| Autor: |
Kwon, Ahreum, Chae, In Hee, You, Eunae, Kim, So Hee, Ahn, Su‐yeon, Lee, Ok‐Jun, Park, Zee‐Yong, Rhee, Sangmyung, Huh, Yun Hyun, Song, Woo Keun |
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| Zdroj: |
Journal of Cellular Physiology; May2020, Vol. 235 Issue 5, p4494-4507, 14p |
| Abstrakt: |
Cancer‐associated fibroblasts (CAFs) in the tumor microenvironment play major roles in supporting cancer progression. A previous report showed that SPIN90 downregulation is correlated with CAF activation and that SPIN90‐deficient CAFs promote breast cancer progression. However, the mechanisms that mediate cancer‐stroma interaction and how such interactions regulate cancer progression are not well understood. Here, we show that extra domain A (EDA)‐containing fibronectin (FN), FN(+)EDA, produced by mouse embryonic fibroblasts (MEFs) derived from Spin90‐knockout (KO) mice increases their own myofibroblast differentiation, which facilitates breast cancer progression. Increased FN(+)EDA in Spin90‐KO MEFs promoted fibril formation in the extracellular matrix (ECM) and specifically interacted with integrin α4β1 as the mediating receptor. Moreover, FN(+)EDA expression by Spin90‐KO MEFs increased proliferation, migration, and invasion of breast cancer cells. Irigenin, a specific inhibitor of the interaction between integrin α4β1 and FN(+)EDA, significantly blocked the effects of FN(+)EDA, such as fibril formation by Spin90‐KO MEFs and proliferation, migration, and invasion of breast cancer cells. In orthotopic breast cancer mouse models, irigenin injection remarkably reduced tumor growth and lung metastases. It was supported by that FN(+)EDA in assembled fibrils was accumulated in cancer stroma of human breast cancer patients in which SPIN90 expression was downregulated. Our data suggest that SPIN90 downregulation increases FN(+)EDA and promotes ECM stiffening in breast cancer stroma through an assembly of long FN(+)EDA‐rich fibrils; moreover, engagement of the Integrin α4β1 receptor facilitates breast cancer progression. Inhibitory effects of irigenin on tumor growth and metastasis suggest the potential of this agent as an anticancer therapeutic. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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