Research Paper #1: Relationship Between Endotoxins, Cancer, and Beyond

Annie Standard
Santa Rosa Junior College
Biology 16: Intro to Biology for Non-Majors
Professor Steven Kessler
November 17, 2020
 1

In the 1890’s, William B. Coley noticed his cancer patients displayed reduction in their

tumors when experiencing bacterial infection. He went on to inject cancer patients with a mix of

bacterial toxins in and around their tumors, with some success at recreating his observations.

Experimentation was discontinued because success was not consistent, and patients experienced

overwhelmingly negative side effects. (Lundlin, Checkoway, 2009, p. 1345) Research on the

tumor-reducing properties of his bacterial concoction continued on and off well into the 1980’s,

and indeed, today, morphing into something known as the hygiene hypothesis. The hygiene

hypothesis, first stated by David Strachan in 1989, loosely states that lack of our exposure to

bacteria in the modern age may be related to less immune function and higher rates of asthma

and allergies. (Marshall, 2019) Studies imply that this may be related to cancer as well.

In the 1940’s, lipopolysaccharide, or LPS, was found to be the main tumor reducing

ingredient in Coley’s experiments. In the 1970’s tumor necrosis factor-alpha (TNF-alpha) was

determined to be the main agent in reducing tumors. In the mid 1980’s, it was found that TNF-

alpha was identical to catechin, the mediator responsible for the symptoms of sepsis and septic

shock, including headache, nausea, vomiting, fever, hypotension, and diarrhea. Human testing

ceased after this discovery due to its dangerous implications, as septic shock is known for its

quick and brutal organ-shutdown. (Lundlin, Checkoway, 2009, p. 1345)

Endotoxins are found in the outer membrane cell walls in gram-negative bacteria, and are

composed of proteins, lipids, and LPS. Endotoxins are released when the bacterial cell lyses;

LPS is the main biological property of endotoxin, specifically the lipid component lipid A, a

phosphoglycolipid. Endotoxins are found in organic materials that surround us in the form of dirt

and dust, therefore continuous exposure is widespread across the planet. (Lundlin, Checkoway,
 2

2009, p. 1344) Endotoxins can be found on the surfaces of plants, animals, and soil, as well as in

the oral and nasal cavities of humans, but concentration is highly variable among various

populations and environments. (K. Radon, 2006, p. 73) Certain occupations provide intense

exposure to individuals, including livestock farmers and textile workers, as well as garbage

handlers, saw-mill workers, other agricultural workers, and sewage treatment workers. (Lundlin,

Checkoway, 2009, p. 1345)

Particular attention has been paid to livestock farmers and cotton textile workers.

Extensive studies have been done on Chinese cotton workers as well as dairy farmers in the US

and Europe. Almost paradoxically, the consistent intense exposure to endotoxin has shown a

decrease in lung cancer among these workers, as well as other cancers. (Lundlin, Checkoway,

2009, p. 1345-1346) Dairy farmers have been found to be five times as less likely to develop

lung cancer, hypothesized to be due to their exposure to gram-negative bacteria from the manure

dust that they inhale. Even smoking dairy-farmers were less likely to develop lung cancer

compared to non-smoking, non-dairy farmers. (Marshall, 2008, p. 34)

The relationship between endotoxins and lung cancer protection is unclear, as studies

suggest that increased exposure to cotton-dust and the endotoxins within it is also related to

toxic-dust syndrome and decreased lung function. (K. Radon, 2006, p. 73-78) Disagreements

also exist when it comes to asthma and allergies, as increased endotoxin in school age children is

shown to decrease asthmatic symptoms, (Sordillo, Hoffman, Celedon, Litoniua, Milton, Gold,

2010) but other studies show that infants exposed have an increase in wheeze. (Horick, Weller,

Kirby, Gold, Li, Spiegelman, 2006)

 3

Endotoxin undoubtedly produces an inflammatory response. There is a speculated

relationship between the inflammation caused by endotoxins and the protection of exposed

groups against cancer. Though the nature of this relationship is not yet understood, it is thought

to be through the activation of immune cells and proinflammatory mediators (cytokines).

