Diffuse-Type Gastric Carcinoma: Progression, Angiogenesis, and Transforming Growth Factor β Signaling

Akiyoshi Komuro, Masakazu Yashiro, Caname Iwata, Yasuyuki Morishita, Erik Johansson, Yoshiko Matsumoto, Akira Watanabe, Hiroyuki Aburatani, Hiroyuki Miyoshi, Kunihiko Kiyono, Yo Taro Shirai, Hiroshi I. Suzuki, Kosei Hirakawa, Mitsunobu Kano, Kohei Miyazono

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Background Diffuse-type gastric carcinoma is a cancer with poor prognosis that has high levels of transforming growth factor β (TGF-β) expression and thick stromal fibrosis. However, the association of TGF-β signaling with diffuse-type gastric carcinoma has not been investigated in detail. Methods We used a lentiviral infection system to express a dominant-negative TGF-β type II receptor (dnTβRII) or green fluorescent protein (GFP) as a control in the diffuse-type gastric carcinoma cell lines, OCUM-2MLN and OCUM-12. These infected cells and the corresponding parental control cells were subcutaneously or orthotopically injected into nude mice. Angiogenesis was inhibited by infecting cells with a lentivirus carrying the gene for angiogenic inhibitor thrombospondin-1 or by injecting mice intraperitoneally with the small-molecule angiogenic inhibitor sorafenib or with anti-vascular endothelial growth factor (VEGF) neutralizing antibody (six or eight mice per group). Expression of phospho-Smad2 and thrombospondin-1 was investigated immunologically in human gastric carcinoma tissues from 102 patients. All statistical tests were two-sided. Results Expression of dnTβRII into OCUM-2MLN cells did not affect their proliferation in vitro, but it accelerated the growth of subcutaneously or orthotopically transplanted tumors in vivo (eg, for mean volume of subcutaneous tumors on day 10 relative to that on day 0: dnTβRII tumors = 3.49 and GFP tumors = 2.46, difference = 1.02, 95% confidence interval [CI] = 0.21 to 1.84; P =. 003). The tumors expressing dnTβRII had higher levels of angiogenesis than those expressing GFP because of decreased thrombospondin-1 production. Similar results were obtained with OCUM-12 cells. Expression of thrombospondin-1 in the dnTβRII tumor or treatment with sorafenib or anti-VEGF antibody reduced tumor growth, whereas knockdown of thrombospondin-1 expression resulted in more accelerated growth of OCUM-2MLN tumors than of GFP tumors (eg, mean tumor volumes on day 14 relative to those on day 0: thrombospondin-1-knockdown tumors = 4.91 and GFP tumors = 3.79, difference = 1.12, 95% CI = 0.80 to 1.44; P

Original languageEnglish
Pages (from-to)592-604
Number of pages13
JournalJournal of the National Cancer Institute
Volume101
Issue number8
DOIs
Publication statusPublished - Apr 2009
Externally publishedYes

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Transforming Growth Factors
Stomach
Thrombospondin 1
Carcinoma
Green Fluorescent Proteins
Neoplasms
Angiogenesis Inhibitors
Tumor Burden
Vascular Endothelial Growth Factor A
Growth
Confidence Intervals
Neoplasm Antibodies
Lentivirus
Growth Factor Receptors
Neutralizing Antibodies
Nude Mice
Fibrosis
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Komuro, A., Yashiro, M., Iwata, C., Morishita, Y., Johansson, E., Matsumoto, Y., ... Miyazono, K. (2009). Diffuse-Type Gastric Carcinoma: Progression, Angiogenesis, and Transforming Growth Factor β Signaling. Journal of the National Cancer Institute, 101(8), 592-604. https://doi.org/10.1093/jnci/djp058

Diffuse-Type Gastric Carcinoma : Progression, Angiogenesis, and Transforming Growth Factor β Signaling. / Komuro, Akiyoshi; Yashiro, Masakazu; Iwata, Caname; Morishita, Yasuyuki; Johansson, Erik; Matsumoto, Yoshiko; Watanabe, Akira; Aburatani, Hiroyuki; Miyoshi, Hiroyuki; Kiyono, Kunihiko; Shirai, Yo Taro; Suzuki, Hiroshi I.; Hirakawa, Kosei; Kano, Mitsunobu; Miyazono, Kohei.

