Studies on MIP-2 and CXCR2 expression in a mouse model of extrahepatic colorectal metastasis

Abstract

Aims The CXC chemokine macrophage inflammatory protein (MIP)-2 has been shown to promote outgrowth of colorectal liver metastasis by enhancing angiogenesis and tumor cell migration. However, the effect of MIP-2 on extrahepatic metastasis is not known yet. With a use of a murine model, we therefore studied cell proliferation and microvascularization of extrahepatic CT26.WT-GFP colorectal tumors after exposure to MIP-2. Methods Green fluorescent protein (GFP)-transfected CT26.WT colorectal cancer cells were implanted in dorsal skinfold chambers of syngeneic BALB/c mice. After 5 days, the tumors were locally exposed to 100 nM MIP-2. Cell proliferation as well as tumor microvascularization and growth were studied during a further 9-day period using intravital fluorescence microscopy, histology and immunohistochemistry. Tumors exposed to PBS served as controls. Results MIP-2 induced a marked CXCR2 expression and promoted a distinct tumor cell proliferation. This was associated with a significant increase of tumor size compared to PBS-treated controls. Of interest, MIP-2 did not affect dilation and permeability of the tumor microvessels, which would be indicators for an enhanced VEGF action. Accordingly, the angiogenic response, e.g. the outgrowth of new microvessels, was not affected, and the density of the established tumor microvascular network was even found decreased after MIP-2 exposure when compared to PBS controls. Conclusion With the use of a murine tumor model, we demonstrate that MIP-2 accelerates growth of experimentally established extrahepatic colorectal metastases by inducing tumor cell proliferation rather than promoting vascularization.