Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma

Tobias Bald, Thomas Quast, Jennifer Landsberg, Meri Rogava, Nicole Glodde, Dorys Lopez-Ramos, Judith Kohlmeyer, Stefanie Riesenberg, Debby Van Den Boorn-Konijnenberg, Cornelia Hömig-Hölzel, Raphael Reuten, Benjamin Schadow, Heike Weighardt, Daniela Wenzel, Iris Helfrich, Dirk Schadendorf, Wilhelm Bloch, Marco E. Bianchi, Claire Lugassy, Raymond L. BarnhillManuel Koch, Bernd K. Fleischmann, Irmgard Förster, Wolfgang Kastenmüller, Waldemar Kolanus, Michael Hölzel, Evelyn Gaffal, Thomas Tüting

Research output: Contribution to journalArticle

269 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)109-113
Number of pages5
JournalNature
Volume507
Issue number7490
DOIs
Publication statusPublished - 2014

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Melanoma
Radiation
Neoplasm Metastasis
Inflammation
Aptitude
Endothelial Cells
Keratinocytes
Neoplasms
Neutrophil Activation
Toll-Like Receptor 4
Neutrophil Infiltration
Melanocytes
Radiation Effects
Cell Communication
Cues
Blood Vessels
Immune System
Neutrophils
Lung
Skin

ASJC Scopus subject areas

  • General

Cite this

Bald, T., Quast, T., Landsberg, J., Rogava, M., Glodde, N., Lopez-Ramos, D., ... Tüting, T. (2014). Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature, 507(7490), 109-113. https://doi.org/10.1038/nature13111

Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. / Bald, Tobias; Quast, Thomas; Landsberg, Jennifer; Rogava, Meri; Glodde, Nicole; Lopez-Ramos, Dorys; Kohlmeyer, Judith; Riesenberg, Stefanie; Van Den Boorn-Konijnenberg, Debby; Hömig-Hölzel, Cornelia; Reuten, Raphael; Schadow, Benjamin; Weighardt, Heike; Wenzel, Daniela; Helfrich, Iris; Schadendorf, Dirk; Bloch, Wilhelm; Bianchi, Marco E.; Lugassy, Claire; Barnhill, Raymond L.; Koch, Manuel; Fleischmann, Bernd K.; Förster, Irmgard; Kastenmüller, Wolfgang; Kolanus, Waldemar; Hölzel, Michael; Gaffal, Evelyn; Tüting, Thomas.

In: Nature, Vol. 507, No. 7490, 2014, p. 109-113.

Research output: Contribution to journalArticle

Bald, T, Quast, T, Landsberg, J, Rogava, M, Glodde, N, Lopez-Ramos, D, Kohlmeyer, J, Riesenberg, S, Van Den Boorn-Konijnenberg, D, Hömig-Hölzel, C, Reuten, R, Schadow, B, Weighardt, H, Wenzel, D, Helfrich, I, Schadendorf, D, Bloch, W, Bianchi, ME, Lugassy, C, Barnhill, RL, Koch, M, Fleischmann, BK, Förster, I, Kastenmüller, W, Kolanus, W, Hölzel, M, Gaffal, E & Tüting, T 2014, 'Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma', Nature, vol. 507, no. 7490, pp. 109-113. https://doi.org/10.1038/nature13111
Bald T, Quast T, Landsberg J, Rogava M, Glodde N, Lopez-Ramos D et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature. 2014;507(7490):109-113. https://doi.org/10.1038/nature13111
Bald, Tobias ; Quast, Thomas ; Landsberg, Jennifer ; Rogava, Meri ; Glodde, Nicole ; Lopez-Ramos, Dorys ; Kohlmeyer, Judith ; Riesenberg, Stefanie ; Van Den Boorn-Konijnenberg, Debby ; Hömig-Hölzel, Cornelia ; Reuten, Raphael ; Schadow, Benjamin ; Weighardt, Heike ; Wenzel, Daniela ; Helfrich, Iris ; Schadendorf, Dirk ; Bloch, Wilhelm ; Bianchi, Marco E. ; Lugassy, Claire ; Barnhill, Raymond L. ; Koch, Manuel ; Fleischmann, Bernd K. ; Förster, Irmgard ; Kastenmüller, Wolfgang ; Kolanus, Waldemar ; Hölzel, Michael ; Gaffal, Evelyn ; Tüting, Thomas. / Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. In: Nature. 2014 ; Vol. 507, No. 7490. pp. 109-113.
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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.",
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AU - Bald, Tobias

AU - Quast, Thomas

AU - Landsberg, Jennifer

AU - Rogava, Meri

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AU - Lopez-Ramos, Dorys

AU - Kohlmeyer, Judith

AU - Riesenberg, Stefanie

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AU - Reuten, Raphael

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AU - Barnhill, Raymond L.

AU - Koch, Manuel

AU - Fleischmann, Bernd K.

AU - Förster, Irmgard

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AU - Tüting, Thomas

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N2 - 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.

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