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