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

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 5 0.032). A comparative transcriptome analysis (22,215 probe sets) of GBP-1-positive (n 5 12) and -negative (n 5 12) tumors showed that particularly IFN-c-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. ' 2008 Wiley-Liss, Inc.Key words: guanylate binding protein-1; interferon-c; colorectal carcinoma; angiogenesis; inflammation Colorectal carcinoma (CRC) is the second most common malignant tumor, both in men and women, in the western world.

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

“…33 In colorectal cancer, GBP1 overexpression in tumor stroma inhibits tumor growth and correlates with improved survival. 34,35 The functions of other GBPs are less clear although animal and in-vitro models suggest a protective role in controlling infection and autoimmunity as GBPs are essential for formation of the inflammasome complex. 36 The inflammasome complex promotes inflammatory cell death through activation of cysteine protease caspase-1 and is purported to have tumor suppressive effects in some studies.…”

Interferon γ-Induced Human Guanylate Binding Protein 1 Inhibits Mammary Tumor Growth in Mice

“…In addition, recent evidence is accumulating showing that hGBP-1 is involved in antitumoral response processes. In a study involving 388 patients with colorectal carcinomas (20), robust hGBP-1 expression was detected in 30% of the tumors in endothelial cells and monocytes of the desmoplastic stroma. Most interestingly, this finding was associated with a reduced tumor angiogenesis and a highly significantly improved prognosis for the patients (20).…”

“…The antiangiogenic activity of hGBP-1 has been recently demonstrated for colorectal carcinomas. In a study investigating more than 380 tumor samples, it was shown that tumors expressing hGBP-1 exhibited reduced angiogenic activity, and this was associated with a significantly improved prognosis for the respective patients (20). In addition, an effect on proliferation of fibroblasts has been demonstrated for murine GBP-2 (21).…”

Chemokines in cancer related inflammation

“…The CXC chemokines (CXCL9, CXCL10 and CXCL11) inhibit endothelial cell proliferation [67] and suppress tumor angiogenesis in diverse tumors [68][69][70]. Therefore, the balance of angiogenic ELR + vs. angiostatic non-ELR chemokines produced in the tumor microenvironment may determine the development of angiogenesis within a tumor tissue and the consequent clinical outcome.…”