A novel highly potent trivalent TGF-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands.

Autor:	Qin T; Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX, USA.; Department of Vascular Surgery, Second Xiangya Hospital and Xiangya School of Medicine, Central South University, Hunan, China., Barron L; Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX, USA., Xia L; Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX, USA.; Department of Gynecology and Obstetrics, Xiangya Hospital and Xiangya School of Medicine, Central South University, Hunan, China., Huang H; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA., Villarreal MM; Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, USA., Zwaagstra J; National Research Council Human Health Therapeutics Portfolio, Montréal, Quebec, Canada, Maureen O'Connor-McCourt is currently affiliated with Formation Biologics, Montréal, Quebec, Canada., Collins C; National Research Council Human Health Therapeutics Portfolio, Montréal, Quebec, Canada, Maureen O'Connor-McCourt is currently affiliated with Formation Biologics, Montréal, Quebec, Canada., Yang J; Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX, USA., Zwieb C; Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, USA., Kodali R; Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA., Hinck CS; Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA., Kim SK; Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, USA., Reddick RL; Department of Pathology, University of Texas Health Science Center, San Antonio, TX, USA., Shu C; Department of Vascular Surgery, Second Xiangya Hospital and Xiangya School of Medicine, Central South University, Hunan, China., O'Connor-McCourt MD; National Research Council Human Health Therapeutics Portfolio, Montréal, Quebec, Canada, Maureen O'Connor-McCourt is currently affiliated with Formation Biologics, Montréal, Quebec, Canada., Hinck AP; Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA., Sun LZ; Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX, USA.; Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, Texas, USA.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2016 Dec 27; Vol. 7 (52), pp. 86087-86102.
DOI:	10.18632/oncotarget.13343
Abstrakt:	The effects of transforming growth factor beta (TGF-β) signaling on prostate tumorigenesis has been shown to be strongly dependent on the stage of development, with TGF-β 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-β pathway, we investigated the effect of systemic treatment with a TGF-β inhibitor on early stages of prostate tumorigenesis. To ensure effective inhibition, we developed and employed a novel trivalent TGF-β receptor trap, RER, comprised of domains derived from the TGF-β type II and type III receptors. This trap was shown to completely block TβRII binding, to antagonize TGF-β1 and TGF-β3 signaling in cultured epithelial cells at low picomolar concentrations, and it showed equal or better anti-TGF-β activities than a pan TGF-β neutralizing antibody and a TGF-β 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-β acts as a promoter rather than a suppressor in the relatively early stages of this spontaneous prostate tumorigenesis model. Thus, inhibition of TGF-β 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.
Databáze:	MEDLINE
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