Research ArticleCancer

Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas

Sci. Signal.  08 Dec 2015:
Vol. 8, Issue 406, pp. ra125
DOI: 10.1126/scisignal.aaa1690

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Growing blood vessels in gliomas

Aggressive gliomas are particularly lethal, in part, because of increased density of blood vessels and abnormal vasculature that enables tumor growth and damages the brain. Various secreted factors, including VEGF and pleiotrophin, act on endothelial cells to promote blood vessel formation. By analyzing patient data, Zhang et al. correlated increased pleiotrophin abundance to more aggressive grades of glioma and decreased survival. When implanted in mice, glioma cells that released pleiotrophin formed larger tumors with more blood vessels and increased VEGF concentrations near the blood vessels. Mice had smaller gliomas and survived longer when treated with inhibitors of ALK, a receptor for pleiotrophin, or an inhibitor of the VEGF receptor. These results suggest that blocking the signals that promote the abnormal blood vessel growth may be beneficial to patients with aggressive gliomas.

Abstract

Glioblastomas are aggressive astrocytomas characterized by endothelial cell proliferation and abnormal vasculature, which can cause brain edema and increase patient morbidity. We identified the heparin-binding cytokine pleiotrophin as a driver of vascular abnormalization in glioma. Pleiotrophin abundance was greater in high-grade human astrocytomas and correlated with poor survival. Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels. Orthotopically implanted gliomas formed from GL261 cells that were engineered to produce pleiotrophin showed increased microvessel density and enhanced tumor growth compared with gliomas formed from control GL261 cells. The survival of mice with pleiotrophin-producing gliomas was shorter than that of mice with gliomas that did not produce pleiotrophin. Vessels in pleiotrophin-producing gliomas were poorly perfused and abnormal, a phenotype that was associated with increased deposition of vascular endothelial growth factor (VEGF) in direct proximity to the vasculature. The growth of pleiotrophin-producing GL261 gliomas was inhibited by treatment with the ALK inhibitor crizotinib, the ALK inhibitor ceritinib, or the VEGF receptor inhibitor cediranib, whereas control GL261 tumors did not respond to either inhibitor. Our findings link pleiotrophin abundance in gliomas with survival in humans and mice, and show that pleiotrophin promotes glioma progression through increased VEGF deposition and vascular abnormalization.

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