Research for molecular mechanism and clinical application of calponin-gene therapy against Peritoneal dissemination of ovarian cancer

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Purpose : Calponin h1 (CNh1), 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 (α-SMA) in the surrounding stromal cells. The purpose of this study is to evaluate the efficacy of intraperitoneal 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 α-SMA 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 CIVh1. With respect to … More changes in cell behavior, the CNh1-transfected peritoneal cells acquired an ability to resist ovarian cancer-induced shrinkage in cell shape, and 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 intraperitoneally (i.p.) inoculated with ovarian cancer cells, we found that the i.p.injected CNh1-adenovirus successfully blocked cancer-induced morphological 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 bifuctionally effective, ie through inhibitory effects on the infected peritoneal cell layers which suppress cancer invasion and, second, through direct anti-tumor effects against invasion and growth properties of cancer cells. Less