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Mammary cancer gene therapy targeting lymphangiogenesis: VEGF-C siRNA and soluble VEGF receptor-2, a splicing variant

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Abstract

Metastasis contributes significantly to cancer mortality, and the most common pathway of initial dissemination is via the afferent ducts of the lymphatics. Overexpression of vascular endothelial growth factor (VEGF)-C has been associated with lymphangiogenesis and lymph node metastasis in a multitude of human neoplasms, including breast cancers. We recently reported that both VEGF-C siRNA and endogenous soluble vascular endothelial growth factor receptor-2 (esVEGFR-2, a new splicing variant) inhibit VEGF-C function and metastasis in a mouse model of metastatic mammary cancer. Here we briefly review our previous experimental work, specifically targeting tumor lymphangiogenesis, in which metastatic mouse mammary cancers received direct intratumoral injections of either expression vectors VEGF-C siRNA or esVEGFR-2, or the empty plasmid vector, once a week for 6 or 8 weeks, followed by in vivo gene electrotransfer of the injected tumors. Throughout our study, both tumor lymphangiogenesis and the multiplicity of lymph node metastasis were significantly inhibited, with an overall reduction in tumor growth, by both VEGF-C siRNA and esVEGFR-2; further, a significant reduction in the number of dilated lymphatic vessels containing intraluminal cancer cells was observed with both treatments. Thus, therapeutic strategies targeting lymphangiogenesis may have great clinical significance for the treatment of metastatic human breast cancer.

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Authors and Affiliations

  1. Laboratory of Anatomy and Histopathology, Faculty of Health Science, Osaka Health Science University, 1-9-27 Temma, Kita-ku, Osaka, 530-0043, Japan

    Masa-Aki Shibata

  2. Department of Ophthalmology and Visual Science and Physiology, University of Kentucky, Lexington, KY, USA

    Jayakrishna Ambati

  3. Department of Molecular Innovation in Lipidology, National Cerebral & Cardiovascular Center Research Institute, Osaka, Japan

    Eiko Shibata & Mariko Harada-Shiba

  4. Department of Breast Cancer and Endocrine Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    Katsuhide Yoshidome

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  1. Masa-Aki Shibata
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  2. Jayakrishna Ambati
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  3. Eiko Shibata
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  4. Katsuhide Yoshidome
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  5. Mariko Harada-Shiba
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Correspondence to Masa-Aki Shibata.

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Shibata, MA., Ambati, J., Shibata, E. et al. Mammary cancer gene therapy targeting lymphangiogenesis: VEGF-C siRNA and soluble VEGF receptor-2, a splicing variant. Med Mol Morphol 45, 179–184 (2012). https://doi.org/10.1007/s00795-012-0576-5

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  • DOI: https://doi.org/10.1007/s00795-012-0576-5

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