Modulating metastasis by a lymphangiogenic switch in prostate cancer

Authors

  • Ebba Brakenhielm,

    1. Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA
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    • The first two authors contributed equally to this work.

  • Jeremy B. Burton,

    1. Department of Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA
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    • The first two authors contributed equally to this work.

  • Mai Johnson,

    1. Department of Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA
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  • Nelson Chavarria,

    1. Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA
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  • Kouki Morizono,

    1. Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA
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  • Irvin Chen,

    1. Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA
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  • Kari Alitalo,

    1. Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Helsinki University Central Hospital, Helsinki, Finland
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  • Lily Wu

    Corresponding author
    1. Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA
    2. Department of Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA
    3. Crump Institute of Molecular Imaging, David Geffen School of Medicine at UCLA, Los Angeles, CA
    • Department of Urology, MRL 2210, Box 951738, University of California, Los Angeles, CA 90095-1738, USA
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    • Fax: +310-206-5343.


Abstract

Prostate cancer dissemination is difficult to detect in the clinic, and few treatment options exist for patients with advanced-stage disease. Our aim was to investigate the role of tumor lymphangiogenesis during metastasis. Further, we implemented a noninvasive molecular imaging technique to facilitate the assessment of the metastatic process. The metastatic potentials of several human prostate cancer xenograft models, LAPC-4, LAPC-9, PC3 and CWR22Rv-1 were compared. The cells were labeled with luciferase, a bioluminescence imaging reporter gene, to enable optical imaging. After tumor implantation the animals were examined weekly during several months for the appearance of metastases. Metastatic lesions were confirmed by immunohistochemistry. Additionally, the angiogenic and lymphangiogenic profiles of the tumors were characterized. To confirm the role of lymphangiogenesis in mediating metastasis, the low-metastatic LAPC-9 tumor cells were engineered to overexpress VEGF-C, and the development of metastases was evaluated. Our results show CWR22Rv-1 and PC3 tumor cell lines to be more metastatic than LAPC-4, which in turn disseminates more readily than LAPC-9. The difference in metastatic potential correlated with the endogenous production levels of lymphangiogenic growth factor VEGF-C and the presence of tumor lymphatics. In agreement, induced overexpression of VEGF-C in LAPC-9 enhanced tumor lymphangiogenesis leading to the development of metastatic lesions. Taken together, our studies, based on a molecular imaging approach for semiquantitative detection of micrometastases, point to an important role of tumor lymphatics in the metastatic process of human prostate cancer. In particular, VEGF-C seems to play a key role in prostate cancer metastasis. © 2007 Wiley-Liss, Inc.

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