title: Interferon gamma-induced human guanylate binding protein 1 inhibits mammary tumor growth in mice.
abstract: Interferon gamma (IFN-gamma) has recently been implicated in cancer immunosurveillance. Among the most abundant proteins induced by IFN-gamma are guanylate binding proteins (GBPs), which belong to the superfamily of large GTPases and are widely expressed in various species. Here, we investigated whether the well-known human GBP-1 (hGBP-1), which has been shown to exert antiangiogenic activities and was described as a prognostic marker in colorectal carcinomas, may contribute to an IFN-gamma-mediated tumor defense. To this end, an IFN-independent, inducible hGBP-1 expression system was established in murine mammary carcinoma (TS/A) cells, which were then transplanted into syngeneic immune-competent Balb/c mice. Animals carrying TS/A cells that had been given doxycycline for induction of hGBP-1 expression revealed a significantly reduced tumor growth compared with mock-treated mice. Immunohistochemical analysis of the respective tumors demonstrated a tightly regulated, high-level expression of hGBP-1. No signs of an enhanced immunosurveillance were observed by investigating the number of infiltrating B and T cells. However, hemoglobin levels as well as the number of proliferating tumor cells were shown to be significantly reduced in hGBP-1-expressing tumors. This finding corresponded to reduced amounts of vascular endothelial growth factor A (VEGF-A) released by hGBP-1-expressing TS/A cells in vitro and reduced VEGF-A protein levels in the corresponding mammary tumors in vivo. The results suggest that hGBP-1 may contribute to IFN-gamma-mediated antitumorigenic activities by inhibiting paracrine effects of tumor cells on angiogenesis. Consequently, owing to these activities GBPs might be considered as potent members in an innate, IFN-gamma-induced antitumoral defense system.
authors.affiliation: Institute of Virology, Department of Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Karoline
authors.initials: K
authors.lastname: Lipnik
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Naschberger
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gonin-Laurent
authors.forename: Petra
authors.initials: P
authors.lastname: Kodajova
authors.forename: Helga
authors.initials: H
authors.lastname: Petznek
authors.forename: Stefanie
authors.initials: S
authors.lastname: Rungaldier
authors.forename: Simonetta
authors.initials: S
authors.lastname: Astigiano
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
authors.forename: Michael
authors.initials: M
authors.lastname: Stürzl
authors.forename: Christine
authors.initials: C
authors.lastname: Hohenadl
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D000818:Animals; D015153:Blotting, Western; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D006651:Histocytochemistry; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000378:metabolism; D014161:Transduction, Genetic; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C490287:GBP1 protein, human; D006454:Hemoglobins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D007371:Interferon-gamma; D019204:GTP-Binding Proteins; D004318:Doxycycline
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7556-61
references.pmid: 9636188
references.citation: Int J Cancer. 2008 Nov 1;123(9):2120-9
references.pmid: 18697200
references.citation: Nat Rev Cancer. 2008 Aug;8(8):579-91
references.pmid: 18596824
references.citation: Int J Cancer. 1999 Feb 9;80(4):624-9
references.pmid: 9935167
references.citation: EMBO J. 2001 Oct 15;20(20):5568-77
references.pmid: 11598000
references.citation: Immunity. 1994 Sep;1(6):447-56
references.pmid: 7895156
references.citation: Cancer Res. 2004 Apr 15;64(8):2799-804
references.pmid: 15087396
references.citation: Br J Pharmacol. 2005 May;145(1):24-33
references.pmid: 15723097
references.citation: Am J Pathol. 2002 Nov;161(5):1749-59
references.pmid: 12414522
references.citation: Immunology. 2007 May;121(1):1-14
references.pmid: 17386080
references.citation: Virology. 1999 Mar 30;256(1):8-14
references.pmid: 10087221
references.citation: J Cell Mol Med. 2006 Jul-Sep;10(3):588-612
references.pmid: 16989723
references.citation: J Biol Chem. 1983 Jun 25;258(12):7746-50
references.pmid: 6305951
references.citation: J Histochem Cytochem. 1994 Aug;42(8):1127-34
references.pmid: 8027531
references.citation: Adv Enzyme Regul. 2005;45:215-27
references.pmid: 16005050
references.citation: J Interferon Cytokine Res. 2005 Aug;25(8):435-43
references.pmid: 16108726
references.citation: Mol Cancer Ther. 2006 Aug;5(8):1927-34
references.pmid: 16928812
references.citation: Biochem J. 2004 Apr 15;379(Pt 2):409-20
references.pmid: 14741045
references.citation: J Interferon Cytokine Res. 2006 May;26(5):328-52
references.pmid: 16689661
references.citation: J Biol Chem. 2002 Feb 22;277(8):6080-7
references.pmid: 11726669
references.citation: Nat Rev Immunol. 2006 Nov;6(11):836-48
references.pmid: 17063185
references.citation: J Immunol. 2007 Dec 1;179(11):7729-40
references.pmid: 18025219
references.citation: J Interferon Cytokine Res. 2007 Jan;27(1):44-52
references.pmid: 17266443
references.citation: Science. 2005 Jan 7;307(5706):58-62
references.pmid: 15637262
references.citation: J Clin Oncol. 2005 Oct 1;23(28):7212-20
references.pmid: 16192605
references.citation: Clin Exp Metastasis. 1983 Oct-Dec;1(4):373-80
references.pmid: 6546207
references.citation: EMBO J. 2000 Sep 1;19(17):4555-64
references.pmid: 10970849
references.citation: FASEB J. 2008 Dec;22(12):4168-78
references.pmid: 18697840
references.citation: Am J Pathol. 2006 Sep;169(3):1088-99
references.pmid: 16936281
references.citation: J Leukoc Biol. 2004 Feb;75(2):163-89
references.pmid: 14525967
references.citation: Ann N Y Acad Sci. 2008;1131:1-12
references.pmid: 18519955
references.citation: Int J Cancer. 1998 May 29;76(5):713-9
references.pmid: 9610731
references.citation: J Gene Med. 2006 Feb;8(2):229-41
references.pmid: 16170834
references.citation: Nature. 2000 Feb 3;403(6769):567-71
references.pmid: 10676968
references.citation: J Natl Cancer Inst. 1996 Apr 17;88(8):536-41
references.pmid: 8606382
references.citation: Carcinogenesis. 2009 May;30(5):851-60
references.pmid: 19237608
references.citation: J Immunother. 2007 Jul-Aug;30(5):490-8
references.pmid: 17589289
references.citation: BMC Genomics. 2008 Apr 10;9:158
references.pmid: 18402675
references.citation: J Histochem Cytochem. 1995 Mar;43(3):345
references.pmid: 7868864
references.citation: Nat Med. 2003 Jun;9(6):685-93
references.pmid: 12778167
references.citation: Cancer Res. 2000 Dec 1;60(23):6670-6
references.pmid: 11118051
references.citation: EMBO J. 2003 Aug 1;22(15):3772-82
references.pmid: 12881412
references.citation: Cell Growth Differ. 1996 Mar;7(3):289-300
references.pmid: 8838859