Many of us have heard that it is possible for viruses to cause cancer—awareness campaigns like the one below, on a London bus, have done a fantastic job of raising awareness of this fact:
Few of us, however, are aware that bacteria can also cause cancers. The most notable example of this is Helicobacter pylori, the organism which causes stomach ulcers and gastritis. With time, inflammatory ulcerative conditions in the stomach lead to a substantially increased likelihood of gastric adenocarcinomas (stomach cancer) and MALT lymphomas (immune tissue cancer)(1,2).
As only 10-20% of patients develop ulcers/inflammation, and 1-3% of those patients develop cancers, this is a minor & indirect mechanism of carcinogenesis (“cancer-induction”) by a bacterium, but an important one nonetheless. As such H. pyloriis the only bacterium currently considered to be a Class 1 carcinogen by the World Health Organisation’s International Agency for Research on Cancer—a category which includes cigarettes, alcohol, and plutonium (3,4). However recent research now suggests that another species may cause cancer much more directly—this one:
The cancer-causing bacterium in question is Fusobacterium nucleatum, a species once thought to be a relatively harmless member of the oral microbiome. Indeed, we have known of its involvement in the oral disease since 1898 (5); its carcinogenic behaviour, however, was not observed until 2011 (6), and the mechanism was not established until 2013 (7).
In the mouth, F. nucleatum acts as a “bridge species” (8). This means that it is neither among the first (“initial colonisers”) nor last species to coat bare tooth enamel—in and of itself, a completely harmless action. However, it is a very “sticky” bacterium, to which others can adhere easily. By attaching to the initial colonisers which coat the tooth, it provides a surface to which pathogenic bacteria can bind in a process known as “bacterial co-aggregation and co-adhesion”(9). Thus, F. nucleatumpromotes an ulcerative and even necrotising form of gum disease called Vincent’s angina or “trench mouth”, alongside other oral disease, by creating a surface which allows harmful bacteria to live and potentially thrive.
While gum disease and other oral tract conditions are certainly of interest when considering the pathology of F. nucleatum, its role in colorectal cancer is altogether more intriguing. Researchers initially established that this species was present in the colorectal tumour microenvironment in 2012 (6). This was an interesting finding on its own, but subsequent research revealed an even more surprising set of findings: F. nucleatum not only thrives in the tumour environment, but can act to induce tumorigenesis in order to create a tumour within which it can thrive (10).
Mechanism of carcinogenesis
So how is it that F. nucleatum “directly” induces cancer formation? The answer lies in a well-understood metabolic pathway known as the “Wnt pathway” (10). This consists of a series of proteins and interactions between them, which eventually lead to a cellular response to whatever phenomenon initially triggered it. The Wnt pathway is known to be involved in cell growth and replication—it is a classic example of a cell proliferation pathway, used as an example in the education of many undergraduate life scientists, and studied the world over.
The proteins which initiate the Wnt pathway, β-catenin and E-cadherin, are bound together in a superstructure known as a “protein complex”. In order for the pathway to be triggered/activated, some trigger molecule/protein has to modify the E-cadherin’s chemistry by adding a phosphate group to it. This then leads to the release of beta-catenin from the protein complex, and the translocation (movement) of the beta-catenin into the nucleus. There, it acts on the cell’s genome to induce the production of proteins which lead to cell growth and replication.
This is precisely the mechanism which Fusobacterium nucleatum exploits in the colon and rectum. It “hijacks” the Wnt pathway by producing a protein, FadA, on its surface. FadA acts as a trigger for the pathway, precisely as described above: it phosphorylates the E-cadherin and induces the movement of beta-catenin into the nucleus, and thus promotes cell growth. This is not normal, as (canonically) bacteria do not dictate growth and development in mammalian cells; this is therefore an abnormal or aberrant cell growth. If this sounds eerily similar to descriptions of cancerous tumours, that is because it is precisely a cancerous colorectal tumour which F. nucleatum’s FadA induces.
So now we have seen how a bacterial infection can lead to tumour formation—but I mentioned earlier that this bacterium can not only do this, but also thrive within the newly-created tumour microenvironment. Indeed, F. nucleatum’s array of surface proteins is not merely limited to FadA. Another interesting surface protein which it expresses is Fap2. This protein’s roles in colorectal cancer are manifold: in the first instance, it allows F. nucleatumto bind to a special sugar residue (Gal-GalNAc) which in mammals is only ever found in/on cancerous cells (11). Once the bacterium has bound, it is able to enter within the tumour mass—explaining the findings in Castellarin et al (2011) which showed a high abundance of this species in colorectal cancers.
This however is only one of its roles: once it has allowed the bacterium access to the inside of the tumour, it then induces the “autophagy pathway”, which enables the bacterium to prevent chemotherapy from killing cancer cells. Cells die either via autophagy or apoptosis, and you can think of this as a dichotomous choice: either one occurs or the other occurs. Since chemotherapy drives apoptosis to kill cancer cells, Fap2’s induction of autophagy effectively prevents any chemotherapeutic action (12).
Thus, F. nucleatumis able to 1) induce, 2) enter, and 3) sustain a cancerous tumour, even in the face of chemotherapy. So the next time someone tries to insist that bacterial infections cannot cause cancer, send them a link to this article and help raise awareness of this absolutely mind-blowing new development in the scientific understanding of cancer.
