A novel highly potent trivalent TGF-ß receptor trap inhibits earlystage tumorigenesis and tumor cell invasion in murine ptendeficient prostate glands

Tai Qin, Lindsey Barron, Lu Xia, Haojie Huang, Maria M. Villarreal, John Zwaagstra, Cathy Collins, Junhua Yang, Christian Zwieb, Ravindra Kodali, Cynthia S. Hinck, Sun Kyung Kim, Robert L. Reddick, Chang Shu, Maureen D. O'Connor-McCourt, Andrew P. Hinck, Lu Zhe Sun

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

The effects of transforming growth factor beta (TGF-ß) signaling on prostate tumorigenesis has been shown to be strongly dependent on the stage of development, with TGF-ß functioning as a tumor suppressor in early stages of disease and as a promoter in later stages. To study in further detail the paradoxical tumor-suppressive and tumor-promoting roles of the TGF-ß pathway, we investigated the effect of systemic treatment with a TGF-ß inhibitor on early stages of prostate tumorigenesis. To ensure effective inhibition, we developed and employed a novel trivalent TGF-ß receptor trap, RER, comprised of domains derived from the TGF-ß type II and type III receptors. This trap was shown to completely block TßRII binding, to antagonize TGF-ß1 and TGF-ß3 signaling in cultured epithelial cells at low picomolar concentrations, and it showed equal or better anti-TGF-ß activities than a pan TGF-ß neutralizing antibody and a TGF-ß receptor I kinase inhibitor in various prostate cancer cell lines. Systemic administration of RER inhibited prostate tumor cell proliferation as indicated by reduced Ki67 positive cells and invasion potential of tumor cells in high grade prostatic intraepithelial neoplasia (PIN) lesions in the prostate glands of Pten conditional null mice. These results provide evidence that TGF-ß acts as a promoter rather than a suppressor in the relatively early stages of this spontaneous prostate tumorigenesis model. Thus, inhibition of TGF-ß signaling in early stages of prostate cancer may be a novel therapeutic strategy to inhibit the progression as well as the metastatic potential in patients with prostate cancer.

Original languageEnglish (US)
Pages (from-to)86087-86102
Number of pages16
JournalOncotarget
Volume7
Issue number52
StatePublished - 2016

Keywords

  • Prostate cancer
  • Pten
  • RER
  • TGF-ß trap
  • Tumorigenesis

ASJC Scopus subject areas

  • Oncology

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