1. An FGFR inhibitor converts the tumor promoting effect of TGF-β by the induction of fibroblast-associated genes of hepatoma cells
- Author
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Haiyang Zhang, Rui Cao, Wang Xd, Xue Yang, Xiong-Zhi Wu, Dan Chen, and Jihui Hao
- Subjects
Male ,Transcriptional Activation ,0301 basic medicine ,Cancer Research ,Carcinoma, Hepatocellular ,Gene Expression ,Mice, Nude ,Biology ,Fibroblast growth factor ,Piperazines ,Transforming Growth Factor beta1 ,03 medical and health sciences ,0302 clinical medicine ,Growth factor receptor ,Tumor Virus ,Tumor Microenvironment ,Genetics ,Animals ,Humans ,Growth factor receptor inhibitor ,Molecular Biology ,Cell Proliferation ,Mice, Inbred BALB C ,Tumor microenvironment ,Liver Neoplasms ,Hep G2 Cells ,Receptors, Fibroblast Growth Factor ,Molecular biology ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Fibroblast growth factor receptor ,Tumor progression ,030220 oncology & carcinogenesis ,Benzamides ,Cancer research ,Pyrazoles ,Tumor promotion ,Neoplasm Transplantation - Abstract
Tumors consistently mimic wound-generating chronic inflammation; however, why they do not heal like wounds with fibrotic scars remains unknown. The components of the tumor microenvironment, such as transforming growth factor β (TGF-β) and fibroblast growth factors (FGFs), may account for this phenomenon. Tumor formation involves continuous activation of the FGF pathway, whereas the repair of tissue injury is a self-limiting process accompanied with controlled activation of the FGF pathway. In the tumor microenvironment TGF-β increases the secretion of FGFs, further promoting the malignant biological properties of tumors. However, during wound healing, sufficient TGF-β together with moderate FGFs lead to matrix deposition and the formation of fibrotic scars. In the present study, TGF-β1 combined with AZD4547, an FGF receptor (FGFR) inhibitor, transformed hepatoma cells into less malignant fibroblast-like cells with respect to morphology, physiological properties, and gene expression profiles. In vivo experiments showed that TGF-β1 combined with AZD4547 not only inhibited tumor growth but also promoted tumor parenchyma fibrosis. Our results indicate that FGFR inhibitor treatment converts the effect of TGF-β on the hepatocellular carcinoma cells from tumor promotion into tumor inhibition by enhancing the induction effect of TGF-β on some fibroblast-associated genes. Converting human liver cancer cells into less malignant fibroblast-like cells and inducing tumor parenchyma cell fibrosis provides an alternative strategy for limiting tumor progression.
- Published
- 2017