Targeting ECM-integrin interaction with liposome-encapsulated small interfering RNAs inhibits the growth of human prostate cancer in a bone xenograft imaging model
Targeting ECM-integrin interaction with liposome-encapsulated small interfering RNAs inhibits the growth of human prostate cancer in a bone xenograft imaging model
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DOI：
10.1016/j.ymthe.2005.05.012
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发表时间：
2005-10-01
影响因子：
12.4
通讯作者：
Hsieh, CL
中科院分区：
文献类型：
--
作者：
Bisanz, K;Yu, J;Hsieh, CL
间质细胞和上皮细胞之间错综复杂的细胞内通讯涉及细胞-细胞、细胞不溶性细胞外基质(ECM)和细胞可溶性因子介导的信号转导过程，是激素耐药和骨转移前列腺癌治疗干预的一个有吸引力的靶点。在本研究中，我们通过抗体功能阻断分析和流式细胞术分析，证明雄激素非依赖性PC3前列腺癌细胞通过细胞表面含有αv整合素受体αvβ1和αvβ5的表达，在成熟骨中主要的非胶原性细胞外基质--玻璃体连结蛋白(VN)上黏附和迁移。针对人整合素αv的小干扰RNA(SiRNAs)显著降低了它们各自在细胞中的mRNA和蛋白表达，导致VN介导的体外癌症进展几乎完全减少。人前列腺癌异种骨移植的体内生物荧光定量分析首次证实，脂质体包裹的人αv-siRNAs显著抑制了荧光素酶标记的PC3肿瘤在骨骼中的生长，这与整合素av的表达减少和肿瘤细胞的凋亡增加有关。这种以整合素为基础的基因治疗特别适用于前列腺癌骨转移的治疗。
The intricate intracellular communication between stromal and epithelia[ cells, which involves cell-cell-, cell-insoluble extracellular matrix- (ECM), and cell-soluble factor-mediated signaling processes, is an attractive target for therapeutic intervention in hormone-refractory and bone-metastatic prostate cancer. In the present study we demonstrated that androgen-independent PC3 prostate cancer cells adhered to and migrated on vitronectin (VN), a major noncollagenous ECM in mature bone, through the expression of alpha v-containing integrin receptors alpha v beta 1 and alpha v beta 5 on the cell surface, as determined by antibody function blocking assay and flow cytometry analysis. Small interfering RNAs (siRNAs) targeting human integrin alpha v markedly reduced their respective mRNA and protein expression in cells, resulting in nearly complete reduction in VN-mediated cancer progression in vitro. In vivo quantitative bioluminescence analysis of human prostate cancer bone xenografts demonstrated for the first time that intratumoral administration of liposome-encapsulated human alpha v-siRNAs significantly inhibits the growth of luciferase-tagged PC3 tumors in skeleton, which was associated with decreased integrin av expression and increased apoptosis in tumor cells. This integrin-based gene therapy is particularly suitable for the treatment of prostate cancer bone metastasis.