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The activated transforming growth factor-beta signaling pathway in peritoneal metastases is a potential therapeutic target in ovarian cancer.

Publication ,  Journal Article
Yamamura, S; Matsumura, N; Mandai, M; Huang, Z; Oura, T; Baba, T; Hamanishi, J; Yamaguchi, K; Kang, HS; Okamoto, T; Abiko, K; Mori, S ...
Published in: Int J Cancer
January 1, 2012

Peritoneal dissemination including omental metastasis is the most frequent route of metastasis and an important prognostic factor in advanced ovarian cancer. We analyzed the publicly available microarray dataset (GSE2109) using binary regression and found that the transforming growth factor (TGF)-beta signaling pathway was activated in omental metastases as compared to primary sites of disease. Immunohistochemical analysis of TGF-beta receptor type 2 and phosphorylated SMAD2 indicated that both were upregulated in omental metastases as compared to primary disease sites. Treatment of the mouse ovarian cancer cell line HM-1 with recombinant TGF-β1 promoted invasiveness, cell motility and cell attachment while these were suppressed by treatment with A-83-01, an inhibitor of the TGF-β signaling pathway. Microarray analysis of HM-1 cells treated with TGF-β1 and/or A-83-01 revealed that A-83-01 efficiently inhibited transcriptional changes that are induced by TGF-β1. Using gene set enrichment analysis, we found that genes upregulated by TGF-β1 in HM-1 cells were also significantly upregulated in omental metastases compared to primary sites in the human ovarian cancer dataset, GSE2109 (false discovery rate (FDR) q = 0.086). Therapeutic effects of A-83-01 in a mouse model of peritoneal dissemination were examined. Intraperitoneal injection of A-83-01 (150 μg given three times weekly) significantly improved survival (p = 0.015). In summary, these results show that the activated TGF-β signaling pathway in peritoneal metastases is a potential therapeutic target in ovarian cancer.

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Published In

Int J Cancer

DOI

EISSN

1097-0215

Publication Date

January 1, 2012

Volume

130

Issue

1

Start / End Page

20 / 28

Location

United States

Related Subject Headings

  • Up-Regulation
  • Transforming Growth Factor beta
  • Thiosemicarbazones
  • Thiocarbamates
  • Survival Rate
  • Smad2 Protein
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptors, Transforming Growth Factor beta
  • Receptor, Transforming Growth Factor-beta Type II
  • RNA, Messenger
 

Citation

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Yamamura, S., Matsumura, N., Mandai, M., Huang, Z., Oura, T., Baba, T., … Konishi, I. (2012). The activated transforming growth factor-beta signaling pathway in peritoneal metastases is a potential therapeutic target in ovarian cancer. Int J Cancer, 130(1), 20–28. https://doi.org/10.1002/ijc.25961
Yamamura, Shogo, Noriomi Matsumura, Masaki Mandai, Zhiqing Huang, Tomonori Oura, Tsukasa Baba, Junzo Hamanishi, et al. “The activated transforming growth factor-beta signaling pathway in peritoneal metastases is a potential therapeutic target in ovarian cancer.Int J Cancer 130, no. 1 (January 1, 2012): 20–28. https://doi.org/10.1002/ijc.25961.
Yamamura S, Matsumura N, Mandai M, Huang Z, Oura T, Baba T, et al. The activated transforming growth factor-beta signaling pathway in peritoneal metastases is a potential therapeutic target in ovarian cancer. Int J Cancer. 2012 Jan 1;130(1):20–8.
Yamamura, Shogo, et al. “The activated transforming growth factor-beta signaling pathway in peritoneal metastases is a potential therapeutic target in ovarian cancer.Int J Cancer, vol. 130, no. 1, Jan. 2012, pp. 20–28. Pubmed, doi:10.1002/ijc.25961.
Yamamura S, Matsumura N, Mandai M, Huang Z, Oura T, Baba T, Hamanishi J, Yamaguchi K, Kang HS, Okamoto T, Abiko K, Mori S, Murphy SK, Konishi I. The activated transforming growth factor-beta signaling pathway in peritoneal metastases is a potential therapeutic target in ovarian cancer. Int J Cancer. 2012 Jan 1;130(1):20–28.
Journal cover image

Published In

Int J Cancer

DOI

EISSN

1097-0215

Publication Date

January 1, 2012

Volume

130

Issue

1

Start / End Page

20 / 28

Location

United States

Related Subject Headings

  • Up-Regulation
  • Transforming Growth Factor beta
  • Thiosemicarbazones
  • Thiocarbamates
  • Survival Rate
  • Smad2 Protein
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptors, Transforming Growth Factor beta
  • Receptor, Transforming Growth Factor-beta Type II
  • RNA, Messenger