title: Tumour hypoxia promotes melanoma growth and metastasis via High Mobility Group Box-1 and M2-like macrophages.
abstract: Hypoxia is a hallmark of cancer that is strongly associated with invasion, metastasis, resistance to therapy and poor clinical outcome. Tumour hypoxia affects immune responses and promotes the accumulation of macrophages in the tumour microenvironment. However, the signals linking tumour hypoxia to tumour-associated macrophage recruitment and tumour promotion are incompletely understood. Here we show that the damage-associated molecular pattern High-Mobility Group Box 1 protein (HMGB1) is released by melanoma tumour cells as a consequence of hypoxia and promotes M2-like tumour-associated macrophage accumulation and an IL-10 rich milieu within the tumour. Furthermore, we demonstrate that HMGB1 drives IL-10 production in M2-like macrophages by selectively signalling through the Receptor for Advanced Glycation End products (RAGE). Finally, we show that HMGB1 has an important role in murine B16 melanoma growth and metastasis, whereas in humans its serum concentration is significantly increased in metastatic melanoma. Collectively, our findings identify a mechanism by which hypoxia affects tumour growth and metastasis in melanoma and depict HMGB1 as a potential therapeutic target.
authors.affiliation: Department of Dermatology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Roman
authors.initials: R
authors.lastname: Huber
authors.affiliation: Department of Dermatology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Meier
authors.affiliation: Department of Dermatology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Otsuka
authors.affiliation: Department of Dermatology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fenini
authors.affiliation: Department of Dermatology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Takashi
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Department of Dermatology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Samuel
authors.initials: S
authors.lastname: Gehrke
authors.affiliation: Department of Dermatology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Widmer
authors.affiliation: Department of Dermatology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Levesque
authors.affiliation: Department of Dermatology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Mangana
authors.affiliation: Department of Dermatology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Katrin
authors.initials: K
authors.lastname: Kerl
authors.affiliation: Skin cancer Unit, German Cancer Research Centre (DKFZ), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergology, University Medical Centre Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Gebhardt
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Chisa
authors.initials: C
authors.lastname: Nakashima
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nonomura
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kabashima
authors.affiliation: Department of Dermatology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Department of Dermatology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Contassot
authors.affiliation: Department of Dermatology, University Hospital Zürich, Zürich 8091, Switzerland.
authors.forename: Lars E
authors.initials: LE
authors.lastname: French
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D005260:Female; D024243:HMGB1 Protein / Q000097:blood / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008546:Melanoma, Experimental / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D010641:Phenotype; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D012878:Skin Neoplasms / Q000097:blood / Q000378:metabolism / Q000473:pathology; D000072258:Tumor Hypoxia
chemical_list: D024243:HMGB1 Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000067759:Receptor for Advanced Glycation End Products; D016753:Interleukin-10