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

被引：1478

作者：

Geller, Leore T. ^{[1
]}

Barzily-Rokni, Michal ^{[2
]}

Danino, Tal ^{[3
,39
]}

Jonas, Oliver H. ^{[4
,5
]}

Shental, Noam ^{[6
]}

Nejman, Deborah ^{[1
]}

Gavert, Nancy ^{[1
]}

Zwang, Yaara ^{[1
]}

Cooper, Zachary A. ^{[7
,8
,40
]}

Shee, Kevin ^{[2
]}

Thaiss, Christoph A. ^{[9
]}

Reuben, Alexandre ^{[8
]}

Livny, Jonathan ^{[2
]}

Avraham, Roi ^{[10
]}

Frederick, Dennie T. ^{[11
]}

Ligorio, Matteo ^{[12
]}

Chatman, Kelly ^{[13
]}

Johnston, Stephen E. ^{[2
]}

Mosher, Carrie M. ^{[2
]}

Brandis, Alexander ^{[14
]}

Fuks, Garold ^{[15
]}

Gurbatri, Candice ^{[16
]}

Gopalakrishnan, Vancheswaran ^{[8
]}

Kim, Michael ^{[8
]}

Hurd, Mark W. ^{[17
]}

Katz, Matthew ^{[8
]}

Fleming, Jason ^{[8
]}

Maitra, Anirban ^{[18
]}

Smith, David A. ^{[2
]}

Skalak, Matt ^{[3
]}

Bu, Jeffrey ^{[3
]}

Michaud, Monia ^{[19
,20
]}

Trauger, Sunia A. ^{[13
]}

Barshack, Iris ^{[21
,22
]}

Golan, Talia ^{[22
,23
]}

Sandbank, Judith ^{[22
]}

Flaherty, Keith T. ^{[12
]}

Mandinova, Anna ^{[2
,24
,25
]}

Garrett, Wendy S. ^{[2
,19
,20
,26
]}

Thayer, Sarah P. ^{[27
]}

Ferrone, Cristina R. ^{[28
]}

Huttenhower, Curtis ^{[2
,29
]}

Bhatia, Sangeeta N. ^{[2
,30
,31
,32
,33
,34
,35
]}

Gevers, Dirk ^{[2
,41
]}

Wargo, Jennifer A. ^{[7
,8
]}

Golub, Todd R. ^{[36
,37
,38
]}

Straussman, Ravid ^{[1
]}

机构：

[1] Weizmann Inst Sci, Dept Mol Cell Biol, Rehovot, Israel

[2] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[3] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[4] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA

[5] Dana Farber Canc Inst, Joint Ctr Canc Precis Med, Boston, MA 02215 USA

[6] Open Univ Israel, Dept Math & Comp Sci, Raanana, Israel

[7] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA

[9] Weizmann Inst Sci, Dept Immunol, Rehovot, Israel

[10] Weizmann Inst Sci, Dept Biol Regulat, Rehovot, Israel

[11] Massachusetts Gen Hosp, Dept Surg Oncol, Boston, MA 02114 USA

[12] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA

[13] Harvard Univ, Fac Arts & Sci, Div Sci, Small Mol Mass Spectrometry Facil, Cambridge, MA 02138 USA

[14] Weizmann Inst Sci, Life Sci Core Facil, Rehovot, Israel

[15] Weizmann Inst Sci, Dept Phys Complex Syst, Rehovot, Israel

[16] Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA

[17] Univ Texas MD Anderson Canc Ctr, Ahmed Ctr Pancreat Canc Res, Houston, TX 77030 USA

[18] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[19] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA

[20] Harvard TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA

[21] Sheba Med Ctr, Dept Pathol, Ramat Gan, Israel

[22] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel

[23] Sheba Med Ctr, Dept Oncol, Ramat Gan, Israel

[24] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA

[25] Harvard Med Sch, Charlestown, MA 02129 USA

[26] Dana Farber Canc Inst, Boston, MA 02115 USA

[27] Univ Nebraska Med Ctr, Dept Surg, Omaha, NE 68198 USA

[28] Massachusetts Gen Hosp, Pancreas & Biliary Surg Program, Boston, MA 02114 USA

