Bald, Tobias ORCID: 0000-0003-0061-235X, Quast, Thomas, Landsberg, Jennifer ORCID: 0000-0001-8029-3883, Rogava, Meri ORCID: 0000-0002-0314-5323, Glodde, Nicole, Lopez-Ramos, Dorys, Kohlmeyer, Judith, Riesenberg, Stefanie, van den Boorn-Konijnenberg, Debby, Hoemig-Hoelzel, Cornelia, Reuten, Raphael ORCID: 0000-0002-9434-4108, Schadow, Benjamin, Weighardt, Heike, Wenzel, Daniela ORCID: 0000-0003-1100-6363, Helfrich, Iris, Schadendorf, Dirk, Bloch, Wilhelm, Bianchi, Marco E., Lugassy, Claire, Barnhill, Raymond L., Koch, Manuel ORCID: 0000-0002-2962-7814, Fleischmann, Bernd K., Foerster, Irmgard, Kastenmueller, Wolfgang, Kolanus, Waldemar, Hoelzel, Michael, Gaffal, Evelyn and Tueting, Thomas (2014). Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature, 507 (7490). S. 109 - 129. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4687

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Abstract

Intermittent intense ultraviolet (UV) exposure represents an important aetiological factor in the development of malignant melanoma(1). The ability of UV radiation to cause tumour-initiating DNA mutations in melanocytes is now firmly established(2), but how the microenvironmental effects of UV radiation(3,4) influence melanoma pathogenesis is not fully understood. Here we report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model(5) 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(6). Angiotropism represents a hitherto underappreciated mechanism of metastasis(7) 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bald, TobiasUNSPECIFIEDorcid.org/0000-0003-0061-235XUNSPECIFIED
Quast, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Landsberg, JenniferUNSPECIFIEDorcid.org/0000-0001-8029-3883UNSPECIFIED
Rogava, MeriUNSPECIFIEDorcid.org/0000-0002-0314-5323UNSPECIFIED
Glodde, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopez-Ramos, DorysUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kohlmeyer, JudithUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riesenberg, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van den Boorn-Konijnenberg, DebbyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoemig-Hoelzel, CorneliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reuten, RaphaelUNSPECIFIEDorcid.org/0000-0002-9434-4108UNSPECIFIED
Schadow, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weighardt, HeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wenzel, DanielaUNSPECIFIEDorcid.org/0000-0003-1100-6363UNSPECIFIED
Helfrich, IrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schadendorf, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bloch, WilhelmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bianchi, Marco E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lugassy, ClaireUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barnhill, Raymond L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koch, ManuelUNSPECIFIEDorcid.org/0000-0002-2962-7814UNSPECIFIED
Fleischmann, Bernd K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Foerster, IrmgardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kastenmueller, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kolanus, WaldemarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelzel, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gaffal, EvelynUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tueting, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-443525
DOI: 10.1038/nature13111
Journal or Publication Title: Nature
Volume: 507
Number: 7490
Page Range: S. 109 - 129
Date: 2014
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-4687
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CIRCULATING TUMOR-CELLS; MALIGNANT-MELANOMA; CYTOKINE RELEASE; ANGIOGENESIS; NEUTROPHILS; EXPRESSION; PROTEIN; IMMUNE; STAGE; MOUSEMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/44352

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