PlGF signaling through NRP1 but not VEGFR1 promotes pediatric medulloblastoma cell survival.
Major finding: PlGF signaling through NRP1 but not VEGFR1 promotes pediatric medulloblastoma cell survival
Mechanism: Tumor-cell–derived SHH induces stromal PlGF expression, which activates MAPK signaling.
Impact: PlGF/NRP1 blockade may inhibit the growth and metastasis of multiple medulloblastoma subtypes.
Children with medulloblastoma, the most common malignant pediatric brain tumor, are generally treated with surgery followed by chemotherapy and radiation, a combination of treatments that increases survival rates but also induces significant toxicity and adverse effects on cognition. Therapies targeting key oncogenic drivers such as sonic hedgehog (SHH) have been unsuccessful, underscoring the importance of identifying alternative actionable pathways. Snuderl and colleagues found that expression of placental growth factor (PGF, also known as PlGF), a member of the VEGF family, was upregulated across all subtypes of pediatric medulloblastoma compared with normal cerebellar tissue, suggesting a role for PlGF in tumorigenesis. In support of this idea, treatment with anti-PlGF blocking antibodies induced tumor regression, reduced spinal cord metastasis, and prolonged survival in mice bearing distinct subtypes of medulloblastoma tumors. Elevated PlGF expression in tumor cells was required for initial tumor growth and also to stimulate production of PlGF by cerebellar stromal cells, which was mediated by paracrine signaling induced by tumor-cell–secreted SHH ligands and provided the main source of PlGF expression. PlGF promoted medulloblastoma cell survival primarily via activation of mitogen-activated protein kinase (MAPK) signaling without substantial effects on tumor angiogenesis or tumor-associated macrophages. In addition, the prosurvival effect of PlGF was dependent on signaling through the intracellular C-terminus of the receptor neuropilin 1 (NRP1); inhibition or downregulation of NRP1 but not VEGF receptor 1 (VEGFR1) diminished MAPK activation, delayed primary tumor growth and metastasis, and improved survival in mice, findings that are similar to the effects of anti-PlGF antibody treatment. Furthermore, NRP1 expression was increased in medulloblastoma samples and was correlated with poor survival in patients. These results indicate that targeted blockade of PlGF/NRP1 signaling may disrupt tumor–stroma interactions and provide therapeutic benefit in children with this disease.
Snuderl M, Batista A, Kirkpatrick ND, Ruiz de Almodovar C, Riedemann L, Walsh EC, et al. Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 2013;152:1065–76.
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