title: Mesenchymal Stem Cells Overexpressing IFN-β Inhibit Breast Cancer Growth and Metastases through Stat3 Signaling in a Syngeneic Tumor Model.
abstract: We previously demonstrated that mesenchymal stem/stromal cells (MSC) are recruited to tumors and that IFN-β produced by MSC inhibited tumor growth in xenograft models. Because of a deficient immune system, murine xenograft models cannot fully recapitulate tumor and immune cell interactions during progression. Therefore we investigated the capacity of MSC to migrate to and engraft into primary breast tumor sites and subsequently explore mechanisms of tumor inhibition by MSC-delivered IFN-β in a syngeneic, immunocompetent murine model. Herein we report that 1) systemically administrated MSC migrate to established 4 T1 breast cancer sites and localize among the tumor-stroma border and throughout the tumor mass; 2) high levels of IFN-β secreted by MSC are detectable in the tumor microenvironment but not in circulation; 3) intratumorally produced IFN-β inactivates constitutive phosphorylation of signal transducer activator transcription factor 3 (Stat3), Src, and Akt and down-regulates cMyc and MMP2 expression in 4 T1 cells, and 4) in mice with established breast cancer IFN-β expressing MSC administered systemically resulted in inhibition of primary cancer growth and in dramatic reduction of pulmonary and hepatic metastases. 5) MSC-IFN-β treated, but not control mice, maintained normal levels of splenic mature dendritic (DC), CD8+ T cells and CD4+/Foxp3+ regulatory T-cells (Treg). Our findings suggest that MSC are capable of migrating to tumor sites in an immunocompetent environment, that IFN-β produced by MSC suppresses breast cancer growth through inhibition of Stat3 signaling, and dramatically reduces pulmonary and hepatic metastases.
  
  
  BACKGROUND
  The online version of this article (doi:10.1007/s12307-010-0041-8) contains supplementary material, which is available to authorized users.
authors.affiliation: Molecular Hematology and Therapy Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 448, Houston, TX 77030-4009 USA.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Ling
authors.forename: Frank
authors.initials: F
authors.lastname: Marini
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.forename: Wendy
authors.initials: W
authors.lastname: Schober
authors.forename: Yuexi
authors.initials: Y
authors.lastname: Shi
authors.forename: Jared
authors.initials: J
authors.lastname: Burks
authors.forename: Karen
authors.initials: K
authors.lastname: Clise-Dwyer
authors.forename: Rui-Yu
authors.initials: RY
authors.lastname: Wang
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhang
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Yuan
authors.forename: Hongbo
authors.initials: H
authors.lastname: Lu
authors.forename: Lisa
authors.initials: L
authors.lastname: Caldwell
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff