Cancer bacteria

Cancer bacteria (not viruses) are infectious organisms which are known, or suspected of causing cancer. While cancer associated bacteria have long been considered to be opportunistic (i.e., infecting healthy tissues "after" cancer has already established itself), recent evidence is showing that some bacteria may be directly involved in causing some cancers. The strongest evidence to date involves the bacterium "H.pylori" and its role in gastric cancer.

In 1890, German bacteriologist Robert Koch defined four requirements to prove that a given organism causes a given disease. These requirements, known as Koch's postulates, guide research into the bacterial cause of many diseases, including cancer, and establish a gold standard of evidence consistent with "proof".

Known to cause cancer

"Helicobacter pylori" colonizes the human stomach and duodenum. In some cases it may cause stomach cancercite journal |author=Egi Y, Ito M, Tanaka S, "et al" |title=Role of Helicobacter pylori infection and chronic inflammation in gastric cancer in the cardia |journal=Jpn. J. Clin. Oncol. |volume=37 |issue=5 |pages=365–9 |year=2007 |month=May |pmid=17578895 |doi=10.1093/jjco/hym029 |url=] [cite journal |author=Peter S, Beglinger C |title=Helicobacter pylori and gastric cancer: the causal relationship |journal=Digestion |volume=75 |issue=1 |pages=25–35 |year=2007 |pmid=17429205 |doi=10.1159/000101564] and MALT lymphomacite journal |author=Morgner A, Bayerdörffer E, Neubauer A, Stolte M |title=Gastric MALT lymphoma and its relationship to Helicobacter pylori infection: management and pathogenesis of the disease |journal=Microsc. Res. Tech. |volume=48 |issue=6 |pages=349–56 |year=2000 |month=Mar |pmid=10738316 |doi=10.1002/(SICI)1097-0029(20000315)48:6<349::AID-JEMT5>3.0.CO;2-7 |url=] . Animal models have demonstrated Koch's third and fourth postulates for the role of "Helicobacter pylori" in the causation of stomach cancer.cite journal |author=Watanabe T, Tada M, Nagai H, Sasaki S, Nakao M |title=Helicobacter pylori infection induces gastric cancer in mongolian gerbils |journal=Gastroenterology |volume=115 |issue=3 |pages=642–8 |year=1998 |month=Sep |pmid=9721161 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S001650859800273X]

uspected to cause cancer

"Mycoplasma" has been implicated in the formation of cancer.cite journal |author=Huang S, Li JY, Wu J, Meng L, Shou CC |title=Mycoplasma infections and different human carcinomas |journal=World J. Gastroenterol. |volume=7 |issue=2 |pages=266–9 |year=2001 |month=Apr |pmid=11819772 |doi= |url=http://www.wjgnet.com/1007-9327/7/266.asp] Specific reports include:
*"Mycoplasma" can “induce malignant transformation of host mammalian cells” by means of "aberrant expression of oncogenes and tumor repressors"cite journal |author=Zhang S, Tsai S, Lo SC |title=Alteration of gene expression profiles during mycoplasma-induced malignant cell transformation |journal=BMC Cancer |volume=6 |issue= |pages=116 |year=2006 |pmid=16674811 |pmc=1559712 |doi=10.1186/1471-2407-6-116 |url=] .
*A "Mycoplasma hyorhinis"-encoded protein known as p37…..(could) infect humans and may facilitate tumor invasiveness" [cite journal |author=Ketcham CM, Anai S, Reutzel R, "et al" |title=p37 Induces tumor invasiveness |journal=Mol. Cancer Ther. |volume=4 |issue=7 |pages=1031–8 |year=2005 |month=Jul |pmid=16020660 |doi=10.1158/1535-7163.MCT-05-0040 |url=] .
*A “significantly high existence of "Mycoplasma sp." DNA" has been reported "in the tissues of patients with conventional (renal cell carcinoma)" as opposed to normal controls. [cite journal |author=Pehlivan M, Pehlivan S, Onay H, Koyuncuoglu M, Kirkali Z |title=Can mycoplasma-mediated oncogenesis be responsible for formation of conventional renal cell carcinoma? |journal=Urology |volume=65 |issue=2 |pages=411–4 |year=2005 |month=Feb |pmid=15708077 |doi=10.1016/j.urology.2004.10.015 |url=]
*"Mycoplasma" infection can be detected in many tumor tissues; continuous infection of "mycoplasma" can lead to transformation of mammalian cells, up-regulating expression of oncogenes, and some biologic changes of tumor cells, suggesting association of "Mycoplasma" infection with tumorigenesis" [cite journal |author=Ning JY, Shou CC |title= [Mycoplasma infection and cancer] |language=Chinese |journal=Ai Zheng |volume=23 |issue=5 |pages=602–4 |year=2004 |month=May |pmid=15142464 |doi= |url=http://www.cjcsysu.cn/fulltextnew.asp?y=2004&m=5&ym=602]

