Efficient inhibition of murine breast cancer growth and metastasis by gene transferred mouse survivin Thr34-->Ala mutant.
Efficient inhibition of murine breast cancer growth and metastasis by gene transferred mouse survivin Thr34-->Ala mutant.
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DOI：
10.1186/1756-9966-27-46
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发表时间：
2008-09-25
期刊：
影响因子：
--
通讯作者：
Wei YQ
中科院分区：
文献类型：
--
作者：
Peng XC;Yang L;Yang LP;Mao YQ;Yang HS;Liu JY;Zhang DM;Chen LJ;Wei YQ
乳腺癌的转移是治疗中的一个重要问题，因为大多数原发性乳腺癌在诊断时都有远处微转移。作为凋亡抑制蛋白（IAP）家族的一员，survivin已被提出作为新的抗癌干预的一个有吸引力的靶点。在这项研究中，我们研究了编码磷酸化缺陷小鼠survivin苏氨酸34→丙氨酸突变体（Msurvivin T34A质粒）的质粒在抑制小鼠原发性乳腺癌和肺转移中的作用。在体外实验中，采用PI染色荧光显微镜和流式细胞术检测Msurvivin T34A质粒与阳离子脂质体（DOTAP/Chol）复合物诱导细胞凋亡的作用。研究了Msurvivin T34A质粒与阳离子脂质体（DOTAP/Chol）复合物在携带4T1 s.c肿瘤的BALB/c雌性小鼠体内的抗肿瘤和抗转移活性。小鼠每周两次静脉注射Msurvivin T34A质粒与阳离子脂质体（DOTAP/Chol）、PORF-9空质粒与阳离子脂质体（DOTAP/Chol）、0.9% NaCl溶液，持续4周。观察肿瘤体积。处死后测量肿瘤净重，统计各组肺转移结节数。采用TUNEL法测定肿瘤组织中凋亡细胞的数量。采用CD31免疫组化方法测定肿瘤组织内微血管密度。通过藻酸盐包膜肿瘤细胞试验评价其对血管生成的影响。通过细胞毒性T淋巴细胞实验，检测Msurvivin T34A质粒与阳离子脂质体（DOTAP/Chol）复合物是否能诱导特异性细胞免疫应答。Msurvivin T34A质粒与阳离子脂质体（DOTAP/Chol）配合使用可显著抑制4T1肿瘤模型的生长和转移。这些抗肿瘤和抗转移反应与直接触发肿瘤细胞凋亡、抑制血管生成和诱导特异性细胞免疫反应有关。本研究结果表明，Msurvivin T34A质粒与阳离子脂质体复合物可能提供一种有效的方法来抑制高转移性小鼠乳腺癌模型的生长和转移，且副作用最小。
Metastasis in breast cancer is a vital concern in treatment because most women with primary breast cancer have micrometastases to distant sites at diagnosis. As a member of the inhibitor of apoptosis protein (IAP) family, survivin has been proposed as an attractive target for new anticancer interventions. In this study, we investigated the role of the plasmid encoding the phosphorylation-defective mouse survivin threonine 34→alanine mutant (Msurvivin T34A plasmid) in suppressing both murine primary breast carcinomas and pulmonary metastases. In vitro study, induction of apoptosis by Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol) was examined by PI staining fluorescence microscopy and flow cytometric analysis. The anti-tumor and anti-metastases activity of Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol) was evaluated in female BALB/c mice bearing 4T1 s.c. tumors. Mice were treated twice weekly with i.v. administration of Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol), PORF-9 null plasmid complexed with cationic liposome (DOTAP/Chol), 0.9% NaCl solution for 4 weeks. Tumor volume was observed. After sacrificed, tumor net weight was measured and Lung metastatic nodules of each group were counted. Assessment of apoptotic cells by TUNEL assay was conducted in tumor tissue. Microvessel density within tumor tissue was determined by CD31 immunohistochemistry. Alginate-encapsulated tumor cells test was conducted to evaluate the effect on angiogenesis. By experiment of cytotoxicity T lymphocytes, we test whether Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol) can induce specific cell immune response. Administration of Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol) resulted in significant inhibition in the growth and metastases of 4T1 tumor model. These anti-tumor and anti-metastases responses were associated with triggering the apoptosis of tumor cells directly, inhibiting angiogenesis and inducing specific cellular immune response. The present findings suggest that the Msurvivin T34A plasmid complexed with cationic liposome may provide an effective approach to inhibit the growth and metastases of a highly metastatic mouse breast cancer model with minimal side effects.
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影响因子：
64.8
作者：
Rosenberg, SA
通讯作者：
Rosenberg, SA
影响因子：
4.8
作者：
Ling, X;Bernacki, RJ;Li, FZ
通讯作者：
Li, FZ
影响因子：
5.7
作者：
Paduano, F;Villa, R;Zaffaroni, N
通讯作者：
Zaffaroni, N
影响因子：
20.3
作者：
Dixelius, J;Larsson, H;Claesson-Welsh, L
通讯作者：
Claesson-Welsh, L
影响因子：
12.4
作者：
Ito, I;Began, G;Ramesh, R
通讯作者：
Ramesh, R