Tumor-specific expression of the RGD-α3(IV)NC1 domain suppresses endothelial tube formation and tumor growth in mice

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

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Abstract

Angiogenesis plays an essential role in tumor growth. This study investigated expression of the noncollagenous domain of α3(IV) collagen (α3(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 α3(IV)NC1 (hTERT/RGD-α3(IV)NC1) were expressed in telomerase-expressing tumor cells, it would inhibit tumor growth by its anti-angiogenic property. Adenoviral transduction of hTERT/RGD-α3(IV)NC1 expressed RGD-α3(IV)NC1 in hTERT-positive tumor cell lines. However, hTERT/RGD-α3(IV)NC1 did not express RGD-α3(IV)NC1 in hTERT-negative cells such as keratinocytes and fibroblasts. The secreted RGD-α3(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-α3(IV)NC1 gene therapy showed limited expression of RGD-α3(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- α3(IV)NC1. In addition, long-term inhibition of tumor growth was achieved by intermittent administration of hTERT/RGD-α3(IV)NC1. In conclusion, our findings demonstrate that tumor-specific antiangiogenic gene therapy utilizing RGD-α3(IV)NC1 under the hTERT promoter inhibited angiogenesis in tumors, resulting in an antitumor effect.

Original languageEnglish
JournalFASEB Journal
Volume20
Issue number11
DOIs
Publication statusPublished - Sep 2006

Fingerprint

telomerase
RNA-directed DNA polymerase
Tumors
neoplasms
mice
Growth
Neoplasms
gene therapy
Gene therapy
angiogenesis
Cells
Genetic Therapy
promoter regions
human TERT protein
keratinocytes
Telomerase
Conditioned Culture Medium
Endothelial cells
cultured cells
Tumor Cell Line

Keywords

  • Adenovirus
  • Angiogenesis
  • Basement membrane
  • Cancer dormancy
  • hTERT

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Tumor-specific expression of the RGD-α3(IV)NC1 domain suppresses endothelial tube formation and tumor growth in mice. / Miyoshi, Toru; Hirohata, Satoshi; Ogawa, Hiroko; Doi, Masayuki; Obika, Masanari; Yonezawa, Tomoko; Sado, Yoshikazu; Kusachi, Shozo; Kyo, Satoru; Kondo, Seiji; Shiratori, Yasushi; Hudson, Billy G.; Ninomiya, Yoshifumi.

In: FASEB Journal, Vol. 20, No. 11, 09.2006.

Research output: Contribution to journalArticle

Miyoshi, Toru ; Hirohata, Satoshi ; Ogawa, Hiroko ; Doi, Masayuki ; Obika, Masanari ; Yonezawa, Tomoko ; Sado, Yoshikazu ; Kusachi, Shozo ; Kyo, Satoru ; Kondo, Seiji ; Shiratori, Yasushi ; Hudson, Billy G. ; Ninomiya, Yoshifumi. / Tumor-specific expression of the RGD-α3(IV)NC1 domain suppresses endothelial tube formation and tumor growth in mice. In: FASEB Journal. 2006 ; Vol. 20, No. 11.
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abstract = "Angiogenesis plays an essential role in tumor growth. This study investigated expression of the noncollagenous domain of α3(IV) collagen (α3(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 α3(IV)NC1 (hTERT/RGD-α3(IV)NC1) were expressed in telomerase-expressing tumor cells, it would inhibit tumor growth by its anti-angiogenic property. Adenoviral transduction of hTERT/RGD-α3(IV)NC1 expressed RGD-α3(IV)NC1 in hTERT-positive tumor cell lines. However, hTERT/RGD-α3(IV)NC1 did not express RGD-α3(IV)NC1 in hTERT-negative cells such as keratinocytes and fibroblasts. The secreted RGD-α3(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-α3(IV)NC1 gene therapy showed limited expression of RGD-α3(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- α3(IV)NC1. In addition, long-term inhibition of tumor growth was achieved by intermittent administration of hTERT/RGD-α3(IV)NC1. In conclusion, our findings demonstrate that tumor-specific antiangiogenic gene therapy utilizing RGD-α3(IV)NC1 under the hTERT promoter inhibited angiogenesis in tumors, resulting in an antitumor effect.",
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AU - Obika, Masanari

AU - Yonezawa, Tomoko

AU - Sado, Yoshikazu

AU - Kusachi, Shozo

AU - Kyo, Satoru

AU - Kondo, Seiji

AU - Shiratori, Yasushi

AU - Hudson, Billy G.

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