this time, acid control was the primary method of treatment for PUD, to only partial success. Among other effects, it is now known that acid suppression alters the stomach milieu to make it less amenable to H. pylori infection.
Toll-like receptor 5, also known as TLR5, is a protein which in humans is encoded by the TLR5 gene. It is a member of the toll-like receptor (TLR) family. TLR5 is known to recognize bacterial flagellin from invading mobile bacteria. It has been shown to be involved in the onset of many diseases, including Inflammatory bowel disease due to the high expression of TLR in intestinal lamina propria dendritic cells. Recent studies have also shown that malfunctioning of TLR5 is likely related to rheumatoid arthritis, osteoclastogenesis, and bone loss. Abnormal TLR5 functioning is related to the onset of gastric, cervical, endometrial and ovarian cancers.
Estimates place the worldwide risk of cancers from infectious causes at 16.1%. Viral infections are risk factors for cervical cancer, 80% of liver cancers, and 15–20% of the other cancers. This proportion varies in different regions of the world from a high of 32.7% in Sub-Saharan Africa to 3.3% in Australia and New Zealand.
Helicobacter felis is a bacterial species in the Helicobacteraceae family, Campylobacterales order, Helicobacter genus. This bacterium is Gram-negative, microaerophilic, urease-positive, and spiral-shaped. Its type strain is CS1T. It can be pathogenic.
Helicobacter salomonis is a species within the Helicobacter genus of Gram-negative bacteria. Helicobacter pylori is by far the best known Helicobacter species primarily because humans infected with it may develop gastrointestinal tract diseases such as stomach inflammation, stomach ulcers, duodenal ulcers, stomach cancers of the nonlymphoma type, and various subtypes of extranodal marginal zone lymphomass, e.g. those of the stomach, small intestines, large intestines, and rectumn. H. pylori is also associated with the development of bile duct cancer and has been associated with a wide range of other diseases, although its role in the development of many of these other diseases requires further study. Humans infected with H. salomonis may develop some of the same gastrointestinal diseases viz., stomach inflammation, stomach ulcers, duodenal ulcers, stomach cancers that are not lymphomas, and extranodal marginal B cell lymphomas of the stomach. Other non-H. pylori Helicobacter species that are known to be associated with these gastrointestinal diseases are Helicobacter bizzozeronii, Helicobacter suis, Helicobacter felis, and Helicobacter heilmannii s.s. Because of their disease associations, these four Helicobacter species plus H. salomonis are often group together and termed Helicobacter heilmannii sensu lato.
Helicobacter typhlonius is a Gram-negative bacterium and opportunistic pathogen found in the genus Helicobacter. Only 35 known species are in this genus, which was described in 1982. H. typhlonius has a small number of close relatives, including Helicobacter muridarum, Helicobacter trogontum, and Helicobacter hepaticus, with the latter being the closest relative and much more prevalent.
Helicobacter heilmannii sensu lato refers to a group of bacterial species within the Helicobacter genus. The Helicobacter genus consists of at least 40 species of spiral-shaped flagellated, Gram-negative bacteria of which the by far most prominent and well-known species is Helicobacter pylori. H. pylori is associated with the development of gastrointestinal tract diseases such as stomach inflammation, stomach ulcers, duodenal ulcers, stomach cancers that are not lymphomas, and various subtypes of extranodal marginal zone lymphomas, e.g. those of the stomach, small intestines, large intestines, and rectum. H. pylori has also been associated with the development of bile duct cancer and has been associated with a wide range of other diseases although its role in the development of many of these other diseases requires further study.
Helicobacter bizzozeronii is a species within the Helicobacter genus of Gram-negative bacteria. Helicobacter pylori is by far the best known Helicobacter species, primarily because humans infected with it may develop gastrointestinal tract diseases such as stomach inflammation, stomach ulcers, duodenal ulcers, stomach cancers of the nonlymphoma type, and various subtypes of extranodal marginal zone lymphomass, e.g. those of the stomach, small intestines, large intestines, and rectumn. H. pylori is also associated with the development of bile duct cancer and has been associated with a wide range of other diseases although its role in the development of many of these other diseases requires further study. Humans infected with H. bizzozeronii are prone to develop some of the same gastrointestinal diseases viz., stomach inflammation, stomach ulcers, duodenal ulcers, stomach cancers that are not lymphomas, and extranodal marginal B cell lymphomas of the stomach. Other non-H. pylori Helicobacter species that are known to be associated with these gastrointestinal diseases are Helicobacter felis, Helicobacter salomonis, Helicobacter suis, and Helicobacter heilmannii s.s. Because of their disease associations, these four Helicobacter species plus H. bizzozeronii are often grouped together and termed Helicobacter heilmannii sensu lato.
Helicobacter suis is a species within the Helicobacter genus of Gram-negative bacteria. Helicobacter pylori is by far the best known Helicobacter species, primarily because humans infected with it may develop gastrointestinal tract diseases such as stomach inflammation, stomach ulcers, duodenal ulcers, stomach cancers of the nonlymphoma type, and various subtypes of extranodal marginal zone lymphomass, e.g. those of the stomach, small intestines, large intestines, and rectumn. H. pylori is also associated with the development of bile duct cancer and has been associated with a wide range of other diseases although its role in the development of many of these other diseases requires further study. Humans infected with H. suis may develop some of the same gastrointestinal diseases - stomach inflammation, stomach ulcers, duodenal ulcers, stomach cancers that are not lymphomas, and extranodal marginal B cell lymphomas of the stomach. Other non-H. pylori Helicobacter species that are known to be associated with these gastrointestinal diseases are Helicobacter bizzozeronii, Helicobacter salomonis, Helicobacter felis, and Helicobacter heilmannii s.s. Because of their disease associations, these four Helicobacter species plus H. suis are often group together and termed Helicobacter heilmannii sensu lato.
Helicobacter heilmannii s.s. is a species within the Helicobacter genus of Gram negative bacteria. Helicobacter pylori is by far the best known Helicobacter species primarily because humans infected with it may develop gastrointestinal tract diseases such as stomach inflammation, stomach ulcers, duodenal ulcers, stomach cancers of the non-lymphoma type, and various subtypes of extranodal marginal zone lymphomass, e.g. those of the stomach, small intestines, large intestines, and rectum. H. pylori is also associated with the development of bile duct cancer and has been associated with a wide range of other diseases although its role in the development of many of these other diseases requires further study. Humans infected with H. heilmannii s.s. may develop some of the same gastrointestinal diseases viz., stomach inflammation, stomach ulcers, duodenal ulcers, stomach cancers that are not lymphomas, and extranodal marginal B cell lymphomas of the stomach. Other non-H. pylori Helicobacter species that are known to be associated with these gastrointestinal diseases are Helicobacter bizzozeronii, Helicobacter suis, Helicobacter felis, and Helicobacter salomonis. Because of their disease associations, these four Helicobacter species plus H. heilmannii s.s. are often group together and termed Helicobacter heilmannii sensu lato.