Liver Resection-Associated Macrophage Inflammatory Protein-2 Stimulates Engraftment but not Growth of Colorectal Metastasis at Extrahepatic Sites

Abstract

Previous studies have shown that liver resection enhances intrahepatic engraftment of CXCR-2-expressing colorectal cancer cells by the action of the CXC chemokine macrophage inflammatory protein (MIP)-2. Herein we studied how liver resection-associated MIP-2 affects extrahepatic tumor cell engraftment and whether MIP-2 also stimulates the growth of already established metastases. Green fluorescent protein-transfected CT26.WT colorectal cancer cells were implanted into dorsal skinfold chambers of syngeneic BALB/c mice. Additionally, all animals underwent a 30% hepatectomy. To study MIP-2 in extrahepatic tumor cell engraftment, animals were treated with an anti-MIP-2 antibody, starting at the day of tumor cell implantation. To study MIP-2 in established metastases, anti-MIP-2 treatment was initiated at day 5 after tumor cell implantation. Hepatectomized animals without neutralization of MIP-2 served as controls. Tumor vascularization and growth as well as tumor cell migration, proliferation, apoptosis, and CXCR-2 expression were studied over 14 days using intravital fluorescence microscopy, histology, and immunohistochemistry. Functional inhibition of MIP-2 significantly delayed extrahepatic tumor cell engraftment but not the growth of established metastases. The initial delay of engraftment was associated with a compensatory stimulation of vascularization and tumor cell migration when compared to controls (P < 0.05). Further, inhibition of tumor cell engraftment by initial anti-MIP-2 treatment was associated with a significant (P < 0.05) reduction of CXCR-2 expression and tumor cell apoptosis. Our study indicates that MIP-2 is involved in extrahepatic engraftment of CT.26 colorectal cancer cells. The MIP-2/CXCR-2 signaling pathway may be a promising target for early antitumor therapy in patients undergoing liver resection.