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[Cancer Research 65, 6901-6909, August 1, 2005]
© 2005 American Association for Cancer Research

Experimental Therapeutics, Molecular Targets, and Chemical Biology

Inhibition of Lymphogenous Metastasis Using Adeno-Associated Virus-Mediated Gene Transfer of a Soluble VEGFR-3 Decoy Receptor

JianMin Lin1, Alshad S. Lalani1, Thomas C. Harding1, Melissa Gonzalez1, Wei-Wei Wu1, Bo Luan1, Guang Huan Tu1, Kathryn Koprivnikar1, Melinda J. VanRoey1, Yulong He2, Kari Alitalo2 and Karin Jooss1

1 Department of Preclinical Oncology and Immunology, Cell Genesys, Inc., South San Francisco, California and 2 Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Haartman Institute, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

Requests for reprints: JianMin Lin, Department of Preclinical Oncology and Immunology, Cell Genesys, Inc., 500 Forbes Boulevard, South San Francisco, CA 94080. Phone: 650-266-2911; Fax: 650-266-3300; E-mail: jianmin.lin{at}cellgenesys.com.

The presence of metastases in regional lymph nodes is a strong indicator of poor patient survival in many types of cancer. It has recently been shown that the lymphangiogenic growth factor, vascular endothelial growth factor-C (VEGF-C), and its receptor, VEGF receptor-3 (VEGFR3), may play a pivotal role in the promotion of metastasis to regional lymph nodes. In this study, human prostate and melanoma tumor models that preferentially metastasize to the lymph nodes following s.c. tumor cell implantation were established from lymph node metastases via in vivo selection. Melanoma tumor cell sublines established from lymph node metastasis express higher amounts of VEGF-C than the parental tumor cells. The inhibition of tumor-derived VEGF-C with a soluble VEGFR3 decoy receptor, sVEGFR3-Fc, expressed via a recombinant adeno-associated viral vector, potently blocks tumor-associated lymphangiogenesis and tumor metastasis to the lymph nodes, when the treatment was initiated before the tumor implantation. In addition, sVEGFR3-Fc serum levels required for efficient blockade of lymph node metastases are strictly dependent on the VEGF-C levels generated by the primary tumor. Recombinant adeno-associated virus–mediated gene transfer of sVEGFR3-Fc may represent a feasible therapeutic strategy for blockade of lymphogenous metastasis.




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