Abstract 4107: Human guanylate-binding protein-1 (GBP-1) in colorectal carcinoma

Abstract

Abstract The human guanylate binding protein 1 (hGBP-1) is a large GTPase which mediates the anti-proliferative and anti-angiogenic effects of pro-inflammatory cytokines (IC), such as IFNγ, TNFα and IL1α/β, on endothelial cells in vitro. The expression of GBP-1 has been investigated in human colorectal carcinoma (CRC). We could show that GBP-1 is expressed in stromal endothelial cells of 32% of the CRC. This expression was correlated with a better outcome for patients with GBP-1 expression in the tumour stroma. A transcriptome analysis revealed that in the tumours, IFN-γ-induced genes including the major antiangiogenic chemokines CXCL9, CXCL10 and CXCL11 were coexpressed with GBP-1, indicating the presence of an active Th-1-like angiostatic immune reaction. However, the presence of GBP-1 was only detected in the stroma, suggesting that in tumour cells the expression of GBP-1 may be suppressed. In order to investigate the effects of GBP-1 on tumour cells, we reintroduced the protein in the DLD-1 colorectal carcinoma cell line, which does not produce GBP-1 in absence or in presence of IFN-γ. The proliferation rate was lower in GBP-1 expressing DLD-1 cells as compared to control cells. In order to better characterize the in vivo anti-tumourigenic effects of GBP-1, we developed a tumour mouse model using the DLD-1 cell line stably expressing GBP-1. Stable DLD-1 clones, which expressed GBP-1, and respective control cells (transfected with the empty vector plasmid) were xenotransplanted into immunodeficient mice. After 36 days, tumour volumes in the GBP-1 group were significantly smaller than in the control group (p<0.001). This experiment was repeated with identical outcome in two different mouse strains. Immunohistochemistry stainings and Western blot analyses of the tumours confirmed that GBP-1 was highly expressed in the GBP-1 group and absent in control tumours. These results show that GBP-1 expression can inhibit tumour growth in an animal mouse model, indicating that tumour cells may have developed mechanisms to inhibit GBP-1 expression in an IFN-γ dominated microenvironment. The responsible mechanisms are investigated in ongoing studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4107.