title: Shigella mediated depletion of macrophages in a murine breast cancer model is associated with tumor regression.
abstract: A tumor promoting role of macrophages has been described for a transgenic murine breast cancer model. In this model tumor-associated macrophages (TAMs) represent a major component of the leukocytic infiltrate and are associated with tumor progression. Shigella flexneri is a bacterial pathogen known to specificly induce apotosis in macrophages. To evaluate whether Shigella-induced removal of macrophages may be sufficient for achieving tumor regression we have developed an attenuated strain of S. flexneri (M90TDeltaaroA) and infected tumor bearing mice. Two mouse models were employed, xenotransplantation of a murine breast cancer cell line and spontanous breast cancer development in MMTV-HER2 transgenic mice. Quantitative analysis of bacterial tumor targeting demonstrated that attenuated, invasive Shigella flexneri primarily infected TAMs after systemic administration. A single i.v. injection of invasive M90TDeltaaroA resulted in caspase-1 dependent apoptosis of TAMs followed by a 74% reduction in tumors of transgenic MMTV-HER-2 mice 7 days post infection. TAM depletion was sustained and associated with complete tumor regression.These data support TAMs as useful targets for antitumor therapy and highlight attenuated bacterial pathogens as potential tools.
authors.affiliation: Institut für Medizinische Strahlenkunde und Zellforschung, Universität Würzburg, Würzburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Galmbacher
authors.forename: Martin
authors.initials: M
authors.lastname: Heisig
authors.forename: Christian
authors.initials: C
authors.lastname: Hotz
authors.forename: Joerg
authors.initials: J
authors.lastname: Wischhusen
authors.forename: Antoine
authors.initials: A
authors.lastname: Galmiche
authors.forename: Birgit
authors.initials: B
authors.lastname: Bergmann
authors.forename: Ivaylo
authors.initials: I
authors.lastname: Gentschev
authors.forename: Werner
authors.initials: W
authors.lastname: Goebel
authors.forename: Ulf R
authors.initials: UR
authors.lastname: Rapp
authors.forename: Joachim
authors.initials: J
authors.lastname: Fensterle
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002469:Cell Separation; D018450:Disease Progression; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D012760:Shigella / Q000378:metabolism*