1.Integrin alpha 11 in the regulation of the myofibroblast phenotype: implications for fibrotic diseases.
Ruchi BANSAL ; Shigeki NAKAGAWA ; Saleh YAZDANI ; Joop VAN BAARLEN ; Anu VENKATESH ; Anna P KOH ; Won Min SONG ; Nicolas GOOSSENS ; Hideo WATANABE ; Mary B BEASLEY ; Charles A POWELL ; Gert STORM ; Naftali KAMINSKI ; Harry VAN GOOR ; Scott L FRIEDMAN ; Yujin HOSHIDA ; Jai PRAKASH
Experimental & Molecular Medicine 2017;49(11):e396-
Tissue fibrosis, characterized by excessive accumulation of aberrant extracellular matrix (ECM) produced by myofibroblasts, is a growing cause of mortality worldwide. Understanding the factors that induce myofibroblastic differentiation is paramount to prevent or reverse the fibrogenic process. Integrin-mediated interaction between the ECM and cytoskeleton promotes myofibroblast differentiation. In the present study, we explored the significance of integrin alpha 11 (ITGA11), the integrin alpha subunit that selectively binds to type I collagen during tissue fibrosis in the liver, lungs and kidneys. We showed that ITGA11 was co-localized with α-smooth muscle actin-positive myofibroblasts and was correlatively induced with increasing fibrogenesis in mouse models and human fibrotic organs. Furthermore, transcriptome and protein expression analysis revealed that ITGA11 knockdown in hepatic stellate cells (liver-specific myofibroblasts) markedly reduced transforming growth factor β-induced differentiation and fibrotic parameters. Moreover, ITGA11 knockdown dramatically altered the myofibroblast phenotype, as indicated by the loss of protrusions, attenuated adhesion and migration, and impaired contractility of collagen I matrices. Furthermore, we demonstrated that ITGA11 was regulated by the hedgehog signaling pathway, and inhibition of the hedgehog pathway reduced ITGA11 expression and fibrotic parameters in human hepatic stellate cells in vitro, in liver fibrosis mouse model in vivo and in human liver slices ex vivo. Therefore, we speculated that ITGA11 might be involved in fibrogenic signaling and might act downstream of the hedgehog signaling pathway. These findings highlight the significance of the ITGA11 receptor as a highly promising therapeutic target in organ fibrosis.
Animals
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Collagen
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Collagen Type I
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Cytoskeleton
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Extracellular Matrix
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Fibrosis
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Hedgehogs
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Hepatic Stellate Cells
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Humans
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In Vitro Techniques
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Kidney
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Liver
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Liver Cirrhosis
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Lung
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Mice
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Mortality
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Myofibroblasts*
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Phenotype*
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Transcriptome
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Transforming Growth Factors
2.Tumor microenvironment in lung cancer-derived brain metastasis.
Wenwen LIU ; Charles A POWELL ; Qi WANG
Chinese Medical Journal 2022;135(15):1781-1791
Brain metastasis (BM) is the leading cause of mortality in lung cancer patients. The process of BM (from initial primary tumor development, migration and intravasation, dissemination and survival in the bloodstream, extravasation, to colonization and growth to metastases) is a complex process for which few tumor cells complete the entire process. Recent research on BM of lung cancer has recently stressed the essential role of tumor microenvironment (TME) in assisting tumor cells in the completion of each BM step. This review summarizes recent studies regarding the effects of TME on tumor cells in the entire process of BM derived from lung cancer. The identification of vulnerable targets in the TME and their prospects to provide novel therapeutic opportunities are also discussed.
Brain Neoplasms/pathology*
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Humans
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Lung Neoplasms/drug therapy*
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Neoplasm Metastasis
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Tumor Microenvironment