A novel highly potent trivalent TGF-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands
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Tai Qin1,2, Lindsey Barron1, Lu Xia1,3, Haojie Huang5, Maria M. Villarreal4, John Zwaagstra9, Cathy Collins9, Junhua Yang1, Christian Zwieb4, Ravindra Kodali8, Cynthia S. Hinck8, Sun Kyung Kim4, Robert L. Reddick6, Chang Shu2, Maureen D. O’Connor-McCourt9, Andrew P. Hinck8, Lu-Zhe Sun1,7
1Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX, USA
2Department of Vascular Surgery, Second Xiangya Hospital and Xiangya School of Medicine, Central South University, Hunan, China
3Department of Gynecology and Obstetrics, Xiangya Hospital and Xiangya School of Medicine, Central South University, Hunan, China
4Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, USA
5Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA
6Department of Pathology, University of Texas Health Science Center, San Antonio, TX, USA
7Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, Texas, USA
8Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
9National Research Council Human Health Therapeutics Portfolio, Montréal, Quebec, Canada, Maureen O'Connor-McCourt is currently affiliated with Formation Biologics, Montréal, Quebec, Canada
Lu-Zhe Sun, email: [email protected]
Andrew P. Hinck, email: [email protected]
Keywords: TGF-β trap, RER, tumorigenesis, Pten, prostate cancer
Received: August 15, 2016 Accepted: November 07, 2016 Published: November 14, 2016
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.
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