In: Journal of the National Cancer Institute, Vol. 101, No. 8, 04.2009, p. 592-604.

Research output: Contribution to journalArticle

Komuro, A, Yashiro, M, Iwata, C, Morishita, Y, Johansson, E, Matsumoto, Y, Watanabe, A, Aburatani, H, Miyoshi, H, Kiyono, K, Shirai, YT, Suzuki, HI, Hirakawa, K, Kano, M & Miyazono, K 2009, 'Diffuse-Type Gastric Carcinoma: Progression, Angiogenesis, and Transforming Growth Factor β Signaling', Journal of the National Cancer Institute, vol. 101, no. 8, pp. 592-604. https://doi.org/10.1093/jnci/djp058
Komuro, Akiyoshi ; Yashiro, Masakazu ; Iwata, Caname ; Morishita, Yasuyuki ; Johansson, Erik ; Matsumoto, Yoshiko ; Watanabe, Akira ; Aburatani, Hiroyuki ; Miyoshi, Hiroyuki ; Kiyono, Kunihiko ; Shirai, Yo Taro ; Suzuki, Hiroshi I. ; Hirakawa, Kosei ; Kano, Mitsunobu ; Miyazono, Kohei. / Diffuse-Type Gastric Carcinoma : Progression, Angiogenesis, and Transforming Growth Factor β Signaling. In: Journal of the National Cancer Institute. 2009 ; Vol. 101, No. 8. pp. 592-604.
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AU - Yashiro, Masakazu

AU - Iwata, Caname

AU - Morishita, Yasuyuki

AU - Johansson, Erik

AU - Matsumoto, Yoshiko

AU - Watanabe, Akira

AU - Aburatani, Hiroyuki

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AU - Kiyono, Kunihiko

AU - Shirai, Yo Taro

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AU - Hirakawa, Kosei

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N2 - Background Diffuse-type gastric carcinoma is a cancer with poor prognosis that has high levels of transforming growth factor β (TGF-β) expression and thick stromal fibrosis. However, the association of TGF-β signaling with diffuse-type gastric carcinoma has not been investigated in detail. Methods We used a lentiviral infection system to express a dominant-negative TGF-β type II receptor (dnTβRII) or green fluorescent protein (GFP) as a control in the diffuse-type gastric carcinoma cell lines, OCUM-2MLN and OCUM-12. These infected cells and the corresponding parental control cells were subcutaneously or orthotopically injected into nude mice. Angiogenesis was inhibited by infecting cells with a lentivirus carrying the gene for angiogenic inhibitor thrombospondin-1 or by injecting mice intraperitoneally with the small-molecule angiogenic inhibitor sorafenib or with anti-vascular endothelial growth factor (VEGF) neutralizing antibody (six or eight mice per group). Expression of phospho-Smad2 and thrombospondin-1 was investigated immunologically in human gastric carcinoma tissues from 102 patients. All statistical tests were two-sided. Results Expression of dnTβRII into OCUM-2MLN cells did not affect their proliferation in vitro, but it accelerated the growth of subcutaneously or orthotopically transplanted tumors in vivo (eg, for mean volume of subcutaneous tumors on day 10 relative to that on day 0: dnTβRII tumors = 3.49 and GFP tumors = 2.46, difference = 1.02, 95% confidence interval [CI] = 0.21 to 1.84; P =. 003). The tumors expressing dnTβRII had higher levels of angiogenesis than those expressing GFP because of decreased thrombospondin-1 production. Similar results were obtained with OCUM-12 cells. Expression of thrombospondin-1 in the dnTβRII tumor or treatment with sorafenib or anti-VEGF antibody reduced tumor growth, whereas knockdown of thrombospondin-1 expression resulted in more accelerated growth of OCUM-2MLN tumors than of GFP tumors (eg, mean tumor volumes on day 14 relative to those on day 0: thrombospondin-1-knockdown tumors = 4.91 and GFP tumors = 3.79, difference = 1.12, 95% CI = 0.80 to 1.44; P

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