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An FGFR inhibitor converts the tumor promoting effect of TGF-β by the induction of fibroblast-associated genes of hepatoma cells

Oncogene volume 36, pages 3831–3841 (2017)Cite this article

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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.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81473441) and the Program for New Century Excellent Talents in University (NO.NCET-11-1068).

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Author notes

  1. H-R Zhang, X-D Wang and X Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China

    H-R Zhang, X Yang, J Hao, R Cao & X-Z Wu

  2. Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

    H-R Zhang, X Yang, J Hao, R Cao & X-Z Wu

  3. Tianjin's Clinical Research Center for Cancer, Tianjin, China

    H-R Zhang, X Yang, J Hao, R Cao & X-Z Wu

  4. Tianjin Medical University General Hospital, Tianjin, China

    X-D Wang

  5. Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China

    D Chen

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  1. H-R Zhang
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Correspondence to X-Z Wu.

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The authors declare that they have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in.

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Zhang, HR., Wang, XD., Yang, X. et al. An FGFR inhibitor converts the tumor promoting effect of TGF-β by the induction of fibroblast-associated genes of hepatoma cells. Oncogene 36, 3831–3841 (2017). https://doi.org/10.1038/onc.2016.512

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