Open AccessTumour hypoxia promotes melanoma growth and metastasis via High Mobility Group Box-1 and M2-like macrophages
Author(s) -
Roman Huber,
Barbara Meier,
Atsushi Otsuka,
Gabriele Fenini,
Takashi Satoh,
Samuel Gehrke,
Daniel Widmer,
Mitchell P. Levesque,
Joanna Mangana,
Katrin Kerl,
Christoffer Gebhardt,
Hiroko Fujii,
Chisa Nakashima,
Yumi omura,
Reinhard Dummer,
Emmanuel Contassot,
Lars E. French
Publication year - 2016
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/srep29914
Subject(s) - hmgb1 , melanoma , metastasis , hypoxia (environmental) , cancer research , immune system , tumor microenvironment , glycation , rage (emotion) , biology , immunology , medicine , receptor , cancer , chemistry , inflammation , organic chemistry , neuroscience , oxygen
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.