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Project

Specific inhibition of Notch2 as a novel therapy for invasive bladder cancer

Funder: Canadian Institutes of Health Research

Funding period
CAD 1 K
USD 969
Funding amount
Abstract
Background: Notch signaling guides decisions regarding cell fate, establishment of cell lineages, stem cell maintenance and differentiation during early development. Notch is active in many adult malignancies where it has been shown to regulate tumor cell proliferation and progression to aggressive disease. We report outcomes of Notch2 knockdown or treatment in our bladder cancer cell models. Methods: UMUC3, UMUC13 and UMUC16 cells were transduced with Notch2 or non-targeting shRNA and were stably propogated. A Notch2-inactivating monoclonal antibody, NRR2Mab, was kindly provided by Genentech. Cells were grown under adherent (AH) or anchorage-independent conditions (AI) and the effects of Notch2 silencing or NRR2Mab inactivation were quantitatively assessed for changes in proliferation, migration and invasive activities using in vitro assays and, for expression of Notch2 or other common stem cell-related genes using quantitative RT-PCR, Western blotting and immunohistochemistry. In vivo effects were evaluated in an orthotopic bladder cancer xenograft model. Results: Cells transduced with the Notch2 shRNA or treated with NRR2Mab demonstrated markedly decreased Notch2 expression. Stable silencing of Notch2 or treatment with NRR2Mab in UMUC3 and 13 diminished cell proliferation under AI but not AH conditions. Likewise, when grown in AI conditions, UMUC3 and 13 were found to be enriched for expression of stem cell genes but Notch2 silencing or NRR2Mab diminished the expression of these genes. Coincidentally, Notch silencing and NRR2Mab treatment significantly inhibited cell migration and invasion of these cells. In vivo, stable Notch2 knockdown cells significantly inhibited xenograft growth for all 3 cell lines. NRR2Mab treatment of host mice also inhibited UMUC13 xenograft growth and metastasis. Conclusions: Our results provide preclinical evidence that Notch2 may be a useful target to block aggressive behaviors and to prevent growth and progression of bladder cancer.
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Specific Inhibition of NOTCH2 Signaling in Bladder Cancer

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USD 33,637
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System

Categories
  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Biotechnology

  • RCDC

    Stem Cell Research

  • RCDC

    Cancer

  • RCDC

    Genetics

  • RCDC

    Urologic Diseases

  • HRCS HC

    Cancer

  • HRCS RAC

    5.2 Cellular and gene therapies

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science