Stromal cell-derived factor (SDF)-1 fördert das Wachstum von kolorektalen Metastasen durch Beschleunigung der Angiogenese, Induktion der Tumorzellproliferation und Inhibition der Apoptose

Abstract

Background: The functional role of the chemokine CXCL 12, known as stromal cell derived factor (SDF)-1, in colorectal cancer has not been fully elucidated yet. Therefore, we analyzed in a mouse model of established extrahepatic colorectal metastasis, whether SDF-1 stimulates tumor cell migration in vitro and angiogenesis and tumor growth in vivo. Methods: Using chemotaxis chambers, CT26. WT colorectal tumor cell migration was studied under stimulation with different concentrations of SDF-1. Furthermore, green fluorescent protein (GFP)-transfected CT26. WT cells were implanted into dorsal skinfold chambers of syngeneic BALB/c mice. After 5 days, the tumors were locally exposed to 100nM SDF-1. Cell proliferation, apoptosis, tumor vascularization 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: In vitro, > 30 % of the CT26. WT cells showed expression of the SDF-1 receptor CXCR4. In the chemotaxis essay, SDF-1 provoked a dose-dependent increase of cell migration. In vivo, SDF-1 stimulated neovascularization and tumor growth. Capillaries of SDF-1-treated tumors showed significant dilation, indicating an increased release of VEGF. SDF-1 treatment was also associated with an increased expression of proliferating cell nuclear antigen (PCNA) and a downregulation of cleaved caspase-3. Conclusion: SDF-1 promotes tumor cell migration of colonic cancer cells in vitro and tumor growth of established extrahepatic metastasis in vivo, which is most probably caused by an angiogenesis-dependent induction of tumor cell proliferation and inhibition of apoptotic cell death.