A number of other bacteria have associations with cancer, although their possible role in carcinogenesis is unclear. "Salmonella typhi" is associated with gallbladder cancer, "Streptococcus bovis" is associated with colorectal cancer and "Chlamydia pneumoniae" with lung cancer.cite journal |author=Mager DL |title=Bacteria and cancer: cause, coincidence or cure? A review |journal=J Transl Med |volume=4 |issue= |pages=14 |year=2006 |pmid=16566840 |pmc=1479838 |doi=10.1186/1479-5876-4-14 |url=http://www.translational-medicine.com/content/4/1/14]

History

In 1890, the Scottish pathologist William Russell reported circumstantial evidence for the bacterial cause of cancer cite journal |author=Russell W |title=An address on a characteristic organism of cancer |journal=Brit Med J |volume=2 |issue= |pages=1356–60 |year=1890] . In 1926, Canadian physician Thomas Glover reported that he could consistently isolate a specific bacterium from the neoplastic tissues of animals and humans.cite journal | last =Glover | first =TJ | authorlink = | coauthors = | title =Progress in Cancer Research | journal =Canada Lancet and Practitioner | volume =67 | issue = | pages =5 | publisher = | date =1926 | url = | doi = | id = | accessdate = ] 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." [cite journal |author=Patterson RS |title=A selected public health bibliography with annotations |journal=American Journal of Public Health |volume=16 |issue=12 |pages=1242 |year=1926 |url=http://www.ajph.org/cgi/reprint/16/12/1240.pdf]

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 1930cite journal |author=Glover TJ |title=The bacteriology of cancer | journal =Canada Lancet and Practitioner | volume =74 | issue = | pages =92–111 | publisher = | date =1930 | url = | doi = | id = | accessdate = ] . 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, T.J. and Engle, J.L. (1938). "Studies in Malignancy". New York: Murdock Foundation.] . 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.cite journal | last = | first = | authorlink = | coauthors = | title =Unproven methods of cancer management: Livingston-Wheeler therapy | journal =CA: A Cancer Journal for Clinicians | volume =40 | issue = | pages =103–108 | publisher =American Cancer Society | date =1990 | url =http://caonline.amcancersoc.org/cgi/reprint/40/2/103 | doi = | id = | accessdate = ]

