Hanseul Yang 1, Sungsu Lee, Seungjoo Lee, Kangsan Kim, Yeseul Yang, Jeong Hoon Kim, Ralf H Adams, James M Wells, Sean J Morrison, Gou Young Koh, Injune Kim
Abstract
Little is known about the transcriptional regulation of tumor angiogenesis, and tumor ECs (tECs) remain poorly characterized. Here, we studied the expression pattern of the transcription factor Sox17 in the vasculature of murine and human tumors and investigated the function of Sox17 during tumor angiogenesis using Sox17 genetic mouse models. Sox17 was specifically expressed in tECs in a heterogeneous pattern; in particular, strong Sox17 expression distinguished tECs with high VEGFR2 expression. Whereas overexpression of Sox17 in tECs promoted tumor angiogenesis and vascular abnormalities, Sox17 deletion in tECs reduced tumor angiogenesis and normalized tumor vessels, inhibiting tumor growth. Tumor vessel normalization by Sox17 deletion was long lasting, improved anticancer drug delivery into tumors, and inhibited tumor metastasis. Sox17 promoted endothelial sprouting behavior and upregulated VEGFR2 expression in a cell-intrinsic manner. Moreover, Sox17 increased the percentage of tumor-associated CD11b+Gr-1+ myeloid cells within tumors. The vascular effects of Sox17 persisted throughout tumor growth. Interestingly, Sox17 expression specific to tECs was also observed in highly vascularized human glioblastoma samples. Our findings establish Sox17 as a key regulator of tumor angiogenesis and tumor progression.
Figure 9
Late Sox17 deletion inhibits tumor growth by improving the efficacy of chemotherapy.
Tumors were grown in control and Sox17iΔEC mice. (A) Tumor growth (volume and mass). Red arrows indicate tamoxifen administration for delayed Sox17 deletion. Cisplatin (or PBS as vehicle) was administered 2 and 3 weeks after implantation (blue arrows). (B) H&E staining, showing tumor necrotic regions (dashed yellow outlines), and necrosis quantitation. (C) Effect of Sox17 deletion on tumor vessel morphogenesis. Tumor vessels (left) are characterized by excessive angiogenesis and poor integrity. Sox17 deletion in tECs (right) inhibits tumor angiogenesis and induces tumor vessel normalization. ECs are shown in red; pericytes are shown in green; basement membrane (BM) is shown in yellow. (A and B) n = 5 per group. *P < 0.05 versus all other groups; †P < 0.05; #P < 0.01. Scale bars: 4 mm.
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