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Journal of Cellular Biochemistry

Hypoxia preconditioning of mesenchymal stromal cells enhances PC3 cell lymphatic metastasis accompanied by VEGFR-3/CCR7 activation

Authors

  • Xin Huang,

    1. Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Science, 2nd Affiliated Hospital, Zhejiang University, Hangzhou, China
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  • Kunkai Su,

    1. Bioinformation Branch, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, 1st Affiliated Hospital, Zhejiang University, Hangzhou, China
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  • Limin Zhou,

    1. Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Zhejiang University, Hangzhou, China
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  • Guofang Shen,

    1. Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Zhejiang University, Hangzhou, China
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  • Qi Dong,

    1. Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Science, 2nd Affiliated Hospital, Zhejiang University, Hangzhou, China
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  • Yijia Lou,

    Corresponding author
    1. Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Zhejiang University, Hangzhou, China
    • Correspondence to: Shu Zheng, MD, PhD, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Science, 2nd Affiliated Hospital, Zhejiang University, Hangzhou 310009, China.

      E-mail: zhengshu@zju.edu.cn

      Correspondence to: Yijia Lou, PhD, Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Zhejiang University, Hangzhou 310058, China.

      E-mail: yijialou@zju.edu.cn

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  • Shu Zheng

    Corresponding author
    1. Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Science, 2nd Affiliated Hospital, Zhejiang University, Hangzhou, China
    • Correspondence to: Shu Zheng, MD, PhD, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Science, 2nd Affiliated Hospital, Zhejiang University, Hangzhou 310009, China.

      E-mail: zhengshu@zju.edu.cn

      Correspondence to: Yijia Lou, PhD, Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Zhejiang University, Hangzhou 310058, China.

      E-mail: yijialou@zju.edu.cn

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ABSTRACT

Mesenchymal stromal cells (MSCs) in bone marrow may enhance tumor metastases through the secretion of chemokines. MSCs have been reported to home toward the hypoxic tumor microenvironment in vivo. In this study, we investigated prostate cancer PC3 cell behavior under the influence of hypoxia preconditioned MSCs and explored the related mechanism of prostate cancer lymphatic metastases in mice. Transwell assays revealed that VEGF-C receptor, VEGFR-3, as well as chemokine CCL21 receptor, CC chemokine receptor 7 (CCR7), were responsible for the migration of PC3 cells toward hypoxia preconditioned MSCs. Knock-in Ccr7 in PC3 cells also improved cell migration in vitro. Furthermore, when PC3 cells were labeled using the hrGfp-lentiviral vector, and were combined with hypoxia preconditioned MSCs for xenografting, it resulted in an enhancement of lymph node metastases accompanied by up-regulation of VEGFR-3 and CCR7 in primary tumors. Both PI3K/Akt/IκBα and JAK2/STAT3 signaling pathways were activated in xenografts in the presence of hypoxia-preconditioned MSCs. Unexpectedly, the p-VEGFR-2/VEGFR-2 ratio was attenuated accompanied by decreased JAK1 expression, indicating a switching-off of potential vascular signal within xenografts in the presence of hypoxia-preconditioned MSCs. Unlike results from other studies, VEGF-C maintained a stable expression in both conditions, which indicated that hypoxia preconditioning of MSCs did not influence VEGF-C secretion. Our results provide the new insights into the functional molecular events and signalings influencing prostate tumor metastases, suggesting a hopeful diagnosis and treatment in new approaches. J. Cell. Biochem. 114: 2834–2841, 2013. © 2013 Wiley Periodicals, Inc.

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