Adenovirus-mediated Calponin h1 gene therapy directed against peritoneal dissemination of ovarian cancer: Bifunctional therapeutic effects on peritoneal cell layer and cancer cells

Tomonori Ogura, Hiroaki Kobayashi, Yousuke Ueoka, Kaoru Okugawa, Kiyoko Kato, Toshio Hirakawa, Shigenari Hashimoto, Shun'ichiro Taniguchi, Norio Wake, Hitoo Nakano

研究成果: ジャーナルへの寄稿記事

12 引用 (Scopus)

抄録

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 α-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 α-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).

元の言語英語
ページ(範囲)5216-5223
ページ数8
ジャーナルClinical Cancer Research
12
発行部数17
DOI
出版物ステータス出版済み - 9 1 2006

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Therapeutic Uses
Adenoviridae
Genetic Therapy
Ovarian Neoplasms
Neoplasms
Actins
calponin
Smooth Muscle
Microfilament Proteins
Aptitude
Cell Shape
Stromal Cells
Growth
Actin Cytoskeleton
Nude Mice
Genes
Cell Movement
Transfection

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

これを引用

Adenovirus-mediated Calponin h1 gene therapy directed against peritoneal dissemination of ovarian cancer : Bifunctional therapeutic effects on peritoneal cell layer and cancer cells. / Ogura, Tomonori; Kobayashi, Hiroaki; Ueoka, Yousuke; Okugawa, Kaoru; Kato, Kiyoko; Hirakawa, Toshio; Hashimoto, Shigenari; Taniguchi, Shun'ichiro; Wake, Norio; Nakano, Hitoo.

:: Clinical Cancer Research, 巻 12, 番号 17, 01.09.2006, p. 5216-5223.

研究成果: ジャーナルへの寄稿記事

Ogura, Tomonori ; Kobayashi, Hiroaki ; Ueoka, Yousuke ; Okugawa, Kaoru ; Kato, Kiyoko ; Hirakawa, Toshio ; Hashimoto, Shigenari ; Taniguchi, Shun'ichiro ; Wake, Norio ; Nakano, Hitoo. / Adenovirus-mediated Calponin h1 gene therapy directed against peritoneal dissemination of ovarian cancer : Bifunctional therapeutic effects on peritoneal cell layer and cancer cells. :: Clinical Cancer Research. 2006 ; 巻 12, 番号 17. pp. 5216-5223.
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abstract = "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 α-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 α-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).",
author = "Tomonori Ogura and Hiroaki Kobayashi and Yousuke Ueoka and Kaoru Okugawa and Kiyoko Kato and Toshio Hirakawa and Shigenari Hashimoto and Shun'ichiro Taniguchi and Norio Wake and Hitoo Nakano",
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T1 - Adenovirus-mediated Calponin h1 gene therapy directed against peritoneal dissemination of ovarian cancer

T2 - Bifunctional therapeutic effects on peritoneal cell layer and cancer cells

AU - Ogura, Tomonori

AU - Kobayashi, Hiroaki

AU - Ueoka, Yousuke

AU - Okugawa, Kaoru

AU - Kato, Kiyoko

AU - Hirakawa, Toshio

AU - Hashimoto, Shigenari

AU - Taniguchi, Shun'ichiro

AU - Wake, Norio

AU - Nakano, Hitoo

PY - 2006/9/1

Y1 - 2006/9/1

N2 - 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 α-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 α-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).

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