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Published on: January 7, 2019
Nitric oxide suppression by secreted frizzled-related protein 2 drives retinoblastoma
Panneerselvam Jayabal1, Fuchun Zhou1, Xiuye Ma1
1Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA.
Abstract:
Retinoblastoma is a cancer of the infant retina primarily driven by loss of the Rb tumor suppressor gene, which is undruggable. Here, we report an autocrine signaling, mediated by secreted frizzled-related protein 2 (SFRP2), which suppresses nitric oxide and enables retinoblastoma growth. We show that coxsackievirus and adenovirus receptor (CXADR) is the cell-surface receptor for SFRP2 in retinoblastoma cells; that CXADR functions as a "dependence receptor," transmitting a growth-inhibitory signal in the absence of SFRP2; and that the balance between SFRP2 and CXADR determines nitric oxide production. Accordingly, high SFRP2 RNA expression correlates with high-risk histopathologic features in retinoblastoma. Targeting SFRP2 signaling by SFRP2-binding peptides or by a pharmacological inhibitor rapidly induces nitric oxide and profoundly inhibits retinoblastoma growth in orthotopic xenograft models. These results reveal a cytokine signaling pathway that regulates nitric oxide production and retinoblastoma cell proliferation and is amenable to therapeutic intervention.
Insights
Secreted frizzled-related protein 2 (SFRP2) enables retinoblastoma growth by suppressing nitric oxide. Targeting this SFRP2 pathway inhibits tumor growth, offering a new therapeutic strategy for this infant retinal cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Retinoblastoma, an infant retinal cancer, is driven by the loss of the Rb tumor suppressor gene, a target currently considered undruggable.
- Existing treatments face challenges, necessitating novel therapeutic targets and strategies for retinoblastoma.
Purpose of the Study:
- To elucidate the role of autocrine signaling in retinoblastoma proliferation.
- To identify novel therapeutic targets for retinoblastoma by investigating the SFRP2/CXADR pathway.
Main Methods:
- Investigated the interaction between secreted frizzled-related protein 2 (SFRP2) and its receptor, coxsackievirus and adenovirus receptor (CXADR), in retinoblastoma cells.
- Assessed the impact of SFRP2/CXADR signaling on nitric oxide production and retinoblastoma cell proliferation.
- Evaluated therapeutic efficacy of targeting SFRP2 signaling in orthotopic xenograft models.
Main Results:
- SFRP2 acts as an autocrine factor that suppresses nitric oxide, promoting retinoblastoma growth.
- CXADR functions as a dependence receptor, mediating SFRP2's effect and inhibiting growth in its absence.
- High SFRP2 RNA expression correlates with high-risk retinoblastoma features, and targeting SFRP2 signaling inhibits tumor growth in vivo.
Conclusions:
- A novel SFRP2-CXADR signaling pathway regulates nitric oxide production and retinoblastoma cell proliferation.
- This pathway represents a promising therapeutic target for retinoblastoma, offering a new avenue for intervention.
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