In 1931, Cornell University pathologist Elise L’Esperance reported the presence of acid-fast, Tuberculosis-like organisms in Hodgkin's disease [cite journal |author=L’Esperance E |title=Studies in Hodgkin’s disease |journal=Annal Surg |volume=93 |issue= |pages=162–8 |year=1931] , French physician George Mazet implicated a bacterial association with leukemia and also Hodgkin's disease [Mazet, G. (June/August 1941). “Etude bacteriolgigue sur la maladie d’Hodgkin”. Montpellier Medicine] and a number of other physicians or scientists, including the German von Brehmer [von Brehmer, W. “Siphonosopra polymorpha n. sp.: ein neuer microorganismus des blutes, seine beziehung zur tumorgenese”. "Med Welt", 8:1178-1185.] , the Irish physician W.M. Crofton [Crofton, W.M. (1936). “The True Nature of Viruses.” Staples Press Ltd, London, England.] and EJ Villesquez of France [Villesquez, E.J. (1955). “Le Parasitisme Latent des Cellules du Sang chez l’ Homme, en Particulier dans le Sang des Cancreeux.” Librarie Maloine, Paris, France.] all reported similar cancer bacteria associations. In one case, an Italian scientist named Clara Fonti reportedly inoculated herself in the chest wall with a metastasizing mammary carcinoma and claimed to note neoplastic changes in her own tissues [Fonti, C.J. (1958). “Eziopatogenese del Cancro”. Amadeo Nicola.& c. Milan, Italy.] .

In some cases, claims were made that anti-sera derived from cancer associated bacteria could be used therapeutically. In 1953, for example, the results of an anti-bacterial vaccine trial involving 100 patients said to be diagnosed with different stages and types of cancer was reported by Dr. John E. White at the 6th International Congress of Microbiology in Rome, Italy. White said there were a number of favorable responses, but critics noted that the trial was not blinded, supervised, or monitored by any independent mainstream cancer agency, and the actual severity as well as diagnostic authenticity of the cancers-in-question not verifiable.

In 1950, a Newark based physician named Virginia Livingston published a paper claiming that a specific "Mycobacterium" was associated with neoplasia [cite journal |author=Wuerthele-Caspe V, Alexander-Jackson E, Anderson JA, Hillier J, Allen RM, Smith LW |title=Cultural properties and pathogenicity of certain microorganisms obtained from various proliferative and neoplastic diseases |journal=Am. J. Med. Sci. |volume=220 |issue=6 |pages=638–46 |year=1950 |month=Dec |pmid=14789767 |doi= |url=] . Livingston believed that this organism was intermittently acid-fast, highly pleomorphic, and taxonomically related to the leprae and tuberculin bacilli. She, along with several colleagues including microbiologist Eleanor-Alexander Jackson, continued research throughout the 1950’s and eventually proposed a name for the bacterium, calling it "Progenitor cryptocides". Livingston also proposed a treatment protocol based on anti-microbial vaccines similar in concept to Glover's which she reported on in a 1965 publication [cite journal |author=Livingston VW, Alexander-Jackson E |title=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=J Am Med Womens Assoc |volume=20 |issue=9 |pages=858–66 |year=1965 |month=Sep |pmid=4220493 |doi= |url=] .

Other investigators were not sure of the exact classification of cancer bacteria, and had claimed to find different taxonomies other than "Mycobacteria". For example, I.C. Diller, who had reported an increased "number of tumors" occurring in mice "injected with a bacterium" isolated from mice and human cancers, referred to several possible classifications. These included a "Corynebacterium" "of undetermined species", "Staphylococcus epidermidis" and an organism related only antigenically to "Mycobacteria". She cited the "extreme pleomorphism" and "tendency to stabilize in forms that mimic other bacteria" as reasons for the difficulty in classification [cite journal |author=Diller IC |title=Tumor incidence in ICR/albino and C57/B16JNIcr male mice injected with organisms cultured from mouse malignant tissue |journal=Growth |volume=38 |issue=4 |pages=507–17 |year=1974 |month=Dec |pmid=4461405 |doi= |url=] .

Beginning in 1963, the National Cancer Institute (NCI) launched its own preliminary investigation of cancer bacteria, and until 1974, conducted several studies which focused primarily on the culturing of cancer bacteria from animal and/or human cancers in an attempt to establish a guilt-by-association relationship between the two [Personal communication from: Carol Case, Chief, Public Inquiries section, Office of Cancer Communications, National Cancer Institute,(October, 1986).] [Source: "Journal of the National Cancer Institute". (1963-1974).] . The NCI investigations involved several different species, including "Mycoplasma orale", "Mycoplasma fermentans", "Mycoplasma neurolyticum" and "Mycoplasma pneumoniae" and many of the studies involved examination of leukemic bloods.