1. Nakamura S, Matsumoto T. Helicobacter pylori and gastric mucosa-associated lymphoid tissue lymphoma: Recent progress in pathogenesis and management. World J Gastroenterol(2013) 19:8181–8187. doi:10.3748/wjg.v19.i45.8181
2. Herrera V, Parsonnet J. Helicobacter pylori and gastric adenocarcinoma. Clin Microbiol Infect(2009) 15:971–976. doi:10.1111/j.1469-0691.2009.03031.x
3. IARC. Biological Agents. IARC Monogr Eval Carcinog Risks Hum(2012) 100B:1–443. doi:ISBN 978 92 832 1319 2
4. Vogiatzi P, Cassone M, Luzzi I, Lucchetti C, Otvos L, Giordano A. Helicobacter pylori as a class I carcinogen: Physiopathology and management strategies. J Cell Biochem(2007) 102:264–273. doi:10.1002/jcb.21375
5. Bennett KW, Eley A. Fusobacteria: New taxonomy and related diseases. J Med Microbiol(1993) 39:246–254. doi:10.1099/00222615-39-4-246
6. Castellarin M, Warren RL, Freeman JD, Dreolini L, Krzywinski M, Strauss J, Barnes R, Watson P, Allen-Vercoe E, Moore RA, et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res(2012) 22:299–306. doi:10.1101/gr.126516.111
7. Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, Clancy TE, Chung DC, Lochhead P, Hold GL, et al. Fusobacterium nucleatum Potentiates Intestinal Tumorigenesis and Modulates the Tumor-Immune Microenvironment. Cell Host Microbe(2013) 14:207–215. doi:10.1016/j.chom.2013.07.007
8. Bolstad AI, Jensen HB, Bakken V. Taxonomy, biology, and periodontal aspects of Fusobacterium nucleatum. Clin Microbiol Rev(1996) 9:55–71.
9. Kolenbrander PE. Oral microbial communities: biofilms, interactions, and genetic systems. Annu Rev Microbiol(2000) 54:413–437. doi:10.1146/annurev.micro.54.1.413
10. Rubinstein MR, Wang X, Liu W, Hao Y, Cai G, Han YW. Fusobacterium nucleatum Promotes Colorectal Carcinogenesis by Modulating E-Cadherin/β-Catenin Signaling via its FadA Adhesin. Cell Host Microbe(2013) 14:195–206. doi:10.1016/j.chom.2013.07.012
11. Abed J, Emgård JEM, Zamir G, Faroja M, Almogy G, Grenov A, Sol A, Naor R, Pikarsky E, Atlan KA, et al. Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc. Cell Host Microbe(2016) 20:215–225. doi:10.1016/j.chom.2016.07.006
12. Yu TC, Guo F, Yu Y, Sun T, Ma D, Han J, Qian Y, Kryczek I, Sun D, Nagarsheth N, et al. Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy. Cell(2017) 170:548–563.e16. doi:10.1016/j.cell.2017.07.008
Cancer is not a particular disease, but rather a term used to group many related diseases (1). This group of diseases is responsible for a large number of deaths worldwide and represents a serious health threat today. Cancerous cells are defined by an uncontrolled cell proliferation – they continuously divide and ignore signals telling them to stop, to the point of forming a tumor. A tumor is referred to as being malignant only if it is capable of spreading throughout the body of the patient. Thus, from a single cell, the entire body can be invaded by malignant tumors (1).
The human host’s immune system tolerates trillions of microorganisms. The bacteria that comprise the gut microbiota line the walls of the intestine and live in a mutually beneficial equilibrium within the host. Meanwhile, the immune system is constantly on the lookout for harmful pathogens that may contribute to disease. It’s safe to say that there’s a perfect and fragile balance existing within our gut. However, when this equilibrium is broken, a number of negative consequences can ensue. One of them is the risk of oncogenesis (formation of cancer) and tumour progression (2).
This break in the equilibrium, also referred to as dysbiosis, can be caused by a number of factors. The arrival of pathogenic (harmful) organisms as well as several environmental (aging, hormones, antibiotics) and genetic (defects in the intestinal immune system) factors promote dysbiosis (2). Not only can these factors affect the risk of colorectal cancer, but the gut microbiota can also promote oncogenesis on a systemic level and lead to breast and hepatocellular (liver) cancers (3).
We’ve seen how disequilibrium in relation to our gut microbiota can affect the risk of tumorigenesis (formation of tumours). On the other hand, it is possible to influence the microbiota for therapeutic purposes. Recent data has suggested that the gut microbiota is capable of modulating the response to cancer therapy and the susceptibility to toxic side effects (4). Commensal organisms are responsible for absorbing and metabolizing drugs. Furthermore, direct interaction with bacteria can affect the efficacy of chemotherapeutic drugs (4). Many of the mechanisms by which the gut microbiota affects inflammation, immunity, carcinogenesis (development of cancer) and response to therapy at the local level have been characterized.
One challenge for clinicians is to determine the best microbiota composition for each condition. The ultimate goal is to discover a bacterial species or a combination of species that both reduces systemic toxicity and promotes anticancer therapy. Thus, targeting the microbiota in cancer and other diseases is likely to become one of the next frontiers for precision and personalized medicine (4).