Carcinoembryonic antigen promotes tumor cell survival in liver through an IL-10-dependent pathway.
Most circulating tumor cells die within 24 h of entering the hepatic microvasculature because their arrest initiates an ischemia-reperfusion (I/R) injury that is cytotoxic. Human colorectal carcinomas (CRC) produce the glycoprotein Carcinoembryonic Antigen (CEA) that increases experimental liver metastasis in nude mice. Since CEA induces release of IL-6 and IL-10, we hypothesized that CEA inhibits the I/R injury through a Kupffer cell-mediated cytokine-dependent pathway. We assessed cytokine effects in CRC co-cultured with liver and in vivo. Human CRC prelabeled with fluorescent dyes were incubated with a reoxygenated suspension of ischemic nude mouse liver fragments in a bioreactor. CEA, rhIL-6 or rhIL-10 were either administered to the donor mice prior to hepatic ischemia or during co-culture. Liver donors were athymic nude or iNOS, IL-6 or IL-10 knock out mice. Ischemic-reoxygenated liver kills Clone A CRC through production of nitric oxide (NO) and superoxide anion. Treatment of liver donors with CEA prior to hepatic ischemia inhibited this in vitro cytotoxicity through an IL-10 and Kupffer cell dependent pathway that inhibited NF-kappaB activation, NO production and iNOS upregulation. IL-10 but not IL-6 enhanced CRC survival in nude mouse liver in vivo. Thus, CEA enhanced metastasis by inducing IL-10 to inhibit iNOS upregulation in host liver.
Jessup
J Milburn
JM
Department of Oncology, Georgetown University Medical Center, Washington, DC, USA. jmj25@georgetown.edu
Samara
R
R
Battle
P
P
Laguinge
L M
LM
D000818:Animals; D002272:Carcinoembryonic Antigen / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D005456:Fluorescent Dyes; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000556:secondary*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism
D002272:Carcinoembryonic Antigen; D005456:Fluorescent Dyes; D015850:Interleukin-6; D016328:NF-kappa B; D013481:Superoxides; D016753:Interleukin-10; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D010100:Oxygen