Carcinoembryonic antigen (CEA) and its receptor hnRNP M are mediators of metastasis and the inflammatory response in the liver

Abstract

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.

Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing

“…Consistent with this notion, our clinical sample analysis revealed a significant positive correlation between hnRNPM and CD44s in breast cancer specimens. It is interesting to note that, in addition to its activity as a splicing regulator, hnRNPM was reported as a cell surface receptor expressed in Kupple macrophages that interacts with carcinoembryonic antigen produced by colorectal cancer cells, which is potentially important for tumor metastasis (Thomas et al 2011). Thus, hnRNPM may function through multiple mechanisms to promote tumor metastasis.…”

The Role of the Carcinoembryonic Antigen Receptor in Colorectal Cancer Progression

“…It has been also shown that upregulation of hnRNPM/CEAR is associated with the more aggressive types of colon [39] and breast cancers [40]. Interaction of CEA with CEAR in macrophages can also result in the secretion of pro-angiogenic factors such as IL-6 [9]. Figure 3A: The effect of CEAR silencing on cell adhesion and invasion.…”

“…However, the molecular mechanism of CEA-induced metastasis is poorly defined and may involve several mechanisms. We identified a novel CEA binding protein (CEAR) on liver macrophages, (Kupffer cells), who's activity alters the liver microenvironment such that implantation and survival of tumor cells increases [9]. Previously this protein was identified as an isoform of the hnRNPM protein [10].…”

Proteomic Characterization of Plasma Cells from Patients with Multiple Myeloma

“…hnRNP M plays role in mediating metastasis and the inflammatory response [76,77], while under-expression of peroxidoxin-6 enhances the susceptibility of cells to tumorigenesis [78]. Isoform 1 of myosin-9 is a known binding protein that binds to a number of proteins related to cancer progression and the unconventional secretory pathway [79].…”