LY2157299 monohydrate, a TGF-βR1 inhibitor, suppresses tumor growth and ascites development in ovarian cancer

Qing Zhang, Xiaonan Hou, Bradley J. Evans, Jamison L. VanBlaricom, Saravut (John) Weroha, William Arthur Cliby

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Transforming growth factor beta (TGF-β) signaling has pleiotropic functions regulating cancer initiation, development, and metastasis, and also plays important roles in the interaction between stromal and cancer cells, making the pathway a potential therapeutic target. LY2157299 monohydrate (LY), an inhibitor of TGF-β receptor I (TGFBRI), was examined for its ability to inhibit ovarian cancer (OC) growth both in high-grade serous ovarian cancer (HGSOC) cell lines and xenograft models. Immunohistochemistry, qRT-PCR, and Western blot were performed to study the effect of LY treatment on expression of cancer-and fibroblast-derived genes. Results showed that exposure to TGF-β1 induced phosphorylation of SMAD2 and SMAD3 in all tested OC cell lines, but this induction was suppressed by pretreatment with LY. LY alone inhibited the proliferation, migration, and invasion of HGSOC cells in vitro. TGF-β1-induced fibroblast activation was blocked by LY. LY also delayed tumor growth and suppressed ascites formation in vivo. In addition, independent of tumor inhibition, LY reduces ascites formation in vivo. Using OVCAR8 xenograft specimens we confirmed the inhibitory effect of LY on TGF-β signaling and tumor stromal expression of collagen type XI chain 1 (COL11A1) and versican (VCAN). These observations suggest a role for anti-TGF-β signaling-directed therapy in ovarian cancer.

Original languageEnglish (US)
Article number260
JournalCancers
Volume10
Issue number8
DOIs
StatePublished - Aug 1 2018

Fingerprint

LY-2157299
Growth and Development
Ascites
Transforming Growth Factor beta
Ovarian Neoplasms
Neoplasms
Heterografts
Collagen Type XI
Fibroblasts
Versicans
Cell Line
Stromal Cells
Growth
Therapeutics
Western Blotting
Immunohistochemistry
Phosphorylation
Neoplasm Metastasis

Keywords

  • Ascites
  • High-grade serous ovarian cancer
  • LY2157299 monohydrate
  • Patient-derived xenografts
  • Stroma
  • TGF-β signaling

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

LY2157299 monohydrate, a TGF-βR1 inhibitor, suppresses tumor growth and ascites development in ovarian cancer. / Zhang, Qing; Hou, Xiaonan; Evans, Bradley J.; VanBlaricom, Jamison L.; Weroha, Saravut (John); Cliby, William Arthur.

In: Cancers, Vol. 10, No. 8, 260, 01.08.2018.

Research output: Contribution to journalArticle

@article{d883c37957aa4dab90b6c447cfd12d9c,
title = "LY2157299 monohydrate, a TGF-βR1 inhibitor, suppresses tumor growth and ascites development in ovarian cancer",
abstract = "Transforming growth factor beta (TGF-β) signaling has pleiotropic functions regulating cancer initiation, development, and metastasis, and also plays important roles in the interaction between stromal and cancer cells, making the pathway a potential therapeutic target. LY2157299 monohydrate (LY), an inhibitor of TGF-β receptor I (TGFBRI), was examined for its ability to inhibit ovarian cancer (OC) growth both in high-grade serous ovarian cancer (HGSOC) cell lines and xenograft models. Immunohistochemistry, qRT-PCR, and Western blot were performed to study the effect of LY treatment on expression of cancer-and fibroblast-derived genes. Results showed that exposure to TGF-β1 induced phosphorylation of SMAD2 and SMAD3 in all tested OC cell lines, but this induction was suppressed by pretreatment with LY. LY alone inhibited the proliferation, migration, and invasion of HGSOC cells in vitro. TGF-β1-induced fibroblast activation was blocked by LY. LY also delayed tumor growth and suppressed ascites formation in vivo. In addition, independent of tumor inhibition, LY reduces ascites formation in vivo. Using OVCAR8 xenograft specimens we confirmed the inhibitory effect of LY on TGF-β signaling and tumor stromal expression of collagen type XI chain 1 (COL11A1) and versican (VCAN). These observations suggest a role for anti-TGF-β signaling-directed therapy in ovarian cancer.",
keywords = "Ascites, High-grade serous ovarian cancer, LY2157299 monohydrate, Patient-derived xenografts, Stroma, TGF-β signaling",
author = "Qing Zhang and Xiaonan Hou and Evans, {Bradley J.} and VanBlaricom, {Jamison L.} and Weroha, {Saravut (John)} and Cliby, {William Arthur}",
year = "2018",
month = "8",
day = "1",
doi = "10.3390/cancers10080260",
language = "English (US)",
volume = "10",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "8",

