Fibrinogen activates focal adhesion kinase (FAK) promoting colorectal adenocarcinoma growth
| Autor: | Matthew J. Flick, Miki Watanabe-Chailland, Bal Krishan Sharma, Rebekah Karns, Rachel Cantrell, Duaa Mureb, Brenton J Francisco, Jacob Mast, Lindsey E. Romick-Rosendale, Joseph S. Palumbo, Patrick W. Whitlock, Leah Rosenfeldt, Sumit Murab |
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| Rok vydání: | 2021 |
| Předmět: |
Senescence
Tumor microenvironment biology Chemistry Colorectal cancer Fibrinogen Context (language use) Hematology Adenocarcinoma medicine.disease Article Hemostatics Fibrin Focal adhesion Mice Downregulation and upregulation In vivo Focal Adhesion Kinase 1 Tumor Microenvironment biology.protein Cancer research medicine Animals Colorectal Neoplasms |
| Zdroj: | J Thromb Haemost |
| ISSN: | 1538-7836 |
| Popis: | Background We previously showed that fibrinogen is a major determinant of the growth of a murine model of colorectal cancer (CRC). Objective Our aim was to define the mechanisms coupling fibrin(ogen) to CRC growth. Results CRC tumors transplanted into the dorsal subcutis of Fib- mice were less proliferative and demonstrated increased senescence relative to those grown in Fib+ mice. RNA-seq analyses of Fib+ and Fib- tumors revealed 213 differentially regulated genes. One gene highly upregulated in tumors from Fib- mice was stratifin, encoding 14-3-3σ, a master regulator of proliferation/senescence. In a separate cohort, we observed significantly increased protein levels of 14-3-3σ and its upstream and downstream targets (i.e., p53 and p21) in tumors from Fib- mice. In vitro analyses demonstrated increased tumor cell proliferation in a fibrin printed three-dimensional environment compared with controls, suggesting that fibrin(ogen) in the tumor microenvironment promotes tumor growth in this context via a tumor cell intrinsic mechanism. In vivo analyses showed diminished activation of focal adhesion kinase (FAK), a key negative regulator of p53, in Fib- tumors. Furthermore, nuclear magnetic resonance-based metabolomics demonstrated significantly reduced metabolic activity in tumors from Fib- relative to Fib+ mice. Together, these findings suggest that fibrin(ogen)-mediated engagement of colon cancer cells activates FAK, which inhibits p53 and its downstream targets including 14-3-3σ and p21, thereby promoting cellular proliferation and preventing senescence. Conclusions These studies suggest that fibrin(ogen) is an important component of the colon cancer microenvironment and may be exploited as a potential therapeutic target. |
| Databáze: | OpenAIRE |
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