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.