Microbial signaling molecules drive cancer development

November 3rd, 2015 by Amy Proal
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For the past century, scientists have associated certain microbes or microbial populations with the development of cancer. A recent study by researchers at Ghent University in Belgium expands on this research by demonstrating a previously undiscovered mechanism by which gastrointestinal microbes can drive cancer processes. The study, Crosstalk between the microbiome and cancer cells by quorum sensing peptides shows how quorum sensing peptides synthesized by common gut bacteria can directly influence cancer cell growth and tumor formation.

Before proceeding, if you want to brush up on the concept of quorum sensing itself, watch this fascinating lecture by Princeton microbiologist Bonnie Bassler. If not, remember that quorum sensing peptides are produced by bacteria for purposes of communication with other microbes in their environment. Or that is their primary function. The above study shows that, at least in the laboratory, these peptides can additionally alter the expression of human genes.

Quorum sensing peptides promote cancer metastasis and tumor progression by activating different receptor pathways.

Quorum sensing peptides promote cancer metastasis and tumor progression by activating different receptor pathways. Source: E. Wynendaele et al. / Peptides 64 (2015) 40–48.

The Belgium team, led by Evelien Wynendaele, used a number of laboratory-based technique to study quorum sensing peptides created by common species of gram negative gut bacteria. In what I believe is one of the first discoveries of its kind, they found that, under laboratory conditions, three of these peptides directly elevated or lowered the expression of human genes in a manner that promotes colon cancer. Indeed, the team found that quorum sensing peptides Phr0662, Extracellular Growth Factor (EDF), and EntF can significantly induce tumor cell invasion. Phr0662 and EDR can further alter human gene expression in a fashion that leads to angiogenesis, cellular invasiveness, tumor growth, and neurovascularization. See the paragraphs at the end of this article for more details on how the team derived their results.

The findings are particularly relevant because there is already an established connection between components of the gut microbiome and the development of colon cancer. A team of researchers from University of Michigan and Baylor College of medicine recently showed that in mice, components of the gut microbiome can act in concert with a carcinogen to drive colon tumor formation. Now Wynendaele and team’s work may provide insight into at least some of the molecular mechanisms underlying these findings. The Belgian research also opens a door for new therapeutic approaches. Can we find a way to block the production of Phr0662, EDF, EntF or similar peptides? Attempting to do so certainly seems like a fruitful avenue for translational medicine.

The study also raises a second major implication. In 2009, in a book chapter written for the J. Craig Venter Institute, I stated the following: “While certain components of the microbiota clearly aid humans…strictly classifying microbes as either commensal or pathogenic may suggest too categorical a distinction. Emerging research suggests that bacteria are no more “good” or “bad” than their human counterparts.”

The results of Wynendaele’s study support this statement. If the quorum sensing peptides described in this study promote cancer, then one might assume that they are synthesized by well defined pathogens. However, the microbes that produce Phr0662, EDF, and EntF are actually common gut bacteria that are generally regarded as commensal (harmless). Indeed, the Belgian team points out that the species producing these peptides are often found in commonly used probiotics.

Peptide Phr0662 is synthesized by species of Bacillus. These species are often included in probiotic supplements, including some used to treat acute gastroenteritis. EDF and EntF are synthesized by E. coli and E. faecium respectively. While both species are known to cause disease under certain conditions, strains of these same microbes are also prolific in the healthy human gut. The two species are frequently described as commensals, and are commonly used in probiotic therapies. For example, along with Streptococcus spp. and B. subtilis, E. coli has been shown to reduce abdominal pain in some patients suffering from irritable bowel syndrome.

Are people consuming these microbes as probiotics at a higher risk for developing colon cancer? Much more research is certainly needed, but we are certainly not screening probiotic strains for their ability to produce disease-promoting quorum sensing peptides. Yet the possibility that some “commensal” strains might create such peptides does not mean we should eschew probiotics. Instead, we should choose probiotic strains with great care. As Wynendaele and team contend, “more safety aspects should be taken into account when using and developing probiotics. In particular, taxonomic identification of the probiotic strain is necessary to avoid pathogenicity, as well as inhibiting the risk of infection and antimicrobial resistance.”

As I stated in 2009, we must exercise caution before deciding that any microbe capable of persisting in the human body is categorically “good.” The genomes of bacteria are large enough that their byproducts can impact many different host metabolic and signaling processes. Some of their gene products and metabolites may benefit their human hosts while, as seen above, others might alter human gene expression in a manner that promotes disease. The same microbe might at once be helpful and harmful to its host.

However, the beneficial or pathogenic capabilities of a microbe may vary depending on its life cycle and host environment. For example, E. coli was found to produce EDF during logarithmic growth states induced by situations of stress. To better account for these variables, we must continue to study how bacterial species alter their gene expression under different in vivo conditions. Certain bacteria are pleimorphic, or able alter their shape or size in response to environmental conditions. More recognition of research already conducted on this phenomenon would be a good place to start.

In the meantime, the common assumption that taking probiotics “can do no harm” must be changed. We cannot be certain that some microbes are solely beneficial. Instead, both the medical and research communities should embrace a new paradigm in which all bacteria are respected as multifaceted entities.

