title: Therapy with siRNA for Vegf-c but not for Vegf-d suppresses wide-spectrum organ metastasis in an immunocompetent xenograft model of metastatic mammary cancer.
abstract: Cancer metastasis contributes significantly to cancer mortality and is facilitated by lymphangiogenesis and angiogenesis. Vascular endothelial growth factors-C and D (VEGF-C and VEGF-D) are heavily involved in lymphangiogenesis. Using small interfering RNA (siRNA) against mouse Vegf-c, and Vegf-d, we sought to inhibit metastasis in a model of metastatic murine mammary cancer. BJMC3879Luc2 cell-induced mammary carcinomas received direct intratumoral injections in vivo of either plasmid VEGF-C/D siRNA (psiVEGF-C, psiVEGF-D) or a vector control followed by in vivo gene electrotransfer weekly for seven weeks. Treatment with psiVEGF-C and with psiVEGF-D resulted in lower tumor volumes as compared to the controls. Treatment with psiVEGF-C suppressed wide-spectrum organ metastasis involving lung and lymph nodes. Treatment with psiVEGF-C further reduced the number of dilated lymphatic vessels with invading cancer cells and inhibited tumor blood microvessel density. In contrast, although treatment with psiVEGF-D was not effective and gave equivocal results, it did induce some insignificant reduction in tumor volume increment, average numbers of lymph node metastases and average number of intratumoral dilated lymphatic vessels. In conclusion, specific silencing of the Vegf-c gene suppresses wide-spectrum organ metastasis, including the lung and lymph nodes. However, therapy with siRNA for Vegf-d was not adequately effective in this murine system.
authors.affiliation: Laboratory of Anatomy and Histopathology, Graduate School of Health Sciences, Osaka Health Science University, 1-9-27 Temma, Kita-ku, Osaka 530-0043, Japan. masaaki.shibata@ohsu.ac.jp.
authors.forename: Masa-Aki
authors.initials: MA
authors.lastname: Shibata
authors.forename: Eiko
authors.initials: E
authors.lastname: Shibata
authors.forename: Junji
authors.initials: J
authors.lastname: Morimoto
authors.forename: Mariko
authors.initials: M
authors.lastname: Harada-Shiba
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000556:secondary / Q000628:therapy*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D007121:Immunocompetence; D008175:Lung Neoplasms / Q000098:blood supply / Q000556:secondary / Q000628:therapy*; D008207:Lymphatic Metastasis; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D055806:Microvessels / Q000473:pathology; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000235:genetics*; D047368:Tumor Burden; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics* / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000235:genetics* / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; C467483:vascular endothelial growth factor C, mouse
keywords: VEGF-C; VEGF-D; mammary cancer; metastasis; siRNA