The Potential Role of Intratumor Bacteria in Chemoresistance

Introduction

Resistance to therapy is a major challenge in the treatment of cancer patients, and the tumor microenvironment has been implicated in resistance. Bacterial species have been detected in tumor tissue. Moreover, growing evidence suggests that bacteria can influence the efficacy of cancer therapies. We recently characterized bacterial species present in pancreatic ductal adenocarcinoma (PDAC) tumors and found that some were able to metabolize and inactivate gemcitabine, a commonly used therapy in the treatment of pancreatic cancer.

Materials and methods

Bacterial metabolism of gemcitabine was explored in vitro. Genetically modified Escherichia coli was utilized to understand the mechanism of gemcitabine metabolism. Results were validated using in vivo mouse models. The presence of bacteria in human PDAC samples was detected by RT-qPCR, bacterial 16S sequencing, fluorescence in situ hybridization (FISH), immunohistochemistry and culturing.

Results and discussion

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 (CDD_L), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDD_L expression, and abrogated by cotreatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intratumor 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, and that bacteria cultured from human PDAC tumors could metabolize gemcitabine.

Conclusion

In summary, these findings indicate that some PDAC tumors contain bacteria that can potentially influence the efficacy of gemcitabine within the tumor. We are now interested in understanding the distribution of bacteria within the tumor, the intra-cellular location of bacteria and the clinical effect of small amounts of bacteria within a cell on the resistance of these cells to gemcitabine.