title: Activin A is anti-lymphangiogenic in a melanoma mouse model.
abstract: Melanoma spreads primarily to the sentinel lymph nodes, and its risk correlates with lymphangiogenesis, which is mainly driven by vascular endothelial growth factor (VEGF)-C. However, anti-lymphangiogenic factors are poorly characterized. We have shown in a melanoma model that Wnt1 reduces lymphangiogenesis by reducing VEGF-C expression. Screening this model for additional potentially anti-lymphangiogenic factors identified increased activin A expression and reduced expression of the antagonist, follistatin (FST), in Wnt1(+) cells. Activin A is known to reduce blood vessel formation, but the effects on lymphangiogenesis are unknown. Here we show that human primary melanoma expresses significantly higher levels of activin A and lower levels of FST compared with nevi and melanoma metastasis. Using our mouse model with melanoma cells overexpressing Wnt1, FST, Wnt1/FST, or the inhibin βA subunit (INHBA, resulting in activin A expression), we found both activin A and Wnt1 to reduce lymphangiogenesis. Whereas Wnt1 also reduced metastasis, this was not seen with activin A. In vitro, activin A phosphorylated SMAD2 in both melanoma and lymphatic endothelium but, although it reduced sprouting of lymphatic endothelium, it enhanced the migration of melanoma cells. In conclusion, activin A is an anti-lymphangiogenic factor, but because of its pleiotropic effects on cell mobility it appears not suitable as a pharmacological target.
authors.affiliation: Skin & Endothelium Research Division SERD, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Heinz
authors.affiliation: Skin & Endothelium Research Division SERD, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Heide Leb
authors.initials: HL
authors.lastname: Niederleithner
authors.affiliation: Skin & Endothelium Research Division SERD, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Emmi
authors.initials: E
authors.lastname: Puujalka
authors.affiliation: Skin & Endothelium Research Division SERD, Department of Dermatology, Medical University of Vienna, Vienna, Austria; Division of General Dermatology, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Ana
authors.initials: A
authors.lastname: Soler-Cardona
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.affiliation: Division of General Dermatology, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Hubert
authors.initials: H
authors.lastname: Pehamberger
authors.affiliation: Skin & Endothelium Research Division SERD, Department of Dermatology, Medical University of Vienna, Vienna, Austria; Division of General Dermatology, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Loewe
authors.affiliation: Skin & Endothelium Research Division SERD, Department of Dermatology, Medical University of Vienna, Vienna, Austria; Division of General Dermatology, Department of Dermatology, Medical University of Vienna, Vienna, Austria. Electronic address: peter.petzelbauer@meduniwien.ac.at.
authors.forename: Peter
authors.initials: P
authors.lastname: Petzelbauer
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D004195:Disease Models, Animal; D005260:Female; D038681:Follistatin / Q000378:metabolism; D006801:Humans; D028322:Inhibin-beta Subunits / Q000378:metabolism*; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D042583:Lymphangiogenesis / Q000502:physiology*; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000556:secondary*; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D012878:Skin Neoplasms / Q000473:pathology*; D051155:Wnt1 Protein / Q000378:metabolism
chemical_list: C503233:FST protein, human; D038681:Follistatin; C495247:WNT1 protein, human; D051155:Wnt1 Protein; C103008:inhibin beta A subunit; D028322:Inhibin-beta Subunits