This article discusses the role of
carcinoembryonic antigen (CEA) as a facilitator of the inflammatory response and its effect on
colorectal cancer hepatic
metastasis.
Colorectal cancer accounts for 11% of all
cancers in the United States and the majority of deaths are associated with liver
metastasis. If left untreated, median survival is only six to 12 months. Resection of liver
metastases offers the only chance for cure. Of the small number of patients who have operable
cancer most will have further
tumor recurrence. The molecular mechanisms associated with
colorectal cancer metastasis to the liver are largely unknown. However CEA production has been shown both clinically and experimentally to be
a factor in an increased metastatic potential of
colorectal cancers to the liver. CEA also has a role in protecting
tumor cells from the effects of anoikis and this affords a selective advantage for
tumor cell survival in the circulation. CEA acts in the liver through its interaction with its receptor (CEAR), a
protein that is related to the
hnRNP M family of
RNA binding proteins. In the liver CEA binds with
hnRNP M on Kupffer cells and causes activation and production of pro- and anti-inflammatory
cytokines including
IL-1,
IL-10,
IL-6 and TNF-α. These
cytokines affect the up-regulation of adhesion molecules on the hepatic sinusoidal endothelium and protect the
tumor cells against cytotoxicity by
nitric oxide (NO) and other reactive
oxygen radicals.
HnRNP M signaling in Kupffer cells appears to be controlled by
beta-adrenergic receptor activation. The cells will respond to the β-
adrenergic receptor agonist terbutaline resulting in reduced TNF-α and increased
IL-10 and
IL-6 production following CEA activation. This has implications for the control of
tumor cell implantation and survival in the liver.