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ETS transcription factors Etv2 and Fli1b are required for tumor angiogenesis

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Abstract

ETS transcription factor ETV2/Etsrp functions as a key regulator of embryonic vascular development in multiple vertebrates. However, its role in pathological vascular development has not been previously investigated. To analyze its role in tumor angiogenesis, we utilized a zebrafish xenotransplantation model. Using a photoconvertible kdrl:NLS-KikGR line, we demonstrated that all tumor vessels originate from the existing embryonic vasculature by the mechanism of angiogenesis. Xenotransplantation of mouse B16 melanoma cells resulted in a significant increase in expression of the ETS transcription factors etv2 and fli1b expression throughout the embryonic vasculature. etv2 null mutants which undergo significant recovery of embryonic angiogenesis during later developmental stages displayed a strong inhibition of tumor angiogenesis. We utilized highly specific and fully validated photoactivatable morpholinos to inhibit Etv2 function after embryonic vasculogenesis has completed. Inducible inhibition of Etv2 function resulted in a significant reduction of tumor angiogenesis and inhibition of tumor growth. Furthermore, inducible inhibition of Etv2 function in fli1b mutant embryos resulted in even stronger reduction in tumor angiogenesis and growth, demonstrating that Etv2 and Fli1b have a partially redundant requirement during tumor angiogenesis. These results demonstrate the requirement for Etv2 and Fli1b in tumor angiogenesis and suggest that inhibition of these ETS factors may present a novel strategy to inhibit tumor angiogenesis and reduce tumor growth.

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Acknowledgements

We thank Timothy Cripe for providing A673 tumor cell line, and Chengjian Zhao for providing B16 melanoma cells. We thank Matthew Kofron and Mike Muntifering at the CCHMC confocal core for their help with the imaging and analysis (the confocal core is supported by the award from the National Institutes of Health 1S10RR029406). The research was supported by the awards from the National Institutes of Health (R01 HL107369), Ohio Cancer Research Associates and Cancer-Free Kids to S.S. and NIH 5T32HL00752 (M.P.C./J. Whitsett).

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    1. Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA

      Kristina Baltrunaite, Michael P. Craig, Sharina Palencia Desai, Praneet Chaturvedi, Ram Naresh Pandey, Rashmi S. Hegde & Saulius Sumanas

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    1. Kristina Baltrunaite
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    Correspondence to Saulius Sumanas.

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    Kristina Baltrunaite and Michael P. Craig have been equally contributed.

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    Baltrunaite, K., Craig, M.P., Palencia Desai, S. et al. ETS transcription factors Etv2 and Fli1b are required for tumor angiogenesis. Angiogenesis 20, 307–323 (2017). https://doi.org/10.1007/s10456-017-9539-8

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