EphA2 signaling is impacted by carcinoembryonic antigen cell adhesion molecule 1-L expression in colorectal cancer liver metastasis in a cell context-dependent manner.

Azadeh Arabzadeh,Valérie Breton,Celia M.T Greenwood,Kevin Mcgregor,Lauren Van Der Kraak,Nicole Beauchemin,Uri David Akavia

doi:10.18632/oncotarget.22236

Abstract

We have shown that carcinoembryonic antigen cell adhesion molecule 1 long isoform (CEACAM1-L) expression in MC38 metastatic colorectal cancer (CRC) cells results in liver metastasis inhibition via CCL2 and STAT3 signaling. But other molecular mechanisms orchestrating CEACAM1-L-mediated metastasis inhibition remain to be defined. We screened a panel of mouse and human CRC cells and evaluated their metastatic outcome after CEACAM1 overexpression or downregulation. An unbiased transcript profiling and a phospho-receptor tyrosine kinase screen comparing MC38 CEACAM1-L-expressing and non-expressing (CT) CRC cells revealed reduced ephrin type-A receptor 2 (EPHA2) expression and activity. An EPHA2-specific inhibitor reduced EPHA2 downstream signaling in CT cells similar to that in CEACAM1-L cells with decreased proliferation and migration. Human CRC patients exhibiting high CEACAM1 in combination with low EPHA2 expression benefited from longer time to first recurrence/metastasis compared to those with high EPHA2 expression. With the added interaction of CEACAM6, we denoted that CEACAM1 high- and EPHA2 low-expressing patient samples with lower CEACAM6 expression also exhibited a longer time to first recurrence/metastasis. In HT29 human CRC cells, down-regulation of CEACAM1 along with CEA and CEACAM6 up-regulation led to higher metastatic burden. Overall, CEACAM1-L expression in poorly differentiated CRC can inhibit liver metastasis through cell context-dependent EPHA2-mediated signaling. However, CEACAM1’s role should be considered in the presence of other CEACAM family members.

Highlights

Liver metastasis of colorectal cancer (CRC) occurs in approximately 30% of CRC patients and is a major cause of CRC related mortality [1]
To determine whether this is a general phenomenon applying to other CRC cells, we investigated a panel of mouse (MC38, CT26) and human (HT29, HCT116, LS174T, LS180, SW620, Colo320, KM12) metastatic CRC cells
Our group has recently shown that Carcino embryonic antigen cell adhesion molecule 1 (CEACAM1)-L expression in murine MC38 poorly differentiated CRC cells dramatically reduced experimental liver metastasis as a consequence of diminished STAT3 activity and lessened CCL2 chemokine expression [22]

Summary

Introduction

Liver metastasis of colorectal cancer (CRC) occurs in approximately 30% of CRC patients and is a major cause of CRC related mortality [1]. While improvements in surgical techniques, chemotherapeutic regimens and the availability of anti-EGFR- and anti-VEGFR2-targeted therapies have contributed to longer survival and better quality of life for CRC metastatic patients, further research is needed to identify novel metastatic targets for therapeutic intervention. Carcino embryonic antigen cell adhesion molecule 1 (CEACAM1), a member of the CEA gene family, is a cell adhesion molecule known to be associated with CRC tumor development and metastasis [2]. Numerous human and murine CEACAM1 splice variants have been identified that differ with respect to the expression of either a short (S) or a long (L) cytoplasmic domain. CEACAM1-L is multifunctional and acts as a negative regulator of many signaling pathways [3] involved in intercellular adhesion regulation [4], insulin and lipid metabolism [5, 6], angiogenesis [7], innate and adaptive immune responses [8,9,10] and microbial and viral pathogen interactions [3]

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