}

TY - JOUR

T1 - LY2157299 monohydrate, a TGF-βR1 inhibitor, suppresses tumor growth and ascites development in ovarian cancer

AU - Zhang, Qing

AU - Hou, Xiaonan

AU - Evans, Bradley J.

AU - VanBlaricom, Jamison L.

AU - Weroha, Saravut (John)

AU - Cliby, William Arthur

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Transforming growth factor beta (TGF-β) signaling has pleiotropic functions regulating cancer initiation, development, and metastasis, and also plays important roles in the interaction between stromal and cancer cells, making the pathway a potential therapeutic target. LY2157299 monohydrate (LY), an inhibitor of TGF-β receptor I (TGFBRI), was examined for its ability to inhibit ovarian cancer (OC) growth both in high-grade serous ovarian cancer (HGSOC) cell lines and xenograft models. Immunohistochemistry, qRT-PCR, and Western blot were performed to study the effect of LY treatment on expression of cancer-and fibroblast-derived genes. Results showed that exposure to TGF-β1 induced phosphorylation of SMAD2 and SMAD3 in all tested OC cell lines, but this induction was suppressed by pretreatment with LY. LY alone inhibited the proliferation, migration, and invasion of HGSOC cells in vitro. TGF-β1-induced fibroblast activation was blocked by LY. LY also delayed tumor growth and suppressed ascites formation in vivo. In addition, independent of tumor inhibition, LY reduces ascites formation in vivo. Using OVCAR8 xenograft specimens we confirmed the inhibitory effect of LY on TGF-β signaling and tumor stromal expression of collagen type XI chain 1 (COL11A1) and versican (VCAN). These observations suggest a role for anti-TGF-β signaling-directed therapy in ovarian cancer.

AB - Transforming growth factor beta (TGF-β) signaling has pleiotropic functions regulating cancer initiation, development, and metastasis, and also plays important roles in the interaction between stromal and cancer cells, making the pathway a potential therapeutic target. LY2157299 monohydrate (LY), an inhibitor of TGF-β receptor I (TGFBRI), was examined for its ability to inhibit ovarian cancer (OC) growth both in high-grade serous ovarian cancer (HGSOC) cell lines and xenograft models. Immunohistochemistry, qRT-PCR, and Western blot were performed to study the effect of LY treatment on expression of cancer-and fibroblast-derived genes. Results showed that exposure to TGF-β1 induced phosphorylation of SMAD2 and SMAD3 in all tested OC cell lines, but this induction was suppressed by pretreatment with LY. LY alone inhibited the proliferation, migration, and invasion of HGSOC cells in vitro. TGF-β1-induced fibroblast activation was blocked by LY. LY also delayed tumor growth and suppressed ascites formation in vivo. In addition, independent of tumor inhibition, LY reduces ascites formation in vivo. Using OVCAR8 xenograft specimens we confirmed the inhibitory effect of LY on TGF-β signaling and tumor stromal expression of collagen type XI chain 1 (COL11A1) and versican (VCAN). These observations suggest a role for anti-TGF-β signaling-directed therapy in ovarian cancer.

KW - Ascites

KW - High-grade serous ovarian cancer

KW - LY2157299 monohydrate

KW - Patient-derived xenografts

KW - Stroma

KW - TGF-β signaling

UR - http://www.scopus.com/inward/record.url?scp=85051392613&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85051392613&partnerID=8YFLogxK

U2 - 10.3390/cancers10080260

DO - 10.3390/cancers10080260

M3 - Article

VL - 10

JO - Cancers

JF - Cancers

SN - 2072-6694

IS - 8

M1 - 260

ER -