(Lundlin, Checkoway, 2009, p. 1344) Pointing back to the hygiene hypothesis, it could be that

the reduction in bacteria in the every day environment throws our immune system off, as the

immune system was originally developed to fight off more pathogens and microbes than we are

exposed to in the modern day. This hypothesis was originally made in reference to allergies, but

researchers are now wondering if this can be applied to the rise in cancer in our developed

nations. It is speculated that the LPS in endotoxin is what keeps the immune systems of cotton

and livestock workers on high alert, which protects them from carcinogens. (Marshall, 2008)

It is possible that an endotoxin can act as an adjuvant, or an immune-boosting response

found in vaccines. The immune boost helps trigger T-Cells which can then target the cancer

cells. Or, perhaps, it is just the stimulation of the immune system by the bacteria that helps bring

it back to normal, as a healthy immune system can fight off and reduce tumors on its own. Back

in 1890, Coley noticed that a higher fever caused by the heat-killed bacteria would fight off the

tumor, so perhaps the fever from bacterial exposure helps to stimulate the immune response

directed towards the cancer. (Marshall, 2008)

Some scientists are trying to revive Coley’s work, including Coley Pharmaceuticals in

Wessely, Massachusetts, who are attempting to develop drugs that mimic the immune responses

to bacteria, and MBVax Bioscience in Ontario Canada, who have reintroduced Coley’s
 4

preparation and have had promising results. (Marshall, 2008) Most interesting to me is the

administering of a bacteria called Mycobacterium Vaccae.

Mycobacterium is bacteria that is found all over the world in organic materials, such as

the ones the previously mentioned workers are continuously exposed to. It is named after cow

dung, (Vacca means cow in latin), which is interesting to point out in light of the dairy farmers

who are found to have cancer-protection. Many mycobacteria are nonpathogens, but some are

strictly pathogenic, such as tuberculosis. Mycobacterium live in the organic environment but also

have the ability to infiltrate an animal and live there. M. Vaccae belongs, therefore, to the same

genus as M. Tuberculosis, but instead, it is non-pathogenic. (Stanford, J. Stanford, C. 2012, p. 3)

M. Vaccae has been found to be helpful in the treatment of tuberculosis, (Weng, H.,

Huang, J.Y., Meng, X.Y., Li, S., Zheng, G.Q., 2016) asthma, (Smit, Van Loveren, Hoekstra,

Shijf, Folkerts, Nijkamp, 2003) melanoma, (Cananzi, Mudan, Dunne, Belonwu, Dalgeish, 2013)

pulmonary allergies in mice, (Adams, Hunt, Martinelli, Palmer, Graham, Brunet, 2004) and even

stress and depression in mice. (Marshall, 2019)

M. Vaccae is found in dirt and organic materials, but it is neither a gram-negative nor

gram-positive bacteria. This points to the fact that it does not produce endotoxins, as they are

components of gram-negative cell-membranes. Also, it is non-pathogenic. Perhaps, under my

personal speculation, this means that the farmers could be inhaling non-pathogenic bacteria such

as M. Vaccae, which then provides protection. This could potentially rule out endotoxins as the

cause of cancer prevention. This could also clarify previous explorations between the
 5

relationship between endotoxin levels in the home and asthmatic children – perhaps it is another

bacterium found in the dust.

Numerous studies have suggested that isolated use of M. Vaccae can be extremely

helpful in the treatment of a wide variety of diseases, including cancer, as seen in the melanoma

study. It is stated that truth of results can be harder to capture when studying the treatment of

cancer and its relationship with immunity, though we have some promising findings so far. One

of the obstacles is the question of ethics, as those with cancer must be treated with traditional

methods alongside the novel treatment. These methods are typically radiation and chemotherapy,

which inherently suppress the immune system. This obviously may interfere with the immune

stimulating properties of the new treatment. (Marshall, 2008)

I personally can see that the reported effects of M. Vaccae are consistent and highly

beneficial, and I believe more research should be done towards discovering ways that we can

utilize the value of non-pathogenic bacteria found in organic materials like dust and dirt.

