title: Mammary cancer gene therapy targeting lymphangiogenesis: VEGF-C siRNA and soluble VEGF receptor-2, a splicing variant.
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.
authors.affiliation: Laboratory of Anatomy and Histopathology, Faculty of Health Science, Osaka Health Science University, 1-9-27 Temma, Osaka 530-0043, Japan. masaaki.shibata@ohsu.ac.jp
authors.forename: Masa-Aki
authors.initials: MA
authors.lastname: Shibata
authors.forename: Jayakrishna
authors.initials: J
authors.lastname: Ambati
authors.forename: Eiko
authors.initials: E
authors.lastname: Shibata
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Yoshidome
authors.forename: Mariko
authors.initials: M
authors.lastname: Harada-Shiba
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D018390:Gene Targeting / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D042583:Lymphangiogenesis / Q000235:genetics*; D008207:Lymphatic Metastasis / Q000235:genetics*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000628:therapy; D051379:Mice; D012326:RNA Splicing; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology*; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
chemical_list: D034741:RNA, Small Interfering; D042582:Vascular Endothelial Growth Factor C; D040301:Vascular Endothelial Growth Factor Receptor-2