Interferon gamma-induced human guanylate binding protein 1 inhibits mammary tumor growth in mice.
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.
Lipnik
Karoline
K
Institute of Virology, Department of Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria.
Naschberger
Elisabeth
E
Gonin-Laurent
Nathalie
N
Kodajova
Petra
P
Petznek
Helga
H
Rungaldier
Stefanie
S
Astigiano
Simonetta
S
Ferrini
Silvano
S
Stürzl
Michael
M
Hohenadl
Christine
C
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
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
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