Crosstalk of carcinoembryonic antigen and transforming growth factor-β via their receptors: comparing human and canine cancer

Abstract

There is accumulating evidence that the transforming growth factor beta (TGF-β) and nuclear factor kappa-B (NFκB) pathways are tightly connected and play a key role in malignant transformation in cancer. Immune infiltration by regulatory T- and B-lymphocytes (Tregs, Bregs) has recently gained increased attention for being an important source of TGF-β. There is a plethora of studies examining the pro-tumorigenic functions of carcinoembryonic antigen (CEA), but its receptor CEAR is far less studied. So far, there is a single connecting report that TGF-β also may signal through CEAR. The crosstalk between cancer tissues is further complicated by the expression of CEAR and TGF-β receptors in stromal cells, and implications of TGF-β in epithelial–mesenchymal transition. Furthermore, tumor-infiltrating Tregs and Bregs may directly instruct cancer cells by secreting TGF-β binding to their CEAR. Therefore, both TGF-β and CEA may act synergistically in breast cancer and cause disease progression, and NFκB could be a common crossing point between their signaling. CEAR, TGF-β1–3, TGF-β-R types I–III and NFκB class I and II molecules have an outstanding human–canine sequence identity, and only a canine CEA homolog has not yet been identified. For these reasons, the dog may be a valid translational model patient for investigating the crosstalk of the interconnected CEA and TGF-β networks.

The Genome-Wide Analysis of Carcinoembryonic Antigen Signaling by Colorectal Cancer Cells Using RNA Sequencing

“…Recently it has been reported that TGF-β may signal through HNRNPM/CEAR [26]. The authors suggested that NF-kappaB could be a common point between these pathways [26]. Our data also show that MAPK pathway is deregulated by CEA overexpression.…”

Towards understanding the mechanisms of actions of carcinoembryonic antigen‐related cell adhesion molecule 6 in cancer progression

“…TGF‐β elaborated in the malignant tumor microenvironment (TME) binds to the type II receptor (T_RII), promoting hetero‐tetramerization with the type I receptor (T_RI) and increasing the phosphorylation of SMAD3 by activated T_RI. Phosphorylated SMAD3 forms a complex with Co‐Smad (SD4), which promotes translocation into the nucleus and activate expression of target genes, specifically CEACAM6 . Hence, HER2 signaling through the TGF‐β pathway may regulate CEACAM6 expression.…”

“…Phosphorylated SMAD3 forms a complex with Co-Smad (SD4), which promotes translocation into the nucleus and activate expression of target genes, specifically CEACAM6. 27 Hence, HER2 signaling through the TGF-b pathway may regulate CEACAM6 expression.…”

Transforming growth factor β1 suppresses proinflammatory gene program independent of its regulation on vascular smooth muscle differentiation and autophagy

“…However, it remains unclear whether STAT3 is involved in TGFβ-regulated VSMC contractile and proinflammatory gene programs. In addition, TGFβ signaling has been shown to crosstalk with nuclear factor κB (NF-κB) pathway [32–37], but the interplay of these two integral pathways and the resulted functional consequences upon the activation of TGFβ cascade in VSMCs are not fully unraveled.…”