Metastasis is the most lethal attribute of human
malignancy. High-level expression of
survivin is involved in both
carcinogenesis and angiogenesis in
cancer. Previous studies indicate that a mutation of the
threonine residue at position 34 (Thr34Ala) of
survivin generates a dominant-negative mutant that induces apoptosis, inhibits angiogenesis, and suppresses highly metastatic
breast carcinoma in mouse models. We investigated the efficacy of gene therapy with a
survivin dominant-negative mutant and possible factors related to
lymph node metastasis. The
metastasis rate was compared between each group in order to find a
survivin-targeted
therapy against lymphangiogenesis in its earliest stages. We established
lymph node metastasis models and treated animals with H22
tumors with Lip-mSurvivinT34A (Lip-mS), Lip-plasmid (Lip-P), or
normal saline (NS). Eight days after the last dose, five randomly chosen mice from each group were sacrificed. We detected the apoptotic index, microvessel density (MVD), lymphatic microvessel density (LMVD), and the expression of
VEGF-D with immunohistochemistry. After the remaining animals were sacrificed, we compared the
tumor-infiltrated lymph nodes in each group. Administration of mSurvivinT34A plasmid complexed with cationic
liposome (
DOTAP/chol) resulted in the efficacious inhibition of
tumor growth and
lymph node metastasis within the mouse H22
tumor model. These responses were associated with
tumor cell apoptosis, and angiogenesis and lymphangiogenesis inhibition. Our results suggested that Lip-mSurvivinT34A induced apoptosis and inhibited
tumor angiogenesis and lymphangiogenesis, thus suppressing
tumor growth and
lymphatic metastasis. The mSurvivinT34A
survivin mutant is a promising strategy of gene therapy to inhibit
lymphatic metastasis.