gms | German Medical Science

Colorectal Cancer (CRC) arises with more than a million new cases and causes more than a half million deaths each year. Inflammation and angiogenesis are closely associated with CRC. It has been shown that angiogenesis contributes to CRC progression. However, it is still a matter of debate whether inflammation may promote or adversely affect tumor growth. The guanylate binding protein-1 (GBP-1) was identified by our group as a marker of endothelial cells (EC), which are activated by inflammatory cytokines (IC) in vitro and in vivo. In addition, we have shown that GBP-1 mediates the anti-angiogenic effects of IC on EC, inhibiting both, proliferation and invasion. Using GBP-1 as a marker we wanted to determine the relation of inflammation to CRC progression and patient´s survival. High expression of GBP-1 was detected in some CRC by immunohistochemical staining. GBP-1 was preferentially expressed by EC and macrophages in the desmoplactic stroma and only rarely by tumor cells. In order to characterize the specific microenvironment associated with GBP-1 expression we searched for genes which are coexpressed with GBP-1. Transcriptome analysis using microarray was performed with total RNA from 12 GBP-1-positive and -negative CRC, respectively. The majority of GBP-1 coregulated genes were IFN- induced genes, chemokines and immunoglobulin genes. Most importantly, 4 of the 5 anti-angiogenic chemokines presently known were among the 15 highest upregulated genes in GBP-1-positive tumors. Thus, an IFN- dominated, highly anti-angiogenic environment is associated with GBP-1 expression in CRC. Immunohistochemical analysis of a large collective of CRC patients (n=416) revealed that GBP-1 is expressed in approximately 20 % of all CRC and is mainly associated with early UICC stages and low metastasis (N=0). Most interestingly, GBP-1 expression in later stages (> UICC stage III) was associated with a significantly (p=0.043) increased cancer-related 5 year survival (21.6 %). These results demonstrate that inflammation is mainly present in early stages of CRC as indicated by GBP-1 expression. CRC that still express GBP-1 in later stages (> UICC stage III) exhibit a significantly increased 5 year survival, which may be explained by the anti-angiogenic microenvironment associated with GBP-1 expression.