title: ETS transcription factors Etv2 and Fli1b are required for tumor angiogenesis.
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.
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Baltrunaite
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Craig
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA.
authors.forename: Sharina
authors.initials: S
authors.lastname: Palencia Desai
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA.
authors.forename: Praneet
authors.initials: P
authors.lastname: Chaturvedi
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA.
authors.forename: Ram Naresh
authors.initials: RN
authors.lastname: Pandey
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA.
authors.forename: Rashmi S
authors.initials: RS
authors.lastname: Hegde
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA. saulius.sumanas@cchmc.org.
authors.forename: Saulius
authors.identifier: http://orcid.org/0000-0002-8605-6122
authors.initials: S
authors.lastname: Sumanas
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian / Q000098:blood supply / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D009369:Neoplasms / Q000098:blood supply* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C509408:Etv2 protein, zebrafish; C000598206:Fli1b protein, zebrafish; D014157:Transcription Factors; D029961:Zebrafish Proteins
keywords: Angiogenesis; ETS transcription factors; Tumor; Xenograft; Zebrafish