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

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 pa...

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Autores principales: Qin, Tai, Barron, Lindsey, Xia, Lu, Huang, Haojie, Villarreal, Maria M., Zwaagstra, John, Collins, Cathy, Yang, Junhua, Zwieb, Christian, Kodali, Ravindra, Hinck, Cynthia S., Kim, Sun Kyung, Reddick, Robert L., Shu, Chang, O’Connor-McCourt, Maureen D., Hinck, Andrew P., Sun, Lu-Zhe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349899/
https://www.ncbi.nlm.nih.gov/pubmed/27863384
http://dx.doi.org/10.18632/oncotarget.13343
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author Qin, Tai
Barron, Lindsey
Xia, Lu
Huang, Haojie
Villarreal, Maria M.
Zwaagstra, John
Collins, Cathy
Yang, Junhua
Zwieb, Christian
Kodali, Ravindra
Hinck, Cynthia S.
Kim, Sun Kyung
Reddick, Robert L.
Shu, Chang
O’Connor-McCourt, Maureen D.
Hinck, Andrew P.
Sun, Lu-Zhe
author_facet Qin, Tai
Barron, Lindsey
Xia, Lu
Huang, Haojie
Villarreal, Maria M.
Zwaagstra, John
Collins, Cathy
Yang, Junhua
Zwieb, Christian
Kodali, Ravindra
Hinck, Cynthia S.
Kim, Sun Kyung
Reddick, Robert L.
Shu, Chang
O’Connor-McCourt, Maureen D.
Hinck, Andrew P.
Sun, Lu-Zhe
author_sort Qin, Tai
collection PubMed
description 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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spelling pubmed-53498992017-04-06 A novel highly potent trivalent TGF-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands Qin, Tai Barron, Lindsey Xia, Lu Huang, Haojie Villarreal, Maria M. Zwaagstra, John Collins, Cathy Yang, Junhua Zwieb, Christian Kodali, Ravindra Hinck, Cynthia S. Kim, Sun Kyung Reddick, Robert L. Shu, Chang O’Connor-McCourt, Maureen D. Hinck, Andrew P. Sun, Lu-Zhe Oncotarget Research Paper 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. Impact Journals LLC 2016-11-14 /pmc/articles/PMC5349899/ /pubmed/27863384 http://dx.doi.org/10.18632/oncotarget.13343 Text en Copyright: © 2016 Qin et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Qin, Tai
Barron, Lindsey
Xia, Lu
Huang, Haojie
Villarreal, Maria M.
Zwaagstra, John
Collins, Cathy
Yang, Junhua
Zwieb, Christian
Kodali, Ravindra
Hinck, Cynthia S.
Kim, Sun Kyung
Reddick, Robert L.
Shu, Chang
O’Connor-McCourt, Maureen D.
Hinck, Andrew P.
Sun, Lu-Zhe
A novel highly potent trivalent TGF-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands
title A novel highly potent trivalent TGF-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands
title_full A novel highly potent trivalent TGF-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands
title_fullStr A novel highly potent trivalent TGF-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands
title_full_unstemmed A novel highly potent trivalent TGF-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands
title_short A novel highly potent trivalent TGF-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands
title_sort novel highly potent trivalent tgf-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine pten-deficient prostate glands
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349899/
https://www.ncbi.nlm.nih.gov/pubmed/27863384
http://dx.doi.org/10.18632/oncotarget.13343
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