Adenovirus-mediated Calponin h1 gene therapy directed against peritoneal dissemination of ovarian cancer:: Bifunctional therapeutic effects on peritoneal cell layer and cancer cells
Adenovirus-mediated Calponin h1 gene therapy directed against peritoneal dissemination of ovarian cancer:: Bifunctional therapeutic effects on peritoneal cell layer and cancer cells
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DOI：
10.1158/1078-0432.ccr-06-0674
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发表时间：
2006-09-01
影响因子：
11.5
通讯作者：
Nakano, Hitoo
中科院分区：
文献类型：
--
作者：
Ogura, Tomonori;Kobayashi, Hiroaki;Nakano, Hitoo
目的：钙调蛋白h1（Calponin h1，CN h1）是肌动蛋白结合蛋白家族的成员之一，它稳定肌动蛋白丝并调节多种细胞生物学表型。最近的研究揭示了肿瘤侵袭性扩散与周围基质细胞中CNh 1和α-平滑肌肌动蛋白表达减少之间的密切相关性。本研究的目的是评估腹膜内CNH 1基因治疗对腹膜播散卵巢cancer.Experimental Design的疗效：我们使用了腺病毒载体，以诱导CNH 1基因进入腹膜细胞和卵巢癌细胞作为一种手段，增强或诱导α-平滑肌肌动蛋白以及CNH 1的表达。通过体外细胞培养和体内动物实验检测了基因转染的效果。结果：在每个转染细胞系中观察到更长和更粗的肌动蛋白纤维的形成，并且这些纤维的定位与外部转导的CNh 1的定位相一致。关于细胞行为的变化，CNh 1转染的腹膜细胞获得了抵抗卵巢癌诱导的细胞形状收缩的能力;因此，癌细胞通过单层腹膜细胞的侵袭被抑制。此外，CNh 1转染的卵巢癌细胞表现出抑制锚定非依赖性生长和侵袭性，后者伴随着受损的细胞运动。伴随的CNh 1转染到腹膜细胞和卵巢癌细胞产生的附加抑制作用，相对于癌细胞通过腹膜细胞单层的侵袭。通过对腹腔接种卵巢癌细胞的裸鼠进行体内实验，我们发现腹腔注射CNh 1腺病毒成功地阻断了肿瘤诱导的腹膜细胞表面的形态学变化，并显著延长了荷瘤小鼠的生存时间。结论：CNh 1基因治疗卵巢癌腹膜转移是一种双功能有效的治疗方法，通过对抑制癌侵袭的感染的腹膜细胞层的抑制作用和通过对癌细胞的侵袭和生长特性的直接抗肿瘤作用）。
Purpose: Calponin h1 (CN h1), one of the family of actin-binding proteins, stabilizes the filaments of actin and modulates various cellular biological phenotypes. Recent studies revealed the close correlation between the invasive tumor spread and the reduced expression of CNh1 and alpha-smooth muscle actin in the surrounding stromal cells. The purpose of this study is to evaluate the efficacy of i.p. CNh1 gene therapy against peritoneal dissemination of ovarian cancer.Experimental Design: We used an adenoviral vector to induce the CNh1 gene into peritoneal cells and ovarian cancer cells as a means of enhancing or inducing the expression of alpha-smooth muscle actin as well as CNh1. The efficacy of gene transfer was examined by in vitro cell culture and in vivo animal experiments.Results: The formation of longer and thicker actin fibers was observed in each transfected cell line, and the localization of these fibers coincided with that of externally transducted CNh1. With respect to changes in cell behavior, the CNh1-transfected peritoneal cells acquired an ability to resist ovarian cancer-induced shrinkage in cell shape; thus, cancer cell invasion through the monolayer of peritoneal cells was inhibited. In addition, CNh1-transfected ovarian cancer cells showed suppressed anchorage-independent growth and invasiveness, the latter of which accompanied impaired cell motility. The concomitant CNh1 transfection into both peritoneal cells and ovarian cancer cells produced an additive inhibitory effect with respect to cancer cell invasion through the peritoneal cell monolayer. By in vivo experiments designed to treat nude mice that had been i.p. inoculated with ovarian cancer cells, we found that the i.p. injected CNh1 adenovirus successfully blocked cancer-induced morphologic changes in peritoneal cell surface and significantly prolonged the survival time of tumor-bearing mice. Moreover, CNh1 adenovirus could successfully enhance the therapeutic effect of an anticancer drug without increase in side effects.Conclusions: Thus, CNh1 gene therapy against peritoneal dissemination of ovarian cancer is bifunctionally effective (i.e., through inhibitory effects on the infected peritoneal cell layers that suppress cancer invasion and through direct antitumor effects against invasion and growth properties of cancer cells).