The NCI studies produced various results. In one study, researchers concluded there was no statistically relevant oncogenic association between certain "Mycoplasma" species [cite journal |author=Ebbesen P, Lind K |title=Lack of evidence for oncogenic or amyloid inducing qualities of Mycoplasma neurolyticum inoculated into BALB-c mice |journal=Acta Pathol Microbiol Scand |volume=76 |issue=4 |pages=594–600 |year=1969 |pmid=4900568 |doi= |url=] . In another, investigators concluded there was “an association between "Mycoplasma" and acute leukemia” [Barile, M.F., et al. (1965). “Isolation of Mycoplasma orale From Leukemic Bone Marrow and Blood by Direct Culture”. "JNCI", 36:155-159.] . Another NCI paper stated the “importance of ("Mycoplasma"/cancer) association(s)” because “latent mycoplasma were repeatedly isolated from mice under stress with malignant disease” [cite journal |author=Tully JG, Rask-Nielsen R |title=Mycoplasma in leukemic and nonleukemic mice |journal=Ann. N. Y. Acad. Sci. |volume=143 |issue=1 |pages=345–52 |year=1967 |month=Jul |pmid=5233768 |doi= |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0077-8923&date=1967&volume=143&spage=345] .

As of October 1986, however, the NCI’s position was that its bacteria investigation failed to reach a definitive conclusion [Case, ibid.] . NCI and other mainstream investigators---while questioning the actual role of cancer bacteria in oncogenesis---believed that such bacteria were common invaders of cancer tissues, acting more as parasites rather than involved in causality. "Mycoplasma" are known to be notorious contaminants of laboratory cultures and other media. Throughout the 1980s and up to the present time, the NCI has been actively involved in cancer virus research.

In 1974, Livingston reported an association between cancer-related bacteria and human choriogondatropin (HCG), a growth hormone commonly associated with pregnancy [cite journal |author=Livingston VW, Livingston AM |title=Some cultural, immunological, and biochemical properties of Progenitor cryptocides |journal=Trans N Y Acad Sci |volume=36 |issue=6 |pages=569–82 |year=1974 |month=Jun |pmid=4530542 |doi= |url=] . Hernan Acevedo, a Pittsburgh-based scientist, also reported that HCG could be synthesized from cancer-related bacteria [cite journal |author=Acevedo HF, Slifkin M, Pouchet GR, Pardo M |title=Immunohistochemical localization of a choriogonadotropin-like protein in bacteria isolated from cancer patients |journal=Cancer |volume=41 |issue=4 |pages=1217–29 |year=1978 |month=Apr |pmid=76504 |doi= |url=] . Livingston believed that HCG was a common denominator linking cancer and bacteria, and alleged that cancer tissues utilize HCG for the purpose of avoiding immunosurveillance, basing her ideas on data suggesting the human embryo uses HCG in the same fashion [cite journal |author=Whyte A, Loke YW |title=Increased sialylation of surface glycopeptides of human trophoblast compared with fetal cells from the same conceptus |journal=J. Exp. Med. |volume=148 |issue=4 |pages=1087–92 |year=1978 |month=Oct |pmid=702061 |pmc=2185013 |doi= |url=] . In a later critique of Livingston’s claims and methods, the NCI argued that "HCG is produced by a variety of bacteria from both cancer patients, and normal tissues".

