Il-Kug Kim,1,* Kangsan Kim,1,* Eunhyeong Lee,2 Dong Sun Oh,2 Chan Soon Park,1 Seongyeol Park,1 Jee Myung Yang,1 Ju-Hee Kim,1 Hyung-Seok Kim,3 David T. Shima,4 Jeong Hoon Kim,5 Seok Ho Hong,5 Young Hyun Cho,5 Young Hoon Kim,5 Jong Bae Park,6 Gou Young Koh,1,2,7 Young Seok Ju,1,2 Heung Kyu Lee,1,2 Seungjoo Lee,5 and Injune Kim1,2 10.1084/jem.20170123
Abstract
High-grade glioma (HGG) is highly angiogenic, but antiangiogenic therapy has transient clinical benefit in only a fraction of patients. Vascular regulators of these heterogeneous responses remain undetermined. We found up-regulation of Sox7 and down-regulation of Sox17 in tumor endothelial cells (tECs) in mouse HGG. Sox7 deletion suppressed VEGFR2 expression, vascular abnormality, hypoxia-driven invasion, regulatory T cell infiltration, and tumor growth. Conversely, Sox17 deletion exacerbated these phenotypes by up-regulating Sox7 in tECs. Anti-VEGFR2 antibody treatment delayed tumor growth by normalizing Sox17-deficient abnormal vessels with high Sox7 levels but promoted it by regressing Sox7-deficient vessels, recapitulating variable therapeutic responses to antiangiogenic therapy in HGG patients. Our findings establish that Sox7 promotes tumor growth via vessel abnormalization, and its level determines the therapeutic outcome of VEGFR2 inhibition in HGG. In 189 HGG patients, Sox7 expression was heterogeneous in tumor vessels, and high Sox7 levels correlated with poor survival, early recurrence, and impaired vascular function, emphasizing the clinical relevance of Sox7 in HGG.
Figure 8.
Vascular and tumor responses to VEGFR2 inhibition are variable according to Sox7 levels in HGG vessels. Control (Ctrl), Sox7i△EC (S7KO), and Sox17i△EC (S17KO) mice bearing HGG were administered with control (IgG) or α-VEGFR2 (DC101) Ab. (A) GL261-GFP HGGs. (B–F) CD31-positive HGG vessels. (B) Vascular network. (C) Col4-positive basement membrane (BM). (D) Ter119-positive erythrocytes. (E) GLUT1 immunostaining. (F) Invasion of GL261-GFP tumor cells at the tumor periphery. (G) Quantification of tumor volume in A. (H) Survival curves for HGG-bearing mice (n = 8). (I and J) Quantification of vessel area (I) and sprouts (J) in B. (K) Quantification of coverage in C. (L) Quantification of hemorrhage in D. (M) Quantification of hypoxic area in E. (N) Quantification of perivascular invasion in F. Values are presented as mean ± SD (n = 5 unless otherwise denoted). , P < 0.05; *, P < 0.01; ***, P < 0.001 versus control/IgG; #, P < 0.05; ###, P < 0.001 versus Sox7iΔEC/IgG; $, P < 0.05; $$, P < 0.01; $$$, P < 0.001 versus Sox17iΔEC/IgG (log-rank test). NS, not significant. Bars: 2 mm (A); 100 µm (B–F).
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