title: Wnt1 is anti-lymphangiogenic in a melanoma mouse model.
abstract: Wnt signals contribute to melanoma progression by boosting their proliferation and survival. Initially, we expected that activated Wnt signaling also improves their proficiency to recruit blood and lymph vessels. To assess this, we added cell culture supernatants (SNs) of Wnt1(+) and Wnt1(-) melanoma to endothelial spheroids. Whereas SNs of Wnt1(-) melanoma cells induced lymphatic sprouts, those of Wnt1(+) cells were unable to do so and this was restored by vascular endothelial growth factor C (VEGF-C). Subsequent testing of several human melanoma lines revealed that Wnt1 suppressed their VEGF-C expression. This Wnt1 effect did not depend on glycogen synthase kinase-3β (GSK3β), β-catenin, or activator protein-1, but was blocked by cyclosporine A (CsA). To analyze Wnt1 effects in melanoma in vivo, we selected Wnt1(-) melanoma cell lines, overexpressed Wnt1, and injected them subepidermally into severe combined immunodeficient (SCID) mice. We found reduced VEGF-C expression, reduced lymphangiogenesis, and delayed metastasis to sentinel nodes in Wnt1(+) as compared with Wnt1(-) melanoma (P<0.05). Concomitant overexpression of VEGF-C or feeding of animals with CsA restored lymphangiogenesis and metastasis in Wnt1(+) melanoma. In conclusion, Wnt1 is anti-lymphangiogenic by suppressing melanoma-derived VEGF-C expression.
authors.affiliation: Skin and Endothelium Research Division (SERD), Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Heide
authors.initials: H
authors.lastname: Niederleithner
authors.forename: Magdalena
authors.initials: M
authors.lastname: Heinz
authors.forename: Stefanie
authors.initials: S
authors.lastname: Tauber
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.forename: Hubert
authors.initials: H
authors.lastname: Pehamberger
authors.forename: Stefan
authors.initials: S
authors.lastname: Sonderegger
authors.forename: Martin
authors.initials: M
authors.lastname: Knöfler
authors.forename: Andreas
authors.initials: A
authors.lastname: Bracher
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Robert
authors.initials: R
authors.lastname: Loewe
authors.forename: Peter
authors.initials: P
authors.lastname: Petzelbauer
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D008545:Melanoma / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D012878:Skin Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured; D042582:Vascular Endothelial Growth Factor C / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D060449:Wnt Signaling Pathway / Q000502:physiology; D051155:Wnt1 Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; C495247:WNT1 protein, human; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; C467483:vascular endothelial growth factor C, mouse; D016572:Cyclosporine