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Science. 2017 Sep 15;357(6356):1156-1160. doi: 10.1126/science.aah5043.

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

Author information

1
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
2
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
3
Institute for Medical Engineering and Science, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
4
Department of Radiology, Brigham and Women's Hospital, Boston, MA 02115, USA.
5
Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
6
Department of Mathematics and Computer Science, Open University of Israel, Raanana, Israel.
7
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
8
Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
9
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
10
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
11
Department of Surgical Oncology, Massachusetts General Hospital, Boston, MA 02114, USA.
12
Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
13
Small Molecule Mass Spectrometry Facility, Faculty of Arts and Sciences Division of Science, Harvard University, Cambridge, MA 02138, USA.
14
Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel.
15
Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
16
Department of Biomedical Engineering, Columbia University, New York City, NY 10027, USA.
17
Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
18
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
19
Harvard T. H. Chan School of Public Health, Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Boston, MA 02115, USA.
20
Department of Pathology, Sheba Medical Center, Ramat Gan, Israel.
21
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
22
Department of Oncology, Sheba Medical Center, Ramat Gan, Israel.
23
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
24
Dana-Farber Cancer Institute, Boston, MA 02115, USA.
25
Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198-6345, USA.
26
Pancreas and Biliary Surgery Program, Massachusetts General Hospital, Boston, MA 02114, USA.
27
Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
28
Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA 02139, USA.
29
Howard Hughes Medical Institute (HHMI), Institute for Medical Engineering and Science, MIT, Cambridge, MA 02139, USA.
30
Division of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
31
Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA 02139, USA.
32
Ludwig Center for Molecular Oncology, MIT, Cambridge, MA 02139, USA.
33
Marble Center for Cancer Nanomedicine, MIT, Cambridge, MA 02139, USA.
34
HHMI, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
35
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
36
Harvard Medical School, Boston, MA 02115, USA.
37
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. ravidst@weizmann.ac.il.

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 intratumor Gammaproteobacteria, dependent on bacterial CDDL 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.

PMID:
28912244
PMCID:
PMC5727343
DOI:
10.1126/science.aah5043
[Indexed for MEDLINE]
Free PMC Article

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