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The Bacteria that Promote Cancer

Microscopy imaging of metastatic cancer cells. Credit: drimafilm/adobe

Microscopy imaging of metastatic cancer cells. Credit: drimafilm/adobe

By Amber Gomersall & Roger Parish

A bacterial protein can trigger inflammation and facilitate the progression of cancer.

More than 25 years ago at the University of Zurich, Roger Parish and his colleagues identified a protein on the surface of mouse fibroblast cells that dramatically changed the normal behaviour of the cells. Generally, when fibroblast cells collide they change their direction of movement and retract from one another. Loss of this contact inhibition helps to drive invasion in cancer.

The fibroblasts displayed normal contact inhibition when the protein was blocked with a monoclonal antibody. However, the cells completely lost contact inhibition when the protein was not blocked.

This protein, named p37, is located on the surface of the bacterium Mycoplasma hyorhinis, where it forms a complex with two other proteins located in the outer membrane of the bacterium. The three proteins constitute a high-affinity transport system that the mycoplasma cells employ to take up molecules such as nutrients.

Mycoplasmas are minute bacteria that lack a cell wall. Several species cause inflammatory diseases in humans. M. pneumonia, for example, causes atypical pneumonia while M. genitalium gives rise to pelvic inflammatory diseases. M. hyorhinis is often present in the respiratory tract of young pigs and causes severe arthritis when they experience stress or a concomitant infection.

Evidence began to accumulate that p37, and hence M. hyorhinis, was associated with cancer. In 2001, for example, a research group from Peking University Cancer Hospital and Institute observed mycoplasma infections in human cancer tissues. They reported that 56% of gastric carcinomas, 55.1% of colon carcinomas and 45.5% of other carcinomas (oesophagus, lung, breast and glioma) were infected with M. hyorhinis, and the p37 protein was identified. In 2014 the Peking University team reported that M. hyorhinis infection correlated with metastasis, and predicted poor survival of gastric cancer patients.

But what is the evidence that infectious bacteria like M. hyorhinis can cause cancer?

The underlying cause for cancer development is a change to genes that control cell division and cell growth. Evidence for an association of infectious viruses and bacteria in chronic inflammatory diseases and cancer is rapidly increasing, and 17% of global cancer is now attributed to infectious agents. For example, human papillomavirus is responsible for cancers of the cervix and penis, while liver cancer has been linked to both hepatitis B and C.

Certain bacteria have also been linked to cancer development. Their capacity to induce chronic inflammation is believed to be involved.

Perhaps the best-known example of bacterially induced cancer involves Helicobacter pylori, a bacterium usually found in the stomach. Inflammation of the stomach lining due to H. pylori colonisation results in chronic gastritis. Stomach and duodenal ulcers can result.

One way in which H. pylori is thought to promote cancer is by inducing chronic inflammatory stress, leading to the activation of multiple cancer-causing pathways. The bacterium produces virulence factors that induce genes encoding pro-inflammatory molecules such as interleukin-6 (IL6). This creates a microenvironment that facilitates the transformation of gastric epithelial cells to cancerous cells.

So could the p37 protein on the surface of M. hyorhinis be involved in the development of cancer?

We found that when purified p37 protein is added to fibro­blast cells it rapidly induced genes encoding three proteins involved in inflammation and cancer metastasis.

  • IL6 is involved in inflammatory diseases such as arthritis, and can induce cell proliferation and invasion.
  • ANGPTL4 also plays an important role in inflammation, cancer growth and metastasis.
  • SAA3 is implicated in several chronic inflammatory diseases, including rheumatoid arthritis, and promotes metastasis.

Many of the genes activated by p37 are part of a signalling cascade involving the STAT3 protein, which regulates the expression of specific genes. STAT3 inhibitors are used therapeutically for inflammatory disease and cancer.

However, when we added a STAT3 inhibitor to the cells, the p37-induced expression of genes was significantly increased rather than inhibited. The reasons for this are unclear, but recent reports from other labs have also found an increased inflammatory response with STAT3 inhibitors and led to a re-evaluation of their therapeutic use.

So how does the p37 protein activate the expression of genes that are involved in inflammation and cancer progression?

We found that p37 binds to a receptor protein on the surface of the fibroblast cells called TLR4, which recognises pathogens and triggers the inflammatory response. Molecules that bind to TLR4 include certain viral proteins and lipopolysaccharides from Gram-negative bacteria.

Activation of TLR4 by infectious agents can trigger numerous signalling cascades, eliciting a strong inflammatory response. One such cascade involves IL6. Elevated expression of TLR4 has been reported in breast, colon, gastric, lung and ovarian cancers. Our research found that the induction of gene expression in mouse fibroblasts by p37 was significantly reduced when the TLR4 receptor was blocked.

The team from Peking University has also recently associated p37–TLR4 with M. hyorhinis-infected human gastric cancer cells. P37-induced expression of ANGPTL4 was only partly inhibited when we blocked the TLR4 receptor, so an additional receptor may play a role in its activation.

How might the induction of pro-inflammatory and cancer-related pathways by p37 in fibroblast cells relate to cancer development? Do the fibroblasts eventually develop into tumour cells when infected by M. hyorhinis?

We don’t know. However, we do know that cancer-associated fibroblasts support tumour growth, development, invasion and metastasis via the release of molecules that facilitate inflammation and the formation of blood vessels. In this context M. hyorhinis infection could play an important role in cancer progression.

Further research is required to answer a number of important questions that may further strengthen the connection between infection with M. hyorhinis and cancers.

  • Do fibroblasts and other cell types eventually develop into tumour cells when infected by M. hyorhinis?
  • Could M. hyorhinis infection participate in the development of human inflammatory diseases such as arthritis?
  • Do other mycoplasma species induce similar responses to those induced by M. hyorhinis? Since other mycoplasma species also possess p37 equivalents, are these proteins also capable of inducing genes involved in inflammation and cancer? If not, why not?
  • What is the second cell surface receptor bound by p37 that participates in the activation of ANGPTL4?

Evidence is growing that certain viruses and bacteria could increase the risk of cancer by promoting general inflammation. As a consequence, other key cellular processes would be affected. Our studies have identified a mechanism, namely the p37 protein, by which a mycoplasma infection can rapidly and strongly induce pro-inflammatory and cancer-related genes.

Amber Gomersall is a PhD graduate of La Trobe University’s Department of Animal, Plant and Soil Sciences, where Roger Parish is an Emeritus Professor.