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Hyperactivated FRS2α-mediated signaling in prostate cancer cells promotes tumor angiogenesis and predicts poor clinical outcome of patients

Oncogene volume 35, pages 1750–1759 (2016)Cite this article

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Abstract

Metastasis of tumors requires angiogenesis, which is comprised of multiple biological processes that are regulated by angiogenic factors. The fibroblast growth factor (FGF) is a potent angiogenic factor and aberrant FGF signaling is a common property of tumors. Yet, how the aberration in cancer cells contributes to angiogenesis in the tumor is not well understood. Most studies of its angiogenic signaling mechanisms have been in endothelial cells. FGF receptor substrate 2α (FRS2α) is an FGF receptor-associated protein required for activation of downstream signaling molecules that include those in the mitogen-activated protein and AKT kinase pathways. Herein, we demonstrated that overactivation and hyperactivity of FRS2α, as well as overexpression of cJUN and HIF1α, were positively correlated with vessel density and progression of human prostate cancer (PCa) toward malignancy. We also demonstrate that FGF upregulated the production of vascular endothelial growth factor A mainly by increasing expression of cJUN and HIF1α. This then promoted recruitment of endothelial cells and vessel formation for the tumor. Tumor angiogenesis in mouse PCa tissues was compromised by tissue-specific ablation of Frs2α in prostate epithelial cells. Depletion of Frs2α expression in human PCa cells and in a preclinical xenograft model, MDA PCa 118b, also significantly suppressed tumor angiogenesis accompanied with decreased tumor growth in the bone. The results underscore the angiogenic role of FRS2α-mediated signaling in tumor epithelial cells in angiogenesis. They provide a rationale for treating PCa with inhibitors of FGF signaling. They also demonstrate the potential of overexpressed FRS2α as a biomarker for PCa diagnosis, prognosis and response to therapies.

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Acknowledgements

We thank Dr Stefan Siwko and Samantha Del Castillo for critical reading of the manuscript. This work was supported in part by the National Institutes of Health CA96824 and DE023106 to FW, CA140388 to NN, WLM and FW, and The Cancer Prevention and Research Institution of Texas CPRIT110555 to FW and WLM, and the National Natural Science Foundation of China 81170699, 81272813 to CW, 81101712, 81270761 to XL, 510180 to WZ and 81072016 to ZYZ.

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Author notes

  1. J Liu, P You and G Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and College of Medicine, Texas A&M Health Science Center, Houston, TX, USA

    J Liu, P You, G Chen, X Fu, X Zeng, C Wang, Y Huang, L An, W L McKeehan & F Wang

  2. Xiamen University Affiliated Zhongshan Hospital, Xiamen, China

    P You & Z Zhang

  3. Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China

    G Chen, X Fu & W Zhong

  4. Institute for Tissue Transplantation and Immunology, Jinan University, Guangzhou, China

    X Zeng

  5. College of Pharmacy, Wenzhou Medical University, Wenzhou, China

    C Wang

  6. The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    X Wan & N Navone

  7. Departments of Pathology and Urology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    C-L Wu

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  1. J Liu
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Correspondence to Z Zhang, W Zhong or F Wang.

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Liu, J., You, P., Chen, G. et al. Hyperactivated FRS2α-mediated signaling in prostate cancer cells promotes tumor angiogenesis and predicts poor clinical outcome of patients. Oncogene 35, 1750–1759 (2016). https://doi.org/10.1038/onc.2015.239

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