Inflammation-associated inhibition of angiogenesis in colorectal carcinoma: molecular mechanisms and prognostic impact

Proinflammatory cytokines (IL-1β, TNF-α and IFN-γ) inhibit proliferation and invasion of endothelial cells. We identified the large GTPase guanylate binding protein-1 (GBP-1) as the intracellular mediator of these anti-angiogenic activities (Guenzi et al. 2001; Guenzi et al. 2003; Naschberger et al. 2005). In recent work we detected that GBP-1 expressing cells show a significantly reduced spreading and migration on fibronectin matrices. Investigating possible mechanisms of these effects, we found that integrin α4 (ITGA-4) was consistently upregulated at both the RNA and protein level in GBP-1 expressing cell cultures. Inhibition of cell spreading and migration by GBP-1 was dependent on the binding of ITGA-4 to fibronectin. The inflammatory cytokines IL-1β and TNF-α induced ITGA-4 expression in endothelial cells and inhibited spreading and migration. Knockdown of GBP-1 by shRNA abrogated inflammatory cytokine induced ITGA-4 expression and restored spreading and migration capabilities of the cells. In order to investigate the clinical impact of this anti-angiogenic activity GBP-1 expression was investigated in colorectal carcinoma (CRC, n=388). GBP-1 was expressed in 32% of the tumors and was associated with a highly significantly improved cancer-related five year-survival. In addition, the protein was identified as an independent prognostic factor and associated with highly significantly reduced angiogenic activity in the tumors. These results indicated that GBP-1 is associated with and regulates an intrinsic inflammation-associated anti-angiogenic reaction which is beneficial for the survival of the patients.