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Tumor-specific expression of the RGD-3(IV)NC1 domain suppresses endothelial tube formation and tumor growth in mice

Toru Miyoshi^*,1, Satoshi Hirohata^*,,1, Hiroko Ogawa^*,, Masayuki Doi^*, Masanari Obika^*,, Tomoko Yonezawa, Yoshikazu Sado, Shozo Kusachi, Satoru Kyo^||, Seiji Kondo^¶, Yasushi Shiratori^*, Billy G. Hudson and Yoshifumi Ninomiya^,2

^* Department of Medicine and Medical Science,

Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama;

Division of Immunology, Shigei Medical Research Institute, Okayama;

Department of Medical Technology, Faculty of Health Science, Okayama University Medical School, Okayama;

^|| Department of Obstetrics and Gynecology, Kanazawa University School of Medicine, Ishikawa, Japan;

^¶ Department of Neurosurgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA; and

Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

²Correspondence: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2–5-1, Shikata-cho, Okayama 700-8558 Japan. E-mail: yoshinin{at}cc.okayama-u.ac.jp

ABSTRACT

Angiogenesis plays an essential role in tumor growth. This study investigated expression of the noncollagenous domain of 3(IV) collagen (3(IV)NC1) transduced into tumors and its inhibition of tumor growth. We hypothesized that if a human telomerase reverse transcriptase (hTERT) promoter-driven RGD motif containing 3(IV)NC1 (hTERT/RGD-3(IV)NC1) were expressed in telomerase-expressing tumor cells, it would inhibit tumor growth by its anti-angiogenic property. Adenoviral transduction of hTERT/RGD-3(IV)NC1 expressed RGD-3(IV)NC1 in hTERT-positive tumor cell lines. However, hTERT/RGD-3(IV)NC1 did not express RGD-3(IV)NC1 in hTERT-negative cells such as keratinocytes and fibroblasts. The secreted RGD-3(IV)NC1 in the conditioned medium from tumor cells inhibited cell proliferation as well as tube formation in cultured endothelial cells, but had no effect on other types of cells. In an in vivo model, adenoviral hTERT/RGD-3(IV)NC1 gene therapy showed limited expression of RGD-3(IV)NC1 in tumors and resulted in a significant decrease of vessel density in tumors. The growth of subcutaneous (s.c.) tumors in nude mice was significantly suppressed by treatment with hTERT/RGD-3(IV)NC1. In addition, long-term inhibition of tumor growth was achieved by intermittent administration of hTERT/RGD-3(IV)NC1. In conclusion, our findings demonstrate that tumor-specific anti-angiogenic gene therapy utilizing RGD-3(IV)NC1 under the hTERT promoter inhibited angiogenesis in tumors, resulting in an antitumor effect.—Miyoshi, T., Hirohata, S., Ogawa, H., Doi, M., Obika, M., Yonezawa, T., Sado, Y., Kusachi, S., Kyo, S., Kondo, S., Shiratori, Y., Hudson, B. G., Ninomiya, Y. Tumor-specific expression of the RGD-3(IV)NC1 domain suppresses endothelial tube formation and tumor growth in mice.

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