title: Inhibition of lymphatic metastases by a survivin dominant-negative mutant.
abstract: 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.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Guang-Chao
authors.initials: GC
authors.lastname: Xu
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Fei
authors.initials: F
authors.lastname: Leng
authors.forename: Li
authors.initials: L
authors.lastname: Pan
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Li
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Yu
authors.forename: Yan
authors.initials: Y
authors.lastname: Shan
authors.forename: Qing-Zhong
authors.initials: QZ
authors.lastname: Yuan
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wen
authors.forename: Bo
authors.initials: B
authors.lastname: Mu
authors.forename: Hua-Shan
authors.initials: HS
authors.lastname: Shi
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.forename: Chun-Ting
authors.initials: CT
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis / Q000235:genetics*; D008081:Liposomes / Q000008:administration & dosage; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D042583:Lymphangiogenesis / Q000235:genetics; D008207:Lymphatic Metastasis; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D010957:Plasmids / Q000008:administration & dosage* / Q000235:genetics*; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D000077022:Survivin
chemical_list: C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008081:Liposomes; D012097:Repressor Proteins; D000077022:Survivin