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.
Highlights
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Tumour-associated macrophages (TAMs) are reported to be associated with poor prognosis in several types of cancer[32,33,34,35], and it has been proposed that monocytes, which continuously infiltrate tumours, once polarized to M2-like macrophages preferentially accumulate in hypoxic tumour areas[36,37,38,39,40]
Metastasis, M2-polarized TAMs can “assist” the tumour in overcoming a hostile hypoxic environment and sustain its progression[24,41]. Therapeutic targeting of this process in cancer is currently limited by an inadequate understanding of factors released by hypoxic cells that may be associated with M2-like macrophage accumulation in the tumour microenvironment
Summary
Unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. We show that the damage-associated molecular pattern High-Mobility Group Box. we demonstrate that HMGB1 drives IL-10 production in M2-like macrophages by selectively signalling through the Receptor for Advanced Glycation End products (RAGE). Hypoxia is a hallmark of a wide range of advanced solid tumours[1] and is often associated with poor prognosis in cancer patients[2]. A hypoxic environment, as frequently observed in solid tumours, results in focal areas of tumour cell necrosis and the release of damage associated molecular patterns (DAMPs) and alarmins, a group of endogenous molecules including hyaluronan fragments, S100 molecules and heat shock proteins, amyloid-β, uric acid, IL-1, IL-33 and high-mobility group box 1 protein (HMGB1)[4]. HMGB1 has been implicated in the development of hepatocellular carcinoma[13] and both colon and inflammation-related skin cancers[14,15]
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