title: Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma.
abstract: Intermittent intense ultraviolet (UV) exposure represents an important aetiological factor in the development of malignant melanoma. The ability of UV radiation to cause tumour-initiating DNA mutations in melanocytes is now firmly established, but how the microenvironmental effects of UV radiation influence melanoma pathogenesis is not fully understood. Here we report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression, independent of its tumour-initiating effects. UV irradiation enhanced the expansion of tumour cells along abluminal blood vessel surfaces and increased the number of lung metastases. This effect depended on the recruitment and activation of neutrophils, initiated by the release of high mobility group box 1 (HMGB1) from UV-damaged epidermal keratinocytes and driven by Toll-like receptor 4 (TLR4). The UV-induced neutrophilic inflammatory response stimulated angiogenesis and promoted the ability of melanoma cells to migrate towards endothelial cells and use selective motility cues on their surfaces. Our results not only reveal how UV irradiation of epidermal keratinocytes is sensed by the innate immune system, but also show that the resulting inflammatory response catalyses reciprocal melanoma-endothelial cell interactions leading to perivascular invasion, a phenomenon originally described as angiotropism in human melanomas by histopathologists. Angiotropism represents a hitherto underappreciated mechanism of metastasis that also increases the likelihood of intravasation and haematogenous dissemination. Consistent with our findings, ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases. Our work indicates that targeting the inflammation-induced phenotypic plasticity of melanoma cells and their association with endothelial cells represent rational strategies to specifically interfere with metastatic progression.
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53115 Bonn, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bald
authors.affiliation: Molecular Immunology and Cell Biology, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quast
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53115 Bonn, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Landsberg
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53115 Bonn, Germany.
authors.forename: Meri
authors.initials: M
authors.lastname: Rogava
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53115 Bonn, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Glodde
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53115 Bonn, Germany.
authors.forename: Dorys
authors.initials: D
authors.lastname: Lopez-Ramos
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53115 Bonn, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Kohlmeyer
authors.affiliation: Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Riesenberg
authors.affiliation: Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany.
authors.forename: Debby
authors.initials: D
authors.lastname: van den Boorn-Konijnenberg
authors.affiliation: Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Hömig-Hölzel
authors.affiliation: Institute for Dental Research and Oral Musculoskeletal Biology, Center for Biochemistry, Medical Faculty, University of Cologne, D-50931 Cologne, Germany.
authors.forename: Raphael
authors.initials: R
authors.lastname: Reuten
authors.affiliation: Immunology and Environment, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schadow
authors.affiliation: Immunology and Environment, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Weighardt
authors.affiliation: Institute for Physiology I, Life & Brain Center, University of Bonn, 53105 Bonn, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Wenzel
authors.affiliation: Department of Dermatology, University Hospital Essen, 45122 Essen, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Helfrich
authors.affiliation: Department of Dermatology, University Hospital Essen, 45122 Essen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, 50933 Cologne, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele University and Scientific Institute, 20132 Milan, Italy.
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.affiliation: Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, University of California Los Angeles (UCLA) Medical Center, Los Angeles, California 90095, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Lugassy
authors.affiliation: Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, University of California Los Angeles (UCLA) Medical Center, Los Angeles, California 90095, USA.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Barnhill
authors.affiliation: Institute for Dental Research and Oral Musculoskeletal Biology, Center for Biochemistry, Medical Faculty, University of Cologne, D-50931 Cologne, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Koch
authors.affiliation: Institute for Physiology I, Life & Brain Center, University of Bonn, 53105 Bonn, Germany.
authors.forename: Bernd K
authors.initials: BK
authors.lastname: Fleischmann
authors.affiliation: Immunology and Environment, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Förster
authors.affiliation: Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, 53105 Bonn, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kastenmüller
authors.affiliation: Molecular Immunology and Cell Biology, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Kolanus
authors.affiliation: Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hölzel
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53115 Bonn, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Gaffal
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53115 Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000528:radiation effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D024243:HMGB1 Protein / Q000378:metabolism; D007113:Immunity, Innate / Q000528:radiation effects; D007249:Inflammation / Q000209:etiology*; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008175:Lung Neoplasms / Q000098:blood supply / Q000209:etiology / Q000556:secondary*; D008297:Male; D008544:Melanocytes / Q000473:pathology / Q000528:radiation effects; D008545:Melanoma / Q000098:blood supply* / Q000209:etiology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000209:etiology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D012878:Skin Neoplasms / Q000098:blood supply / Q000209:etiology / Q000473:pathology*; D013471:Sunburn / Q000150:complications / Q000209:etiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4