Signal regulatory protein α is associated with tumor-polarized macrophages phenotype switch and plays a pivotal role in tumor progression

Authors

  • Yu-fei Pan,

    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, P.R. China
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    • Supported by grants from National Natural Science Foundation of China (81001075, 91229205), the Funds for Creative Research Groups of China (81221061), the State Key Project for Liver Cancer (2012ZX10002-009, 2013ZX10002-010) and the Key Project for Military (BWS11J036).

  • Ye-xiong Tan,

    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, P.R. China
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    • Supported by grants from National Natural Science Foundation of China (81001075, 91229205), the Funds for Creative Research Groups of China (81221061), the State Key Project for Liver Cancer (2012ZX10002-009, 2013ZX10002-010) and the Key Project for Military (BWS11J036).

  • Min Wang,

    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, P.R. China
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  • Jian Zhang,

    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, P.R. China
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  • Bo Zhang,

    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, P.R. China
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  • Chun Yang,

    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, P.R. China
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  • Zhi-wen Ding,

    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, P.R. China
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  • Li-wei Dong,

    Corresponding author
    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, P.R. China
    • Address reprint requests to: Hong-yang Wang, M.D., or Li-wei Dong, Ph.D., International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, 225 Changhai Road, 200438, Shanghai, China. E-mail: hywangk@vip.sina.com or donliwei@126.com; fax: +86 21 6556 6851.

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  • Hong-yang Wang

    Corresponding author
    1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, P.R. China
    2. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, P.R. China
    • Address reprint requests to: Hong-yang Wang, M.D., or Li-wei Dong, Ph.D., International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, 225 Changhai Road, 200438, Shanghai, China. E-mail: hywangk@vip.sina.com or donliwei@126.com; fax: +86 21 6556 6851.

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  • Potential conflict of interest: Nothing to report.

  • These authors contributed equally to this work.

Abstract

Macrophages (Mψ) are the major component of infiltrating leukocytes in tumors and exhibit distinct phenotypes according to the microenvironment. We have recently found that signal regulatory protein α (SIRPα), the inhibitory molecule expressed on myeloid cells, plays a critical role in controlling innate immune activation. Here, we identify that SIRPα is down-regulated on monocytes/Mψ isolated from peritumoral areas of hepatocellular carcinoma (HCC) samples, while its level is moderately recovered in intratumor Mψ. In vitro assays demonstrate that SIRPα expression is significantly reduced on Mψ when cocultured with hepatoma cells. This reduction is partly due to the soluble factors in the tumor microenvironment. Knockdown (KD) of SIRPα prolongs activation of nuclear factor kappa B (NF-κB) and PI3K-Akt pathways as Mψ encounter tumor cells, leading to an increased capacity of Mψ for migration, survival, and proinflammatory cytokine production. Enhanced Stat3 and impaired Stat1 phosphorylation are also observed in tumor-exposed SIRPα-KD Mψ. Adoptive transfer with SIRPα-KD Mψ accelerates mouse hepatoma cells growth in vivo by remolding the inflammatory microenvironment and promoting angiogenesis. SIRPα accomplishes this partly through its sequestration of the signal transducer Src homology 2-containing phosphotyrosine phosphatase (SHP2) from IκB kinase β (IKKβ) and PI3K regulatory subunit p85 (PI3Kp85). Conclusion: These findings suggest that SIRPα functions as an important modulator of tumor-polarized Mψ in hepatoma, and the reduction of SIRPα is a novel strategy used by tumor cells to benefit their behavior. Therefore, SIRPα could be utilized as a potential target for HCC therapy. (Hepatology 2013;58:680–691)

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