title: Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma.
abstract: Angiogenesis is not only dependent on endothelial cell invasion and proliferation, it also requires pericyte coverage of vascular sprouts for stabilization of vascular walls. Clinical efficacy of angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway is still limited to date. We hypothesized that the level of vessel maturation is critically involved in the response to antiangiogenic therapies. To test this hypothesis, we evaluated the vascular network in spontaneously developing melanomas of MT/ret transgenic mice after using PTK787/ZK222584 for anti-VEGF therapy but also analyzed human melanoma metastases taken at clinical relapse in patients undergoing adjuvant treatment using bevacizumab. Both experimental settings showed that tumor vessels, which are resistant to anti-VEGF therapy, are characterized by enhanced vessel diameter and normalization of the vascular bed by coverage of mature pericytes and immunoreactivity for desmin, NG-2, platelet-derived growth factor receptor beta, and the late-stage maturity marker alpha smooth muscle actin. Our findings emphasize that the level of mural cell differentiation and stabilization of the vascular wall significantly contribute to the response toward antiangiogenic therapy in melanoma. This study may be useful in paving the way toward a more rational development of second generation antiangiogenic combination therapies and in providing, for the first time, a murine model to study this.
authors.affiliation: Department of Dermatology, University Hospital Essen, Essen, Germany. iris.helfrich@uk-essen.de
authors.forename: Iris
authors.initials: I
authors.lastname: Helfrich
authors.forename: Inka
authors.initials: I
authors.lastname: Scheffrahn
authors.forename: Sönke
authors.initials: S
authors.lastname: Bartling
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.forename: Verena
authors.initials: V
authors.lastname: von Felbert
authors.forename: Mark
authors.initials: M
authors.lastname: Middleton
authors.forename: Masahi
authors.initials: M
authors.lastname: Kato
authors.forename: Süleyman
authors.initials: S
authors.lastname: Ergün
authors.forename: Helmut G
authors.initials: HG
authors.lastname: Augustin
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002455:Cell Division; D015687:Cell Hypoxia; D003893:Desmin; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D010641:Phenotype; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D020533:Angiogenesis Inhibitors; D003893:Desmin; D042461:Vascular Endothelial Growth Factor A; D020797:Receptor, Platelet-Derived Growth Factor beta