Inhibition of hepatic endothelial E-selectin expression by C-raf antisense oligonucleotides blocks colorectal carcinoma liver metastasis.
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.
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D019040:E-Selectin / Q000096:biosynthesis* / Q000235:genetics; D004727:Endothelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D019040:E-Selectin; D007375:Interleukin-1; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019908:Proto-Oncogene Proteins c-raf