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Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Oncotarget 2016 ; 7 (52): 86087-102 Nephropedia Template TP
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A novel highly potent trivalent TGF-? receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands #MMPMID27863384
Qin T; Barron L; Xia L; Huang H; Villarreal MM; Zwaagstra J; Collins C; Yang J; Zwieb C; Kodali R; Hinck CS; Kim SK; Reddick RL; Shu C; O?Connor-McCourt MD; Hinck AP; Sun LZ
Oncotarget 2016[Dec]; 7 (52): 86087-102 PMID27863384show ga
The effects of transforming growth factor beta (TGF-?) signaling on prostate tumorigenesis has been shown to be strongly dependent on the stage of development, with TGF-? 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-? pathway, we investigated the effect of systemic treatment with a TGF-? inhibitor on early stages of prostate tumorigenesis. To ensure effective inhibition, we developed and employed a novel trivalent TGF-? receptor trap, RER, comprised of domains derived from the TGF-? type II and type III receptors. This trap was shown to completely block T?RII binding, to antagonize TGF-?1 and TGF-?3 signaling in cultured epithelial cells at low picomolar concentrations, and it showed equal or better anti-TGF-? activities than a pan TGF-? neutralizing antibody and a TGF-? 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-? acts as a promoter rather than a suppressor in the relatively early stages of this spontaneous prostate tumorigenesis model. Thus, inhibition of TGF-? 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.