title: A novel highly potent trivalent TGF-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands.
abstract: 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.
authors.affiliation: 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.
authors.forename: Tai
authors.initials: T
authors.lastname: Qin
authors.affiliation: Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Barron
authors.affiliation: 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.
authors.forename: Lu
authors.initials: L
authors.lastname: Xia
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Villarreal
authors.affiliation: National Research Council Human Health Therapeutics Portfolio, Montréal, Quebec, Canada, Maureen O'Connor-McCourt is currently affiliated with Formation Biologics, Montréal, Quebec, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Zwaagstra
authors.affiliation: National Research Council Human Health Therapeutics Portfolio, Montréal, Quebec, Canada, Maureen O'Connor-McCourt is currently affiliated with Formation Biologics, Montréal, Quebec, Canada.
authors.forename: Cathy
authors.initials: C
authors.lastname: Collins
authors.affiliation: Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Junhua
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Zwieb
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kodali
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA.
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Hinck
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Sun Kyung
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Pathology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Reddick
authors.affiliation: Department of Vascular Surgery, Second Xiangya Hospital and Xiangya School of Medicine, Central South University, Hunan, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Shu
authors.affiliation: National Research Council Human Health Therapeutics Portfolio, Montréal, Quebec, Canada, Maureen O'Connor-McCourt is currently affiliated with Formation Biologics, Montréal, Quebec, Canada.
authors.forename: Maureen D
authors.initials: MD
authors.lastname: O'Connor-McCourt
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Hinck
authors.affiliation: 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.
authors.forename: Lu-Zhe
authors.initials: LZ
authors.lastname: Sun
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D010766:Phosphorylation; D011467:Prostate / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Pten; RER; TGF-β trap; prostate cancer; tumorigenesis