Orally administered bifidobacteria as vehicles for delivery of agents to systemic tumors.
Certain bacteria have emerged as biological gene vectors with natural tumor specificity, capable of specifically delivering genes or gene products to the tumor environment when intravenously (i.v.) administered to rodent models. We show for the first time that oral administration of bacteria to mice resulted in their translocation from the gastrointestinal tract (GIT) with subsequent homing to and replication specifically in tumors. The commensal, nonpathogenic Bifidobacterium breve UCC2003 harboring a plasmid expressing lux fed to mice bearing subcutaneous (s.c.) tumors were readily detected specifically in tumors, by live whole-body imaging, at levels similar to i.v. administration. Reporter gene expression was visible for >2 weeks in tumors. Mice remained healthy throughout experiments. Cytokine analyses indicated a significant upregulation of interferon-gamma (IFN-gamma) in the GIT of bifidobacteria-fed mice, which is associated with increases in epithelial permeability. However, B. breve feeding did not increase systemic levels of other commensal bacteria. The presence of tumor was not necessary for translocation to systemic organs to occur. These findings indicate potential for safe and efficient gene-based treatment and/or detection of tumors via ingestion of nonpathogenic bacteria expressing therapeutic or reporter genes.
Cronin
Michelle
M
Cork Cancer Research Centre, Mercy University Hospital and Leslie C. Quick Jnr. Laboratory, University College Cork, Cork, Ireland.
Morrissey
David
D
Rajendran
Simon
S
El Mashad
Shereen M
SM
van Sinderen
Douwe
D
O'Sullivan
Gerald C
GC
Tangney
Mark
M
D000284:Administration, Oral; D000818:Animals; D001644:Bifidobacterium / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification; D016207:Cytokines / Q000378:metabolism; D057075:Enzyme Assays; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D041981:Gastrointestinal Tract / Q000382:microbiology; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics* / Q000276:immunology; D007111:Immunity, Cellular / Q000276:immunology; D056724:Immunity, Humoral / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016133:Polymerase Chain Reaction
D016207:Cytokines; D007371:Interferon-gamma
J Gastroenterol Hepatol. 2007 Apr;22(4):464-71
17376034
BMC Microbiol. 2008 Sep 24;8:161
18816375
Gut. 2000 Jul;47(1):79-87
10861268
Infect Immun. 1983 Mar;39(3):1252-9
6341234
Acta Pharmacol Sin. 2005 May;26(5):629-34
15842785
J Infect Dis. 1988 May;157(5):1032-8
3283254
J Cell Biochem. 2009 Apr 15;106(6):992-8
19199339
J Natl Cancer Inst. 2008 Oct 1;100(19):1389-400
18812551
Cancer Gene Ther. 2005 Feb;12(2):133-40
15565182
Antonie Van Leeuwenhoek. 1990 Aug;58(2):87-93
2264727
Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):755-60
15644448
J Bacteriol. 2003 Apr;185(8):2571-81
12670982
Anticancer Res. 2009 Jun;29(6):1873-8
19528442
Breast Cancer. 2006;13(1):27-31
16518059
Cancer Gene Ther. 2003 Feb;10(2):105-11
12536198
Biosci Biotechnol Biochem. 2002 Nov;66(11):2362-6
12506973
Cell Cycle. 2009 Mar 15;8(6):870-5
19221501
J Infect Dis. 1985 Jul;152(1):99-103
3925032
Food Chem Toxicol. 2000 Feb-Mar;38(2-3):153-61
10717355
Infect Immun. 2000 Feb;68(2):752-9
10639443
J Infect Dis. 1991 Dec;164(6):1168-72
1835471
Cancer Res. 2006 Aug 1;66(15):7647-52
16885365
FEMS Microbiol Lett. 2001 Oct 16;204(1):33-8
11682174
J Dairy Sci. 1989 Jan;72(1):30-5
2925954
Curr Opin Drug Discov Devel. 2002 Mar;5(2):200-3
11926126
J Pathol. 2006 Jan;208(2):290-8
16362987
Infect Immun. 2006 Sep;74(9):5391-6
16926434
Nutr Rev. 2008 Apr;66(4):192-202
18366533
J Appl Microbiol. 2005;98(6):1303-15
15916644
Curr Gene Ther. 2005 Dec;5(6):607-18
16457650
Jikken Dobutsu. 1985 Jan;34(1):1-16
3987819
Cancer Gene Ther. 2000 Feb;7(2):269-74
10770636
Ann Surg. 2007 May;245(5):795-802
17457174
Adv Exp Med Biol. 1999;473:11-30
10659341
Infect Immun. 1979 Feb;23(2):403-11
154474
Cancer Lett. 2008 Jan 18;259(1):16-27
18063294
Infect Immun. 1980 Feb;27(2):461-7
6966611
Curr Gene Ther. 2010 Feb;10(1):46-55
20158470
Nat Biotechnol. 2004 Mar;22(3):313-20
14990953
Clin Diagn Lab Immunol. 2003 Jul;10(4):696-701
12853407
Appl Environ Microbiol. 2007 May;73(9):3091-4
17351089
Hum Gene Ther. 2010 Apr;21(4):405-16
20105075
Photochem Photobiol Sci. 2008 Jun;7(6):675-80
18528551
Gene Ther. 1997 Aug;4(8):791-6
9338007
Infect Immun. 1979 Sep;25(3):820-27
159260
Appl Environ Microbiol. 2008 Oct;74(20):6271-9
18689518
Curr Gene Ther. 2010 Feb;10(1):3-14
20156191
Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10170-4
17548809
Appl Environ Microbiol. 2008 Feb;74(3):660-6
18083875
Gastroenterology. 1994 Sep;107(3):643-9
8076751
Curr Stud Hematol Blood Transfus. 1992;(59):44-65
1533359
J Pharmacol Exp Ther. 2007 Mar;320(3):1013-22
17178936
J Hyg (Lond). 1972 Jun;70(2):335-42
4626276
Infect Immun. 1985 Mar;47(3):793-8
3972454
Appl Environ Microbiol. 2009 Mar;75(6):1534-45
19168652
Immunology. 1985 Sep;56(1):43-50
4043995
Am J Clin Nutr. 2001 Feb;73(2 Suppl):465S-470S
11157359