Targeting Placental Growth Factor/Neuropilin 1 Pathway Inhibits Growth and Spread of Medulloblastoma
Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes suggérant l'intérêt de développer des inhibiteurs du facteur de croissance placentaire pour le traitement des médulloblastomes
Medulloblastoma is the most common pediatric malignant brain tumor. Although current therapies improve survival, these regimens are highly toxic and are associated with significant morbidity. Here, we report that placental growth factor (PlGF) is expressed in the majority of medulloblastomas, independent of their subtype. Moreover, high expression of PlGF receptor neuropilin 1 (Nrp1) correlates with poor overall survival in patients. We demonstrate that PlGF and Nrp1 are required for the growth and spread of medulloblastoma: PlGF/Nrp1 blockade results in direct antitumor effects in vivo, resulting in medulloblastoma regression, decreased metastasis, and increased mouse survival. We reveal that PlGF is produced in the cerebellar stroma via tumor-derived Sonic hedgehog (Shh) and show that PlGF acts through Nrp1 and not vascular endothelial growth factor receptor 1 to promote tumor cell survival. This critical tumor-stroma interaction mediated by Shh, PlGF, and Nrp1 across medulloblastoma subtypes supports the development of therapies targeting PlGF/Nrp1 pathway. º PlGF is expressed in medulloblastomas, regardless of their genetic subtype º The majority of PlGF protein is secreted by cerebellar stromal cells º Stromal PlGF production is stimulated by paracrine Shh secretion from cancer cells º Targeting PlGF/Nrp1 pathway suppresses growth and spread of medulloblastoma Placental growth factor (PlGF) and its receptor neuropilin 1 are required for the growth of medulloblastoma, the most common malignant brain tumor in children. Experiments in mice suggest that inhibition of PlGF or neuropilin may be an effective therapeutic strategy for suppressing the growth of these tumors.