STROMAL GROWTH FACTORS IN BENIGN PROSTATIC HYPERPLASIA

Summary

Principal Investigator: David Rowley
Affiliation: Texas Medical Center
Country: USA
Abstract: Studies from the previous two project periods have characterized properties of ps20, a novel protein secreted by prostate smooth muscle. We have reported the cloning of full length cDNA (rat and human) and genomic DNA (mouse and human). The ps20 protein is a new member of the whey acidic protein (WAP) family. This family exhibits growth and differentiation functions. We have made antibody probes to ps20, localized ps20 expression to smooth muscle cells (SMC) in vivo, produced recombinant biologically active ps20, localized ps20 gene to human chromosome 16q24.3, and identified CD9 as a putative membrane interacting/signaling protein. Expression of ps20 was preferential to smooth muscle in vivo, including prostate gland and vascular smooth muscle. Recombinant ps20 induced phenotypic modulation of prostate smooth muscle cells to the migratory, synthetic phenotype in vitro, characteristic of hyperplastic SMC in vascular wall (atherosclerosis) diseases and in culture. In addition, ps20 blocked TGF-beta1 induced phenotypic modulation of SMCs to the contractile phenotype and maintained cells in the synthetic phenotype. Expression of ps20 was specifically regulated by TGF-beta1 in smooth muscle, suggesting an autocrine negative feedback loop. Immunoprecipitation-Western experiments suggests an interaction between ps20 and the CD9 membrane protein in SMCs. These studies suggest ps20 may be a fundamental mediator of smooth muscle phenotype. Benign prostatic hyperplasia (BPH) is a stromal-based disease typified by hyperplastic smooth muscle and ps20-positive SMCs. The present proposal will address the hypothesis that ps20 functions as a key autocrine regulator of synthetic SMC phenotype and that ps20 and the synthetic SMC phenotype play roles in the genesis of BPH. To extend our studies and address this hypothesis in detail we propose: l.) To define the ps20-induced smooth muscle phenotype and identify specific ps20-interacting proteins. 2.) To determine whether there is a correlation between expression of synthetic smooth muscle markers, a nodular BPH phenotype, and ps20 expression in human BPH specimens; 3.) To determine the in vivo function of ps20 by targeted gene knockout in mice, and; 4.) To determine the inductive function of ps20 in vivo by targeted overexpression using prostate tissue-tissue recombination mouse models.
Funding Period: 1992-09-30 - 2007-06-30
more information: NIH RePORT

Top Publications

  1. pmc FGFR1 is essential for prostate cancer progression and metastasis
    Feng Yang
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Cancer Res 73:3716-24. 2013
  2. ncbi Stromal expression of connective tissue growth factor promotes angiogenesis and prostate cancer tumorigenesis
    Feng Yang
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
    Cancer Res 65:8887-95. 2005
  3. ncbi Fibroblast growth factor-2 mediates transforming growth factor-beta action in prostate cancer reactive stroma
    F Yang
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Oncogene 27:450-9. 2008
  4. pmc WFDC1/ps20 is a novel innate immunomodulatory signature protein of human immunodeficiency virus (HIV)-permissive CD4+ CD45RO+ memory T cells that promotes infection by upregulating CD54 integrin expression and is elevated in HIV type 1 infection
    R Alvarez
    Department of Infectious Diseases, King s College London, 2nd Floor New Guy s House, Guy s Campus, London SE1 9NU, United Kingdom
    J Virol 82:471-86. 2008
  5. pmc Elevated epithelial expression of interleukin-8 correlates with myofibroblast reactive stroma in benign prostatic hyperplasia
    Isaiah G Schauer
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
    Urology 72:205-13. 2008
  6. pmc Keratinocyte-derived chemokine induces prostate epithelial hyperplasia and reactive stroma in a novel transgenic mouse model
    Isaiah G Schauer
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
    Prostate 69:373-84. 2009

Detail Information

Publications6

  1. pmc FGFR1 is essential for prostate cancer progression and metastasis
    Feng Yang
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Cancer Res 73:3716-24. 2013
    ..Together, these results suggest a critical and permissive role of ectopic FGFR1 signaling in prostate tumorigenesis and particularly in mechanisms of metastasis...
  2. ncbi Stromal expression of connective tissue growth factor promotes angiogenesis and prostate cancer tumorigenesis
    Feng Yang
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
    Cancer Res 65:8887-95. 2005
    ..These data suggest that CTGF is a downstream mediator of TGF-beta1 action in cancer-associated reactive stroma and is likely to be one of the key regulators of angiogenesis in the tumor-reactive stromal microenvironment...
  3. ncbi Fibroblast growth factor-2 mediates transforming growth factor-beta action in prostate cancer reactive stroma
    F Yang
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Oncogene 27:450-9. 2008
    ..In summary, these data show that TGF-beta signaling in reactive stroma is angiogenic and tumor promoting and that this effect is mediated in part through a TbetaRII/Smad3-dependent upregulation of FGF-2 expression and release...
  4. pmc WFDC1/ps20 is a novel innate immunomodulatory signature protein of human immunodeficiency virus (HIV)-permissive CD4+ CD45RO+ memory T cells that promotes infection by upregulating CD54 integrin expression and is elevated in HIV type 1 infection
    R Alvarez
    Department of Infectious Diseases, King s College London, 2nd Floor New Guy s House, Guy s Campus, London SE1 9NU, United Kingdom
    J Virol 82:471-86. 2008
    ..Disrupting the ps20 pathway may therefore provide a novel anti-HIV strategy...
  5. pmc Elevated epithelial expression of interleukin-8 correlates with myofibroblast reactive stroma in benign prostatic hyperplasia
    Isaiah G Schauer
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
    Urology 72:205-13. 2008
    ..Whether a reactive stroma response exists in BPH, whether this correlates with elevated IL-8, and whether IL-8 can induce a reactive stroma phenotype have not been determined. This study was designed to specifically address these issues...
  6. pmc Keratinocyte-derived chemokine induces prostate epithelial hyperplasia and reactive stroma in a novel transgenic mouse model
    Isaiah G Schauer
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
    Prostate 69:373-84. 2009
    ..Thus, we sought to determine whether overexpressed IL-8 and keratinocyte-derived chemokine (KC), the functional murine homolog of IL-8, induce prostate epithelial hyperplasia and a reactive phenotype...