Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine

Abstract

Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2′,2′-difluorodeoxycytidine) into its inactive form, 2′,2′-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDDL), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intra-tumor Gammaproteobacteria, dependent on bacterial CDDL expression, and abrogated by co-treatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intra-tumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria.

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

“…The phenomenon that other cells than tumour cells, or even microbes inactivate or scavenge antineoplastic drugs is indeed compelling. A recent study has shown that intratumoural bacteria may significantly add to gemcitabine resistance in PDA 56. In this study, the authors compared the growth kinetics between tumours established from mycoplasma-positive and mycoplasma-negative tumour cells following gemcitabine therapy.…”

Dual Functionality nanobioconjugates: a New Tool for Intracellular Bacterial Targeting in Cancer cells?

“…Strong links have also been reported for Salmonella typhi causing gall bladder cancer, Mycoplasma resulting in ovarian and lung cancer and many more [3]. A recent article in the journal Science demonstrated that the presence of bacteria inside tumor have also the potential to create resistance against cancer therapy due to their inherent capability of cleaving chemotherapeutics into inactive metabolites [5]. In this way, specific links between infectious pathogens and cancer can greatly impact the design of therapy.…”

Bacterial snack attack deactivates a drug

“…However, microbial metabolism is not always beneficial for the host. Writing in Science, Geller et al 4 report that bacteria within a tumour can metabolize an anticancer drug into an inactive form and thereby render it ineffective.…”