[29] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

[30] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA

[31] MIT, Howard Hughes Med Inst, Inst Med Engn & Sci, Cambridge, MA 02139 USA

[32] Brigham & Womens Hosp, Div Med, 75 Francis St, Boston, MA 02115 USA

[33] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA

[34] MIT, Ludwig Ctr Mol Oncol, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[35] MIT, Marble Ctr Canc Nanomed, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[36] Broad Inst MIT & Harvard, HHMI, Cambridge, MA 02142 USA

[37] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[38] Harvard Med Sch, Boston, MA 02115 USA

[39] Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA

[40] Medimmune, Gaithersburg, MD 20878 USA

[41] Janssen Pharmaceut LLC, Janssen Human Microbiome Inst, Cambridge, MA 02142 USA

来源：

SCIENCE | 2017年 / 357卷 / 6356期

基金：

以色列科学基金会;

关键词：

CANCER; IDENTIFICATION; GENE;

D O I：

10.1126/science.aah5043

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：1156 / +

页数：5

共 22 条

[1]

CLONING OF THE NUPC GENE OF ESCHERICHIA-COLI ENCODING A NUCLEOSIDE TRANSPORT-SYSTEM, AND IDENTIFICATION OF AN ADJACENT INSERTION ELEMENT, IS186 [J].

CRAIG, JE ;

ZHANG, YB ;

GALLAGHER, MP .

MOLECULAR MICROBIOLOGY, 1994, 11 (06) :1159-1168

[2]

Bacteria and tumours: causative agents or opportunistic inhabitants? [J].

Cummins, Joanne ;

Tangney, Mark .

INFECTIOUS AGENTS AND CANCER, 2013, 8

[3]

The Pancreas Cancer Microenvironment [J].

Feig, Christine ;

Gopinathan, Aarthi ;

Neesse, Albrecht ;

Chan, Derek S. ;

Cook, Natalie ;

Tuveson, David A. .

CLINICAL CANCER RESEARCH, 2012, 18 (16) :4266-4276

[4]

nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer [J].

Frese, Kristopher K. ;

Neesse, Albrecht ;

Cook, Natalie ;

Bapiro, Tashinga E. ;

Lolkema, Martijn P. ;

Jodrell, Duncan I. ;

Tuveson, David A. .

CANCER DISCOVERY, 2012, 2 (03) :260-269

[5]

An implantable microdevice to perform high-throughput in vivo drug sensitivity testing in tumors [J].

Jonas, Oliver ;

Landry, Heather M. ;

Fuller, Jason E. ;

Santini, John T., Jr. ;

Baselga, Jose ;

Tepper, Robert I. ;

Cima, Michael J. ;

Langer, Robert .

SCIENCE TRANSLATIONAL MEDICINE, 2015, 7 (284) :284ps10

[6]

KEGG: Kyoto Encyclopedia of Genes and Genomes [J].

Kanehisa, M ;

Goto, S .

NUCLEIC ACIDS RESEARCH, 2000, 28 (01) :27-30

[7]

Microenvironmental regulation of therapeutic response in cancer [J].

Klemm, Florian ;

Joyce, Johanna A. .

TRENDS IN CELL BIOLOGY, 2015, 25 (04) :198-213

[8]

Local bacteria affect the efficacy of chemotherapeutic drugs [J].

Lehouritis, Panos ;

Cummins, Joanne ;

Stanton, Michael ;

Murphy, Carola T. ;

McCarthy, Florence O. ;

Reid, Gregor ;

Urbaniak, Camilla ;

Byrne, William L. ;

Tangney, Mark .

SCIENTIFIC REPORTS, 2015, 5

[9]

Single-molecule mRNA detection and counting in mammalian tissue [J].

Lyubimova, Anna ;

Itzkovitz, Shalev ;

Junker, Jan Philipp ;

Fan, Zi Peng ;

Wu, Xuebing ;

van Oudenaarden, Alexander .

NATURE PROTOCOLS, 2013, 8 (09) :1743-1758

[10]

Differences of small intestinal bacteria populations in adults and children with/without celiac disease: Effect of age, gluten diet, and disease [J].

Nistal, Esther ;

Caminero, Alberto ;

Herran, Alexandra R. ;

Arias, Laura ;

Vivas, Santiago ;

Ruiz de Morales, Jose M. ;

Calleja, Sara ;

Saenz de Miera, Luis E. ;

Arroyo, Paula ;

Casqueiro, Javier .

INFLAMMATORY BOWEL DISEASES, 2012, 18 (04) :649-656

← 1 2 3 →