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: 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 Nonomura, Kenji Kabashima, Reinhard Dummer, Emmanuel Contassot, Lars E French
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 29914 (07 18 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27426915 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HMGB1 Protein
• Hypoxia-Inducible Factor 1, alpha Subunit
• Receptor for Advanced Glycation End Products
• Interleukin-10

Topics

• Animals
• Cell Proliferation
• Female
• HMGB1 Protein (blood, metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Interleukin-10 (metabolism)
• Macrophages (metabolism, pathology)
• Male
• Melanoma, Experimental (blood, metabolism, pathology)
• Mice, Inbred C57BL
• Phenotype
• Receptor for Advanced Glycation End Products (metabolism)
• Skin Neoplasms (blood, metabolism, pathology)
• Tumor Hypoxia