Interaction of the chemokines I-TAC (CXCL11) and SDF-1 (CXCL12) in the regulation of tumor angiogenesis of colorectal cancer.
The chemokine CXCL12 has a decisive role in tumor progression by mediating pro-angiogenic and pro-metastatic effects through its receptor CXCR4. The CXCL12 pathway is connected with another chemokine, CXCL11, through its second receptor CXCR7. CXCL11 also binds to the CXCR3 receptor. CXCL11 function in tumor angiogenesis is likely receptor dependent because CXCR3 predominantly mediates angiostatic signals whereas CXCR7 mediated signaling is rather angiogenic. We therefore studied the interaction of CXCL12 and CXCL11 in an in vivo model of colorectal cancer metastasis. GFP-transfected CT26.WT colorectal cancer cells were implanted into the dorsal skinfold chamber of syngeneic BALB/c mice. The animals received either peritumoral application of CXCL11 or intraperitoneal injections with neutralizing antibodies against CXCL11, CXCL12 or both. Tumor growth characteristics, angiogenesis, cell migration, invasive tumor growth, tumor cell proliferation and apoptosis were studied by intravital fluorescence microscopy and immunohistochemistry during an observation period of 14 days. Local exposure to CXCL11 significantly stimulated tumor growth compared to controls and enhanced invasive growth characteristics without affecting tumor angiogenesis and tumor cell migration. Neither CXCL11 nor CXCL12-blockade had a significant impact on tumor growth and angiogenesis, whereas the combined neutralization of CXCL11 and CXCL12 almost completely abrogated tumor vessel formation. As a consequence, tumor growth and invasive growth characteristics were reduced compared to the other groups. The results of the present study underline the interaction of CXCL12 and CXCL11 during tumor angiogenesis. The combined blockade of both signaling pathways may provide an interesting anti-angiogenic approach for anti-tumor therapy.
Department of General, Visceral, Vascular and Pediatric Surgery, University of Saarland, Homburg/Saar, Germany.|Department of Medical Oncology, Hematology, Immunology, Rheumatology and Pulmology, University Hospital of Tübingen, Tübingen, Germany.
Kathrin
K
Rupertus
Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
Janine
J
Sinistra
Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
Claudia
C
Scheuer
Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
Ruth M
RM
Nickels
Department of General, Visceral, Vascular and Pediatric Surgery, University of Saarland, Homburg/Saar, Germany.|Klinik St. Anna Ärztehaus Lützelmatt, Luzern, Switzerland.
Martin K
MK
Schilling
Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
Michael D
MD
Menger
Department of General, Visceral, Vascular and Pediatric Surgery, University of Saarland, Homburg/Saar, Germany. otto.kollmar@med.uni-goettingen.de.|Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany. otto.kollmar@med.uni-goettingen.de.
Otto
O
Kollmar
D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D054371:Chemokine CXCL11 / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D054371:Chemokine CXCL11; D054377:Chemokine CXCL12
Angiogenesis; CXCL11; CXCL12; Chemokines; Colorectal cancer; I-TAC; SDF-1