More on how Wynendaele and team derived their results

As part of a preliminary study, Wynendaele and team showed that three quorum sensing peptides or metabolites thereof (Phr0662, EDF-analog, and an EntF metabolite), significantly induce tumor cell invasion through a collagen type 1 extracellular matrix. The findings are significant because this epithelial to mesenchymal (EMT)-like process initiated by the peptides is “one of the main mechanisms involved in colorectal cancer metastasis, establishing metastatic disseminations with potential life-threatening consequences.”

The research team further corroborated the ability of these same peptides to contribute to colon cancer development by performing whole transcriptome analysis of both placebo and peptide-treated tumor cells. A number of human genes found to be either up or down-regulated by the quorum sensing peptides were associated with cellular invasion and proliferation. For example, microRNA222 is highly expressed in endothelial cells, and possesses a number of key anti-angiogenic properties through its targets. The team’s transcription analysis found that expression of microRNA222 is significantly down-regulated 24 hours after addition of peptides Phr0662 and EDF-analog, thus increasing angiogenesis in affected cells.

Chick Chorioallantoic Membrane assay results further confirmed the ability of Phr0662 to promote angiogensis. Wynendaele and team show that addition of the Phr0662 to chick egg tumor cells promoted neurovascularization, thereby facilitating tumor metastasis. When chick tumor cells were not present, addition of Phr0662 alone did not promote neurovascularization. This confirmed that crosstalk between the peptide and the cancer cells was necessary for neurovascularization to take place.

Cytokine screening performed after Phr0662 treatment of cancer cells provided even more evidence of its ability to promote angiogenesis. Increased expression of a number of human inflammatory cytokines (VEGF, Il-6, and SDF-1alpha for example) are activated by Phr0662. Upregulation of these cytokines can lead to rapid vascularization of tumor cells and additionally increase their angiogenic potential.

Take home messages

  • By creating quorum sensing peptides, certain bacteria can directly up or down-regulate human genes in a manner that promotes colon cancer development.
  • Common probiotic strains are not screened for their ability to produce cancer-promoting quorum sensing peptides.
  • A single microbe might be able to both benefit and harm its host at the same time. Changes in in vivo conditions may alter the manner in which a microbe impacts its host.
  • Rather than categorically classifying certain microbes as “good”, we should embrace a more nuanced view of their possible actions in vivo.

9 thoughts on “Microbial signaling molecules drive cancer development

  1. James VanWinkle

    I have missed your blogging. Thank you for taking the time to restart. You are one of the treasures of the world. 😀

    Reply
  2. Pippit Carlington

    Very interesting article. I’ve been reading lately alot about ALS which many researchers now think is caused by something which causes the environment in and around the motor neuron to become toxic. It could be a certain specific “fatal” combination of pathogens and the affect they have on genes. Definitely makes me think!

    Reply
  3. Amy Proal Post author

    HI Pippit,

    So glad that you found the article to be thought provoking. Components of the microbiome could certainly play a role in ALS disease processes. I look forward to possible research on the topic!

    James,

    Thank you so much for your comment. It’s great to know you value my insight.

    Reply
    1. Amy Proal Post author

      Hi Mary,

      Thanks for your interest in Microbe Minded! If you click on the “recent posts” link at the top of the site, there is a place where you can sign up for email alerts about future posts.

      Reply
  4. Amy Proal Post author

    Thanks for sharing. As indicated by the first study, many pathogens require iron in order to survive and proliferate. That is why the authors suggest that increased iron intake may be detrimental for patients with Mtb. More on the battle between pathogens and their hosts for iron here:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920840/

    The second study is interesting in that ferroportin helps transport iron out of cells. If ferroportin levels are lower in breast cancer cells, then less iron would be expected to leave the cells. This would leave more iron inside such cells that pathogens could acquire.

    A microbiome has now been shown to persist in breast tissue. Also one study found that the microbiome of tumor cells in breast cancer appears to change (become less diverse) over time:

    http://aem.asm.org/content/80/10/3007.full

    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0083744

    It is possible that then, that in breast cancer, some pathogens may persist inside the cells. Under such conditions, these pathogens might benefit from iron in the cell. Patients expressing lower levels of ferroportin could then be at a higher risk for disease (as the study indicates). Still much more research is needed here to clarify exactly what’s going on.

    I’ve always found it interesting that many doctors prescribe iron supplements (often in high doses) for autoimmune and inflammatory conditions. There should be more consideration as to whether the supplements benefit the patient, or possible pathogens contributing to disease. Or in other words, the low levels of iron often seen in patients with chronic disease may be a result, rather than a cause, of the disease process.

    Reply
  5. Helen

    Great article on the battle for iron. I was aware that people with iron-overload diseases are more susceptible to certain infections. Interesting about Borellia using magnesium (as well as, or instead of, iron???)

    It’s recently been discovered that people with MS have malfunctioning genes which code iron-transport proteins:

    http://www.biomedcentral.com/1471-2350/13/70

    http://www.google.com/patents/WO2012123785A1?cl=en

    There do seem to be plenty of doctors over-prescribing both prescription and supplement treatments! I have a chronic c.pneumonaie infection and MS, and my specialist recommends I keep my iron levels low to help treat this (along with antibiotics of course). Have also read that lactoferrin is helpful for treating c.pneumonaie infections – which makes sense as it would bind free iron. I’ll be adding this to my regime in the future.

    Reply
  6. Amy Proal Post author

    Hi Helen,

    Thanks for sharing the studies! It’s interesting that your doctor keeps your iron levels low. I’m glad you’ve found a physician that seems to be a good fit for you.

    Reply

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