Sox17 promotes tumor angiogenesis and destabilizes tumor vessels in mice
Hanseul Yang, … , Gou Young Koh, Injune Kim
Hanseul Yang, … , Gou Young Koh, Injune Kim
Published December 17, 2012
Citation Information: J Clin Invest. 2013;123(1):418-431. https://doi.org/10.1172/JCI64547.
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Research Article Oncology

Sox17 promotes tumor angiogenesis and destabilizes tumor vessels in mice

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.

Authors

Hanseul Yang, 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

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Figure 1

Sox17 expression specific to tECs is coincident with increased angiogenesis.

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Sox17 expression specific to tECs is coincident with increased angiogen...
LLC and B16F10 tumors grown in Sox17GFP/+ mice (A–C and F) or wild-type mice (D, E, and G) were analyzed. (A–C) Images showing Sox17 expression (GFP) in tumor vessels (PECAM), but not in tumor-associated macrophages (CD11b+) or pericytes (α-SMA+), 2 weeks after implantation. (D) Sox17 transcripts specific to tECs purified from tumors 2 weeks after implantation. FACS plot shows cell populations purified from tumors. tHCs, tumor hematopoietic cells; OCs, other cells. (E) Sox17 expression in tECs at 1, 2, and 3 weeks after implantation. (F) Sox17 expression in individual tECs, as determined by FACS. Percentages of Sox17high tECs are shown. Cells from Sox17+/+ mice were used to establish background expression. (G) Images of tumor vessels showing different patterns of angiogenesis in LLC and B16F10 tumors at 1, 2, and 3 weeks after implantation. (A–C and G) Scale bars: 100 μm. (D–F) n = 3 (D and E) or 3–5 (F) per group. *P < 0.05, †P < 0.01 versus LLC tECs; #P < 0.001 versus tECs.