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Inhibition of Hepatic Endothelial E-Selectin Expression by C-raf Antisense Oligonucleotides Blocks Colorectal Carcinoma Liver Metastasis¹

Departments of Surgery and Medicine, McGill University Health Center, Royal Victoria Hospital, Montreal, Quebec, H3A 1A4 Canada [A-M. K., L. F., P. B.], and ISIS Pharmaceuticals, Carlsbad Research Center, Carlsbad, California 92008 [E. W., B. M.]

Cytokine-dependent induction of E-selectin expression is mediated through cooperative signaling involving the Ras/Raf/mitogen-activated protein kinase pathway. We previously reported that metastatic tumor cells entering the hepaticcirculation rapidly induce a cytokine cascade leading to E-selectin induction (A-M. Khatib, et al., Cancer Res., 59:1356–1361, 1999).Here, we investigated the effect of a blockade of E-selectin induction on colorectal carcinoma metastasis using rodent (host)-specific C-raf antisense oligonucleotides and human colorectal carcinoma CX-1 cells. Pretreatment of hepatic endothelial cells in vitro with the antisense oligonucleotides abrogated E-selectin-dependent CX-1 adhesion. In vivo, pretreatment of nude mice with these oligonucleotides abrogated E-selectin induction in response to intrasplenic/portal inoculation of CX-1 cells, and this reduced the number of liver metastases by 86% relative to controls. The results suggest that the inhibition of tumor-induced, hepatic microvessel E-selectin expression may provide a useful strategy for the prevention of hepatic metastasis.

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