Glioblastoma multiforme (GBM) is a highly proliferative and locally invasive cancer with poor prognosis and a high recurrence rate. Although anti-VEGF (vascular endothelial growth factor) therapy offers short-term benefit to GBM patients, this approach fails as the tumor develops into a more invasive and drug-resistant phenotype and ultimately recurs. Recently, both glioma stemlike cells (GSCs) and brain tumor–initiating cells (BTICs) have been implicated in GBM recurrence and its resistance to therapy. We observed that patient-derived GBM cells expressing shRNAs of VEGF or neuropilin-1 (NRP-1) attenuate cancer stem cell markers, inhibit the tumor-initiating cell’s neurosphere-forming capacity, and migration. Furthermore, both VEGF and NRP-1 knockdown inhibit the growth of patient-derived GBM xenografts in both zebrafish and mouse models. Interestingly, NRP-1–depleted patient-derived GBM xenografts substantially prolonged survival in mice compared to that of VEGF depletion. Our results also demonstrate that NRP-1 ablation of patient-derived GBM cells improves the sensitivity of TMZ and enhances the overall survival of the respective tumor-bearing mice. This improved outcome may provide insight into the inhibition of GBM progression and effective treatment strategies by targeting NRP-1 in addition to chemotherapy and radiotherapy.
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NRP1 inhibition modulates radiosensitivity of medulloblastoma by targeting cancer stem cells
Cancer Cell International Open Access 01 December 2022
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The authors thank Dr Leonard Zon, Children’s Hospital, Boston, Massachusetts, for providing the Casper zebrafish strain, and Dr Ying Wang, Mayo Clinic, Jacksonville, for assistance with lentiviral preparation. The work was supported by the NIH Grant to DM R01CA 78383, RO1HL140411, R01CA150190, Florida Department of Health Cancer Research Chair Fund Florida #3 J. AQH was supported by the Mayo Clinic Professorship and a Clinician Investigator award, the Florida Department of Health Cancer Research Chair Fund, and the NIH (R43CA221490, R01CA200399, R01CA195503, and R01CA216855).
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Angom, R.S., Mondal, S.K., Wang, F. et al. Ablation of neuropilin-1 improves the therapeutic response in conventional drug-resistant glioblastoma multiforme. Oncogene 39, 7114–7126 (2020). https://doi.org/10.1038/s41388-020-01462-1
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