title: 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 = 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-gamma-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.
authors.affiliation: Division of Molecular and Experimental Surgery, Department of Surgery, University of Erlangen-Nuremberg, Schwabachanlage 10, Erlangen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Naschberger
authors.forename: Roland S
authors.initials: RS
authors.lastname: Croner
authors.forename: Susanne
authors.initials: S
authors.lastname: Merkel
authors.forename: Arno
authors.initials: A
authors.lastname: Dimmler
authors.forename: Philipp
authors.initials: P
authors.lastname: Tripal
authors.forename: Kerstin U
authors.initials: KU
authors.lastname: Amann
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Brueckl
authors.forename: Thomas
authors.initials: T
authors.lastname: Papadopoulos
authors.forename: Christine
authors.initials: C
authors.lastname: Hohenadl
authors.forename: Werner
authors.initials: W
authors.lastname: Hohenberger
authors.forename: Michael
authors.initials: M
authors.lastname: Stürzl
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D054357:Chemokine CXCL10 / Q000032:analysis; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000276:immunology* / Q000401:mortality; D005260:Female; D019204:GTP-Binding Proteins / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012189:Retrospective Studies; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C490287:GBP1 protein, human; D007371:Interferon-gamma; D019204:GTP-Binding Proteins