Acevedo reported in additional studies that “the synthesis and expression of HCG, its subunits, and its fragments, is a common biochemical denominator of cancer, providing the scientific basis for studies of its prevention and/or control by active and/or passive immunization against these sialoglycoproteins” [cite journal |author=Acevedo HF, Tong JY, Hartsock RJ |title=Human chorionic gonadotropin-beta subunit gene expression in cultured human fetal and cancer cells of different types and origins |journal=Cancer |volume=76 |issue=8 |pages=1467–75 |year=1995 |month=Oct |pmid=8620425 |doi= |url=] .

In 1990, the NCI published a review of Livingston's theories and said that her methods of classifying the cancer bacterium she referred to as "Progenitor cryptocides" had contained "some remarkable errors". Independent analysis of this organism using DNA-DNA hybridization technology revealed its actual classification as "Staphylococcus epidermidis", not a "Mycobacterium" as Livingston had stated.

According to Dr. Alva Johnson, a professor at the Department of Microbiology and Immunology at the Eastern Virginia Medical School who had independently reviewed the NCI critique, Livingston had not preserved earlier samples of her cultures taken from the blood and tissues of cancer patients in which she claimed "Mycobacteria" existed and instead routinely screened cancer patients’ urine samples for HCG-positive bacteria assuming these were positive for "Mycobacteria" [Personal communication from: Dr. Alva Johnson, Dept of Microbiology and Immunology, Eastern Virginia Medical School, May 27, 1992.] . Johnson noted that Livingston’s assumptions reflected “sloppy” science, and adversely affected the protocols needed to build consensus among medical peers [ibid.] .

Livingston died in 1990 and five years later Dr. Shyh-Ching Lo, a researcher with the Armed Forces Institute of Pathology in Washington, D.C., published a paper titled “Mycoplasmas and oncogenesis: persistent infection and multistage malignant transformation” [cite journal |author=Tsai S, Wear DJ, Shih JW, Lo SC |title=Mycoplasmas and oncogenesis: persistent infection and multistage malignant transformation |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue=22 |pages=10197–201 |year=1995 |month=Oct |pmid=7479753 |pmc=40763 |doi= |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=7479753] . According to Lo, "Mycoplasma fermentans" and "Mycoplasma penetrans" induced malignant cell transformation in cultured mouse embryo cells, C3H/10T1/2 (C3H) after 6 serial passages lasting 1 wk per passage. He further wrote that up until the 11th passage, “malignant changes were reversible if mycoplasmas were eradicated by antibiotic treatment”, but at 18 passages, “irreversible…..transformation” occurred.

Subsequent to Lo’s paper and as of 2007, there were a minimum of 14 published papers in the peer reviewed literature claiming to document an association between various species of "Mycoplasma" and various animal and human cancers.

Cancer Bacteria as Contaminants

Scientists have long suspected that cancer bacteria may be contaminants which infiltrate tissue cell cultures, or invade cancer tissues after the disease has started, as opposed to being a direct cause of cancer. Research is now under way in an effort to clarify this relationship.

In a recent study, investigators examined deep tissue specimens taken from patients with Oral Squamous Cell Carcinoma. Using rRNA gene sequencing, and addressing the issue of contamination with sterilizing immersion techniques, the investigators noted a “diversity of bacterial taxa...including several putatively novel species.” Some of the bacterial species were “isolated only from either the tumorous or nontumorous tissue” indicating “a degree of restriction.” The investigators said that “Successful surface decontamination of the specimens indicates that the bacteria detected were from within the tissue”.

Rather than finding one taxonomy, the researchers noted a “diversity of bacterial groups” and concluded that the “significance of these bacteria within the tumor warrants further study" [cite journal |author=Hooper SJ, Crean SJ, Lewis MA, Spratt DA, Wade WG, Wilson MJ |title=Viable bacteria present within oral squamous cell carcinoma tissue |journal=J. Clin. Microbiol. |volume=44 |issue=5 |pages=1719–25 |year=2006 |month=May |pmid=16672398 |pmc=1479175 |doi=10.1128/JCM.44.5.1719-1725.2006 |url=] .

References

See also

*Virus cancer link


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