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

Autor: Aaron Prodeus, Marzena Cydzik, Samira Alminawi, Jean Gariépy, Aws Abdul-Wahid, Nicholas W. Fischer, Anne L. Martel, Neil L. Berinstein, John E. Shively, Zeina Ghorab
Rok vydání: 2018
Předmět:
Zdroj: International Journal of Cancer. 143:1963-1977
ISSN: 1097-0215
0020-7136
DOI: 10.1002/ijc.31586
Popis: 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.
Databáze: OpenAIRE
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