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

ABSTRACT

There is accumulating evidence that the transforming growth factor beta (TGF-ß) 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-ß. 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-ß also may signal through CEAR. The crosstalk between cancer tissues is further complicated by the expression of CEAR and TGF-ß receptors in stromal cells, and implications of TGF-ß in epithelial-mesenchymal transition. Furthermore, tumor-infiltrating Tregs and Bregs may directly instruct cancer cells by secreting TGF-ß binding to their CEAR. Therefore, both TGF-ß 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-ß1-3, TGF-ß-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-ß networks.