American Association for Cancer Research
15357163mct130637-sup-fig_6.pdf (1.01 MB)

Supplementary Figure 6 from Hypoxia-Regulated Overexpression of Soluble VEGFR2 Controls Angiogenesis and Inhibits Tumor Growth

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journal contribution
posted on 2023-04-03, 14:48 authored by Guillaume Collet, Nathalie Lamerant-Fayel, Magdalena Tertil, Bouchra El Hafny-Rahbi, Jacek Stepniewski, Alan Guichard, Alexandra Foucault-Collet, Krzysztof Klimkiewicz, Stéphane Petoud, Agata Matejuk, Catherine Grillon, Alicja Jozkowicz, Jozef Dulak, Claudine Kieda

PDF - 1037KB, Effect of the IFP1.4 and mCherry expression on the B16F10 cells proliferation.



VEGFs are found at high levels in hypoxic tumors. As major components directing pathologic neovascularization, they regulate stromal reactions. Consequently, novel strategies targeting and inhibiting VEGF overproduction upon hypoxia offer considerable potential for modern anticancer therapies controlling rather than destroying tumor angiogenesis. Here, we report the design of a vector expressing the soluble form of VEGF receptor-2 (sVEGFR2) driven by a hypoxia-responsive element (HRE)-regulated promoter. To enable in vivo imaging by infrared visualization, mCherry and IFP1.4 coding sequences were built into the vector. Plasmid construction was validated through transfection into embryonic human kidney HEK293 and murine B16F10 melanoma cells. sVEGFR2 was expressed in hypoxic conditions only, confirming that the gene was regulated by the HRE promoter. sVEGFR2 was found to bind efficiently and specifically to murine and human VEGF-A, reducing the growth of tumor and endothelial cells as well as impacting angiogenesis in vitro. The hypoxia-conditioned sVEGFR2 expression was shown to be functional in vivo: Tumor angiogenesis was inhibited and, on stable transfection of B16F10 melanoma cells, tumor growth was reduced. Enhanced expression of sVEGFR2 was accompanied by a modulation in levels of VEGF-A. The resulting balance reflected the effect on tumor growth and on control of angiogenesis. A concomitant increase of intratumor oxygen tension also suggested an influence on vessel normalization. The possibility to express an angiogenesis regulator as sVEGFR2, in a hypoxia-conditioned manner, significantly opens new strategies for tumor vessel–controlled normalization and the design of adjuvants for combined cancer therapies. Mol Cancer Ther; 13(1); 165–78. ©2013 AACR.