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Targeting Placental Growth Factor/Neuropilin 1 Pathway Inhibits Growth and Spread of Medulloblastoma

Author:
Snuderl, Matija, Batista, Ana, Kirkpatrick, Nathaniel D., Ruiz de Almodovar, Carmen, Riedemann, Lars, Walsh, Elisa C., Anolik, Rachel, Huang, Yuhui, Martin, John D., Kamoun, Walid, Knevels, Ellen, Schmidt, Thomas, Farrar, Christian T., Vakoc, Benjamin J., Mohan, Nishant, Chung, Euiheon, Roberge, Sylvie, Peterson, Teresa, Bais, Carlos, Zhelyazkova, Boryana H., Yip, Stephen, Hasselblatt, Martin, Rossig, Claudia, Niemeyer, Elisabeth, Ferrara, Napoleone, Klagsbrun, Michael, Duda, Dan G., Fukumura, Dai, Xu, Lei, Carmeliet, Peter, Jain, Rakesh K.
Source:
Cell 2013 v.152 pp. 1065-1076
ISSN:
0092-8674
Subject:
antineoplastic agents, brain, cell viability, metastasis, mice, morbidity, neoplasm cells, patients, toxicity, vascular endothelial growth factor receptors
Abstract:
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.
Agid:
926716