title: Tumor invasion of Salmonella enterica serovar Typhimurium is accompanied by strong hemorrhage promoted by TNF-alpha.
abstract: BACKGROUND
  Several facultative anaerobic bacteria with potential therapeutic abilities are known to preferentially colonize solid tumors after systemic administration. How they efficiently find and invade the tumors is still unclear. However, this is an important issue to be clarified when bacteria should be tailored for application in cancer therapy.
  
  
  RESULTS
  We describe the initial events of colonization of an ectopic transplantable tumor by Salmonella enterica serovar Typhimurium. Initially, after intravenous administration, bacteria were found in blood, spleen, and liver. Low numbers were also detected in tumors associated with blood vessels as could be observed by immunohistochemistry. A rapid increase of TNF-alpha in blood was observed at that time, in addition to other pro-inflammatory cytokines. This induced a tremendous influx of blood into the tumors by vascular disruption that could be visualized in H&E stainings and quantified by hemoglobin measurements of tumor homogenate. Most likely, together with the blood, bacteria were flushed into the tumor. In addition, blood influx was followed by necrosis formation, bacterial growth, and infiltration of neutrophilic granulocytes. Depletion of TNF-alpha retarded blood influx and delayed bacterial tumor-colonization.
  
  
  CONCLUSIONS
  Our findings emphasize similarities between Gram-negative tumor-colonizing bacteria and tumor vascular disrupting agents and show the involvement of TNF-alpha in the initial phase of tumor-colonization by bacteria.
authors.affiliation: Molecular Immunology, HZI-Helmholtz Centre for Infection Research, Braunschweig, Germany. sara.leschner@helmholtz-hzi.de
authors.forename: Sara
authors.initials: S
authors.lastname: Leschner
authors.forename: Kathrin
authors.initials: K
authors.lastname: Westphal
authors.forename: Nicole
authors.initials: N
authors.lastname: Dietrich
authors.forename: Nuno
authors.initials: N
authors.lastname: Viegas
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Jablonska
authors.forename: Marcin
authors.initials: M
authors.lastname: Lyszkiewicz
authors.forename: Stefan
authors.initials: S
authors.lastname: Lienenklaus
authors.forename: Werner
authors.initials: W
authors.lastname: Falk
authors.forename: Nelson
authors.initials: N
authors.lastname: Gekara
authors.forename: Holger
authors.initials: H
authors.lastname: Loessner
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000382:microbiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019779:Salmonella enterica / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D014409:Tumor Necrosis Factor-alpha
references.citation: Cell Cycle. 2009 Mar 15;8(6):870-5
references.pmid: 19221501
references.citation: Cancer Res. 2006 Aug 1;66(15):7647-52
references.pmid: 16885365
references.citation: Cancer Biol Ther. 2005 Aug;4(8):840-5
references.pmid: 16210914
references.citation: Front Biosci. 2007 May 01;12:3880-91
references.pmid: 17485344
references.citation: Int J Cancer. 2007 Aug 1;121(3):666-74
references.pmid: 17397027
references.citation: J Infect Dis. 2000 Jun;181(6):1996-2002
references.pmid: 10837181
references.citation: Adv Drug Deliv Rev. 2005 Jan 2;57(1):135-52
references.pmid: 15518926
references.citation: Microcirculation. 1997 Mar;4(1):25-33
references.pmid: 9110281
references.citation: Nature. 1981 May 21;291(5812):238-9
references.pmid: 7015147
references.citation: Nat Biotechnol. 2004 Mar;22(3):313-20
references.pmid: 14990953
references.citation: Biotechnol Bioeng. 2006 Jul 5;94(4):710-21
references.pmid: 16470601
references.citation: Trends Microbiol. 2006 Apr;14(4):190-6
references.pmid: 16500103
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10170-4
references.pmid: 17548809
references.citation: Vascul Pharmacol. 2002 Nov;39(4-5):187-99
references.pmid: 12747959
references.citation: Vaccine. 2007 May 22;25(21):4183-92
references.pmid: 17399861
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):755-60
references.pmid: 15644448
references.citation: Am J Pathol. 2000 Apr;156(4):1363-80
references.pmid: 10751361
references.citation: Lancet Oncol. 2003 Sep;4(9):548-56
references.pmid: 12965276
references.citation: Nat Rev Cancer. 2005 Jun;5(6):423-35
references.pmid: 15928673
references.citation: Cell Microbiol. 2008 Jun;10(6):1235-48
references.pmid: 18208564
references.citation: Cancer Immunol Immunother. 1984;18(2):107-12
references.pmid: 6391653
references.citation: Hum Gene Ther. 2002 Jul 1;13(10):1225-33
references.pmid: 12133275
references.citation: Cancer Res. 2005 May 1;65(9):3920-7
references.pmid: 15867392
references.citation: Cancer Res. 2008 Apr 15;68(8):2952-60
references.pmid: 18413765
references.citation: Eur J Cancer. 2000 Dec;36(18):2397-402
references.pmid: 11094316
references.citation: Cancer Res. 1997 Oct 15;57(20):4537-44
references.pmid: 9377566
references.citation: Cancer Res. 1999 Apr 1;59(7):1626-34
references.pmid: 10197639
references.citation: J Clin Oncol. 2002 Jan 1;20(1):142-52
references.pmid: 11773163
references.citation: Clin Orthop Relat Res. 1991 Jan;(262):3-11
references.pmid: 1984929
references.citation: Cancer Res. 1980 Jun;40(6):2061-8
references.pmid: 6989495
references.citation: J Immunol. 1990 Dec 1;145(11):3762-6
references.pmid: 2246512
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15083-8
references.pmid: 14657371
references.citation: Cancer Res. 1991 May 15;51(10):2524-30
references.pmid: 2021932
references.citation: J Immunother. 2003 Mar-Apr;26(2):179-80
references.pmid: 12616110
references.citation: Eur J Cancer. 1996 Sep;32A(10):1712-8
references.pmid: 8983279
references.citation: J Cell Biochem. 2009 Apr 15;106(6):992-8
references.pmid: 19199339
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15172-7
references.pmid: 15471990
references.citation: Cancer Res. 2003 Sep 1;63(17):5188-93
references.pmid: 14500342
references.citation: Cancer Res. 1991 Jan 1;51(1):265-73
references.pmid: 1988088
references.citation: Mol Ther. 2005 May;11(5):707-16
references.pmid: 15851009