Secreted Wnt Inhibitors in the Biology of Osteosarcoma

Summary

Principal Investigator: Bang H Hoang
Abstract: DESCRIPTION (provided by applicant): Applicant: Dr. Hoang, the candidate, is currently a tenure-track Assistant Professor at the University of California, Irvine. As evident from his biography, the candidate has demonstrated a steadfast commitment to a career in academic medicine. To this end, he would like to continue his research training in a mentored environment with the goal of becoming an independent investigator in musculoskeletal oncology. Environment: The candidate is jointly mentored by several nationally and internationally recognized experts in Wnt signaling in human cancer and the genetics of osteosarcoma. The University of California, Irvine is a collegial environment with a tradition of nurturing career development of young clinician scientists. Research: Osteosarcoma (OS) remains a pediatric bone cancer with substantial mortality due to a high metastatic rate. Although Wnt signaling is activated in several human malignancies, its role in the pathobiology of OS progression is largely unknown. Our preliminary work suggested that secreted Wnt inhibitors modulate the following pro-invasive pathways in OS: (1) Transcriptional repressors Slug and Twist, (2) MMP-2 and 9, and (3) the hepatocyte growth factor receptor Met. Blocking receptor-mediated Wnt signaling by a dominant negative receptor or by the secreted inhibitor Dkk-3 dramatically decreases the invasive potential and motility of OS cells. These findings lead us to propose the following specific aims: 1) To examine whether secreted Wnt inhibitors can decrease invasive capacity of OS cells by suppressing E-cadherin transcriptional repressors;2) To test the hypothesis that secreted Wnt inhibitors decrease OS invasiveness by suppressing MMP-2 and 9 or by regulating Met-dependent activity;3) To determine whether overexpression of Wnt inhibitors will reduce lung metastasis in vivo in a tail-vein injection nude mouse model. These studies will bridge a gap in our knowledge on the role of secreted Wnt inhibitors in the biology of OS. Lessons learned from this investigation may be applicable to a wider range of human sarcomas and serves as a basis for future studies by the applicant as an independent investigator in musculoskeletal oncology.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Wnt inhibitory factor 1 decreases tumorigenesis and metastasis in osteosarcoma
    Elyssa M Rubin
    Department of Oncology, Children s Hospital of Orange County, Orange, California, USA
    Mol Cancer Ther 9:731-41. 2010
  2. pmc WIF1, a Wnt pathway inhibitor, regulates SKP2 and c-myc expression leading to G1 arrest and growth inhibition of human invasive urinary bladder cancer cells
    Yaxiong Tang
    Department of Urology, University of California at Irvine, Irvine, CA 92868, USA
    Mol Cancer Ther 8:458-68. 2009

Detail Information

Publications2

  1. pmc Wnt inhibitory factor 1 decreases tumorigenesis and metastasis in osteosarcoma
    Elyssa M Rubin
    Department of Oncology, Children s Hospital of Orange County, Orange, California, USA
    Mol Cancer Ther 9:731-41. 2010
    ..Together, these data suggest that WIF-1 exerts potent antiosteosarcoma effect in vivo in mouse models. Therefore, the reexpression of WIF-1 in WIF-1-deficient osteosarcoma represents a potential novel treatment and preventive strategy...
  2. pmc WIF1, a Wnt pathway inhibitor, regulates SKP2 and c-myc expression leading to G1 arrest and growth inhibition of human invasive urinary bladder cancer cells
    Yaxiong Tang
    Department of Urology, University of California at Irvine, Irvine, CA 92868, USA
    Mol Cancer Ther 8:458-68. 2009
    ..These observations suggest a mechanism for transformation of bladder epithelium on loss of WIF1 function and provide new targets such as SKP2 for intervention in WIF1-deficient bladder cancer...