S erum‐derived carcinoembryonic antigen ( CEA ) activates fibroblasts to induce a local re‐modeling of the extracellular matrix that favors the engraftment of CEA ‐expressing tumor cells

• Published in: International journal of cancer 2018-10, Vol.143 (8), p.1963-1977
• Main Authors: Abdul‐Wahid, Aws, Cydzik, Marzena, Fischer, Nicholas W., Prodeus, Aaron, Shively, John E, Martel, Anne, Alminawi, Samira, Ghorab, Zeina, Berinstein, Neil L., Gariépy, Jean
• Format: Article
• Language: English
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.31586

Elevated levels of the carcinoembryonic antigen (CEA; CEACAM5) in the serum of colorectal cancer (CRC) patients represent a clinical biomarker that correlates with disease recurrence. However, a mechanistic role for soluble CEA (sCEA) in tumor progression and metastasis remains to be established. In our study, we report that sCEA acts as a paracrine factor, activating human fibroblasts by signaling through both the STAT3 and AKT1‐mTORC1 pathways, promoting their transition to a cancer‐associated fibroblast (CaF) phenotype. sCEA‐activated fibroblasts express and secrete higher levels of fibronectin, including cellular EDA + ‐fibronectin (Fn‐EDA) that selectively promote the implantation and adherence of CEA‐expressing cancer cells. Immunohistochemical analyses of liver tissues derived from CRC patients with elevated levels of sCEA reveal that the expression of cellular Fn‐EDA co‐registers with CEA‐expressing liver metastases. Taken together, these findings indicate a direct role for sCEA as a human fibroblast activation factor, in priming target tissues for the engraftment of CEA‐expressing cancer cells, through the differentiation of tissue‐resident fibroblasts, resulting in a local change in composition of the extracellular matrix. What's new? Despite its use in managing colorectal cancer patients, the biological significance of elevated serum levels of the carcinoembryonic antigen (CEA) remains to be elucidated. This study shows that soluble CEA secreted by CEA‐expressing tumor cells acts as a paracrine factor, activating human fibroblasts by signaling through both the STAT3 and AKT1‐mTORC1 pathways and promoting their transition to a cancer‐associated fibroblast (CaF)‐like state. This event engenders a change in the matricellular landscape of target tissues, selectively favoring the implantation of metastatic CEA‐expressing cells. These findings offer an insight into a yet‐unknown mechanism in which CEA directly participates in the metastatic cascade.