Looking back, we can see that we have made strides in understanding the nature of bacteria since

the 19th century. It’s true that bacteria can have harmful effects but doing our best to explore the

wide world of mycobacterium could mean a better quality of life for many, and could lead to

more understanding in terms of cancer prevention. Instead of working from our biases that we

grew up with (for instance, that germs are bad and best avoided at all costs), perhaps we can find

a more balanced and realistic approach to our treatments and disease prevention which is

inclusive of the holistic, complex relationship that we have with bacteria that surrounds us inside

and out.
 Works Cited

Adams, V. C., Hunt, J. R.F., Martinelli, R., Palmer, R., Rook, G. A.W., & Brunet, L. R. (2004).

Mycobacterium vaccae induces a population of pulmonary CD11c+ cells with regulatory

potential in allergic mice. European Journal of Immunology, 34(3), 631-638.

https://doi.org/10.1002/eji.200324659

Cananzi, F. C.M., Mudan, S., Dunne, M., Belonwu, N., & Dalgleish, A. G. (2013). Long-term

survival and outcome of patients originally given mycobacterium vaccae for metastatic

malignant melanoma. Human Vaccines & Immunotherapeutics, 9(11).

https://doi.org/10.4161/hv.25618

Horick, N., Weller, E. A., Kirby, M. D., Gold, D. R., Li, R., & Spiegelman, D. L. (2006). Home

endotoxin exposure and wheeze in infants: Correction for bias due to exposure

measurement error. Environmental Health Perspectives, 114(1), 135-140.

https://doi.org/10.1289/ehp.7981

Lundlin, J. I., & Checkoway, H. (2009). Endotoxin and cancer. Environmental Health

Perspectives, 117(9), 1344-1350. https://doi.org/10.1289/ehp.0800439

Marshall, J. (2008). Filthy healthy. New Scientist, 197(2638), 34-37. Retrieved from SIRS Issues

Researcher database.

Radon, K. (2006). The two sides of the "endotoxin coin". Occupational & Environmental

Medicine, 63(1), 73-78. https://doi.org/10.1136/oem.2004.017616

Smit, J. J., Van Loveren, H., Hoesktra, M. O., Shijf, M. A., Folkerts, G., & Nijkamp, F. P.

(2003). Mycobacterium vaccae administration during allergen sensitization or challenge

suppresses asthmatic features. Clinical & Experimental Allergy, 33(8), 1083-1089.

https://doi.org/10.1046/j.1365-2222.2003.01727.x
Sordillo, J. E., Hoffman, E. B., Celedon, J. C., Litonjua, A. A., Milton, D. K., & Gold, D. R.

(2010). Multiple microbial exposures in the home may protect against asthma or allergy

in childhood. Clinical & Experimental Allergy, 40(6), 902-910.

https://doi.org/10.1111/j.1365-2222.2010.03509.x

Stanford, J., & Stanford, C. (2012). Mycobacteria and their world. International Journal of

Mycobacteriology, 1(1), 3-12. https://doi.org/10.1016/j.ijmyco.2012.01.001

University of Colorado at Boulder, & Marshall, L. (2019, May 29). Healthy, stress-busting fat

found hidden in dirt. Retrieved March 17, 2020, from Science Daily website:

https://www.sciencedaily.com/releases/2019/05/190529094003.htm

Weng, H., Huang, J. Y., Meng, X. Y., Li, S., & Zhang, G. Q. (2016). Adjunctive therapy of

mycobacterium vaccae vaccine in the treatment of multidrug-resistant tuberculosis: A

systematic review and meta-analysis. Biomed Rep., 4(5), 595-600.

https://doi.org/10.3892/br.2016.624

Bacteria and Mycoplasms detail: Bacteria Collection: Mycobacterium vaccae

     Additional (Culture Collections, Comp.). (n.d.). Retrieved from Public

     Health England website: https://www.phe-culturecollections.org.uk/products/

     bacteria/detail.jsp?collection=nctc&refId=NCTC%2010916&additional=true

       "Neither gram-positive or gram-negative"