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The critical role of mast cell‐derived hypoxia‐inducible factor‐1α in human and mice melanoma growth
Author(s) -
Jeong HyunJa,
Oh HyunA,
Nam SunYoung,
Han NaRa,
Kim YoungSick,
Kim JeongHwa,
Lee SeokJong,
Kim MinHo,
Moon PhilDong,
Kim HyungMin,
Oh HyunA
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27937
Subject(s) - mast cell , histamine , stromal cell , melanoma , angiogenesis , cancer research , cell growth , vascular endothelial growth factor , biology , bone marrow , carcinogenesis , tryptase , immunology , pathology , medicine , endocrinology , cancer , vegf receptors , genetics
Mast cells play an important role in tumorigenesis. Histamine released from mast cells stimulates new vessel formation by acting through the histamine1 (H1) receptor. Despite the evidence of the role of mast cells in tumor growth and angiogenesis, the potential mechanism remains to be elucidated. Therefore, we investigated the role of mast cell‐derived HIF‐1α in melanoma growth. Here, we identify that the most positive cells for HIF‐1α staining are seen in mast cells of human and animal melanoma tissue. The number of the stromal cell types (fibroblasts, macrophages and endothelial cells) was also increased in melanoma tissues. In activated bone marrow‐derived mast cells (BMMCs), expressions of HIF‐1α and VEGF were increased. Histamine also induced the expressions of HIF‐1α and VEGF in BMMCs. H1 receptor antagonists significantly improved overall survival rates and substantially suppressed tumor growth as well as the infiltration of mast cells and levels of VEGF through the inhibition of HIF‐1α expression in B16F10 melanoma‐bearing mice. Furthermore, the injection of HIF‐1α depleted BMMCs markedly inhibited the growth of tumors and migration of mast cells and increased the survival rate of the mice. These findings emphasize that the growth of melanoma can actually be exacerbated by mast cell‐derived HIF‐1α. In aggregate, our results reveal a novel role for mast cell‐derived HIF‐1α in the melanoma microenvironment and have important implications for the design of therapeutic strategies.