title: The activated transforming growth factor-beta signaling pathway in peritoneal metastases is a potential therapeutic target in ovarian cancer.
abstract: 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.
authors.affiliation: Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Yamamura
authors.forename: Noriomi
authors.initials: N
authors.lastname: Matsumura
authors.forename: Masaki
authors.initials: M
authors.lastname: Mandai
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Huang
authors.forename: Tomonori
authors.initials: T
authors.lastname: Oura
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Baba
authors.forename: Junzo
authors.initials: J
authors.lastname: Hamanishi
authors.forename: Ken
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Kang
authors.forename: Takako
authors.initials: T
authors.lastname: Okamoto
authors.forename: Kaoru
authors.initials: K
authors.lastname: Abiko
authors.forename: Seiichi
authors.initials: S
authors.lastname: Mori
authors.forename: Susan K
authors.initials: SK
authors.lastname: Murphy
authors.forename: Ikuo
authors.initials: I
authors.lastname: Konishi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D009852:Omentum / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010534:Peritoneal Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051899:Smad2 Protein / Q000378:metabolism; D015996:Survival Rate; D013859:Thiocarbamates / Q000494:pharmacology; D013882:Thiosemicarbazones; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C507011:A-83-01; D014408:Biomarkers, Tumor; D011720:Pyrazoles; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D013859:Thiocarbamates; D013882:Thiosemicarbazones; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II