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Bacteria Can Make Tumors Worse

Since the topic of bacteria effects on human disease came up here just the other day, I wanted to point out a new article that comes at this idea from a different direction.

This research got going when cells from pancreatic and colon tumor samples were co-cultured with human dermal fibroblasts. The cancer cell lines unexpectedly became more resistant to gemcitabine under these conditions, and it turned out that just transferring the medium from such cultures to other tumor cells was enough to reproduce the effect. However, if the medium was passed through a 0.45 micron filter beforehand, it did not bring on resistance at all. That immediately sets off alarm bells about bacterial contamination, and so it proved.

The human fibroblasts, on closer inspection, contained Mycoplasma DNA (at this point, the cell culture people in the audience can groan and say “What doesn’t?”). Treating the fibroblasts with an antibiotic also abolished the resistance effect on the later tumor cell cultures, an effect that could be reversed by re-inoculation with the M. hyorhinis species that seems to be the culprit. But it’s not just that one – they tried infecting the fibroblast cultures with 27 different bacteria, and half of them led to the same problem.

The Mycoplasma problem had been noted in cell culture just a few years ago, and the real culprit is a deaminase enzyme that turns gemcitabine into the (inactive) uridine analog. But this paper goes further. The authors (a large multinational team) show that rodent tumor xenograft can be inoculated with bacteria, and this treatment also makes the tumors much less responsive to gemcitabine, an effect reversed by antibiotics. They took this experiment all the way down to an implantable device inside the tumor mass to release antibiotic locally, and showed that only around the site of release did gemcitabine have the desired effect.

The final test was to see if this is happening in human patients. The paper details how tissue samples from pancreatic ductal carcinoma patients were carefully tested for bacterial ribosomal DNA, and the results were pretty stark: 76% of the tumor samples showed up with bacterial contamination, as compared to 15% of normal tissue controls. In situ hybridization confirmed the result. Sequencing suggests that these bacteria have migrated in from the duodenum, and the species detected all produce the deaminase enzyme. Finally, adding the bacteria from the human samples to the cell culture experiments showed that they indeed confer gemcitabine resistance – Robert Koch would be proud to read this paper, for sure.

This work immediately suggests that any cancer patients receiving gemcitabine be treated with antibiotics, and I hope that this affects clinical practice quickly. You wonder how many similar stories are out there that we don’t know about yet!

 

 

Note: All opinions, choices of topic, etc. are strictly my own – I don’t in any way speak for my employer

11 comments on “Bacteria Can Make Tumors Worse”

  1. Lane Simonian says:

    It may be more complicated than this, but Nuclear factor-kappa B activity plays a role in tumor cell’s resistance to gemcitabine and bacteria increase activation of Nuclear factor-kappa B. So this approach may hold real promise.

  2. Coleman says:

    Am I the only one surprised by how susceptible the pancreas seemingly is to bacterial colonization?

    1. MrRogers says:

      If you think about the anatomy for a moment, it shouldn’t be too big a surprise. The pancreas connects to the lumen of the small intestine–not exactly a sterile environment. Unless you imagine that the sphincter of Oddi will prevent all backflow, some colonization will come as no surprise.

      1. Komm says:

        Great, now I can’t stop imagining the sphincter of Oddi as actually the sphincter of Odin and laughing my butt off at the mental image.

        1. NJBiologist says:

          If you’ve ever felt abdominal pain after too many sugary sweets, that’s just the Sphincter of Odin swinging Mjolnir at your beta cells. (Odin still has it because there is no Sphincter of Thor.)

  3. Barry says:

    And bacteria can make tumors regress. Before there were “checkpoint” inhibitors of PD-1 and PD-1L and CDK4, there were other maneuvers to disinhibit the host T-cell response:
    ” these reports note regression concomitant with infections including diphtheria, gonorrhea, hepatitis, influenza, malaria, measles, smallpox, syphilis, and tuberculosis as well as various other pyogenic and nonpyogenic infections. Observation of this non-specific effect led to the emergence of active cancer immunotherapies…the infection was responsible for the miraculous cure. He later realized that the patient’s activated immunity in response to the acute infection was the key factor in cancer regression.”

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312698/

    1. Mol Biologist says:

      Yes, definitely would agree with this point since bacteria/ or obligate parasites such as Plasmodium falciparum would use the mechanism of communication and mutual aid to fight tumor by replenishing host tissue.
      Every single cell which surrounding the tumor would benefit and get assistance to restore their metabolism. Important parts would be delivered by way bacteria or others (infections including diphtheria, gonorrhea, hepatitis, influenza, malaria, measles, smallpox, syphilis, and tuberculosis as well as various other pyogenic and nonpyogenic infections) as used to do it. However, it could happens only in “particular tumors” or at early stage of cancer before host metabolism would be irreversibly affected by tumor. Here is an example https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1065011/

  4. Curt F. says:

    It is great, and remarkable, that all this work was published as a single unit. In today’s world a more common scenario would be that this becomes 5 or 6 distinct papers, each of which on its own could be solid work. But the work, and the paper, is far more memorable when presented as a cohesive whole in a single document.

    I don’t know if this format is optimal for the career prospects of the 40 or so middle authors, but it sure is better for me. Hats off to the entire team.

  5. yuri says:

    Symbiosis can be a cruel mistress

  6. cynical1 says:

    Derek, thank you for this post. My next door neighbor is currently suffering with pancreatic cancer. His PET scans have not been encouraging after a few rounds of chemo. Not surprisingly, he is receiving gemcitabine.

    After reading the post yesterday, I downloaded the paper, read it and then went next door. As a rule, I don’t typically offer medical advice unless specifically asked. Ironically, my neighbor’s son from out of state was visiting and he also happens to be a physician. So I sat down and had a chat with both of them, dumbed it down for them, gave them the paper which I am hoping that the son will be able to at least partially understand and told them if it were me, I would be taking a course of Cipro for at least a week to 10 days before my next round of chemo. I also told them to check with his oncologist about the half life of gemcitabine and continue antibiotic treatment until it was eliminated from his system. That was my good deed for the day. I don’t know if they are going to take my advice but I certainly made an impression. The son could literally write his dad the script for Cipro if he wants. My neighbor’s wife came up to me as I was leaving with tears in her eyes and gave me a hug so I think I made a good case.

    As an aside, my next door neighbor was rather surprised to find out that I spent 30 years working as a medicinal chemist in drug discovery. Go figure.

    1. tangent says:

      Hey, thanks for having that rule, and thanks for making an exception in this case. Both are the decent thing to do for a person. These have been your thanks from a random person on the internet.

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