Angiostatic immune reaction in colorectal carcinoma: Impact on survival and perspectives for antiangiogenic therapy

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Abstract
Angiogenesis and inflammation are the 2 major stroma reactions in colorectal carcinoma (CRC). Guanylate binding protein‐1 (GBP‐1) is a key mediator of angiostatic effects of inflammation. Therefore, we hypothesized that GBP‐1 may be a biomarker of intrinsic angiostasis associated with an improved outcome in CRC patients. GBP‐1 was strongly expressed in endothelial cells and immune cells in the desmoplastic stroma of 32% of CRC as determined by immunohistochemical investigation of 388 sporadic CRC. Cancer‐related 5‐year survival was highly significant (p < 0.001) increased (16.2%) in patients with GBP‐1‐positive CRC. Multivariate analysis showed that GBP‐1 is an independent prognostic factor indicating a reduction of the relative risk of cancer‐related death by the half (p = 0.032). A comparative transcriptome analysis (22,215 probe sets) of GBP‐1‐positive (n = 12) and ‐negative (n = 12) tumors showed that particularly IFN‐γ‐induced genes including the major antiangiogenic chemokines CXCL9, CXCL10 and CXCL11 were coexpressed with GBP‐1. Altogether our findings indicated that GBP‐1 may be a novel biomarker and an active component of a Th‐1‐like angiostatic immune reaction in CRC. This reaction may affect patient's response to antiangiogenic therapy and the identification of such tumors may provide a novel criterion for patient selection. Moreover, the induction of a Th‐1‐like angiostatic immune reaction may be a promising approach for the clinical treatment of CRC.