Combination therapy with short interfering RNA vectors against VEGF-C and VEGF-A suppresses lymph node and lung metastasis in a mouse immunocompetent mammary cancer model.
Cancer metastasis contributes significantly to cancer mortality and is facilitated by lymphangiogenesis and angiogenesis. Vascular endothelial growth factor-C (VEGF-C) and VEGF-A are involved in lymphangiogenesis and angiogenesis. To inhibit metastasis, combination therapy with vector-based small interfering RNA (siRNA) against VEGF-C and/or VEGF-A was conducted on murine metastatic mammary cancer. Syngeneic, inoculated, metastatic mammary cancers received direct intratumoral injection of plasmid siRNA vector targeting VEGF-C (psiRNA-VEGF-C), VEGF-A (psiRNA-VEGF-A), both VEGF-C and VEGF-A (both psiRNA-VEGF-C and psiRNA-VEGF-A vectors injected, referred to as the psiRNA-VEGF-C+A group) or a scrambled sequence (psiRNA-SCR) as control, once a week for 8 weeks. Gene electrotransfer was performed on the tumors after each injection. Tumor volume was significantly lower in the psiRNA-VEGF-A and the psiRNA-VEGF-C+A groups throughout the study. Lymph node metastasis was significantly less frequent in all therapeutic groups, whereas the multiplicity of lung metastases was significantly lower in the psiRNA-VEGF-C+A group only. All siRNA therapeutic groups showed a significant reduction in the number of dilated lymphatic vessels containing intraluminal cancer cells and microvessel density. Our data suggest that specific silencing of the VEGF-C or VEGF-A gene alone can inhibit lymph node metastasis. However, combination siRNA therapy targeting both VEGF-C and VEGF-A inhibits both lymph node and lung metastasis, rendering this combined therapy more beneficial than either alone. The observed anti-metastatic activity of siRNA-expressing vectors targeting VEGF-C or VEGF-A may be of high clinical significance in the treatment of metastatic breast cancer.
Shibata
M-A
MA
Division of Basic Medicine I, Department of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan. shibatam@art.osaka-med.ac.jp
Morimoto
J
J
Shibata
E
E
Otsuki
Y
Y
D000818:Animals; D001835:Body Weight; D003131:Combined Modality Therapy; D005260:Female; D005822:Genetic Vectors; D008175:Lung Neoplasms / Q000556:secondary*; D008198:Lymph Nodes / Q000378:metabolism; D008207:Lymphatic Metastasis; D008325:Mammary Neoplasms, Experimental / Q000473:pathology* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D055806:Microvessels / Q000378:metabolism; D009362:Neoplasm Metastasis; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000037:antagonists & inhibitors* / Q000378:metabolism
D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C