title: The critical role of mast cell-derived hypoxia-inducible factor-1α in human and mice melanoma growth.
abstract: 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.
authors.affiliation: Biochip Research Center, Hoseo University, 165, Sechul-ri, Baebang-myun, Asan, Chungnam 336-795, Republic of Korea.
authors.forename: Hyun-Ja
authors.initials: HJ
authors.lastname: Jeong
authors.forename: Hyun-A
authors.initials: HA
authors.lastname: Oh
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Nam
authors.forename: Na-Ra
authors.initials: NR
authors.lastname: Han
authors.forename: Young-Sick
authors.initials: YS
authors.lastname: Kim
authors.forename: Jeong-Hwa
authors.initials: JH
authors.lastname: Kim
authors.forename: Seok-Jong
authors.initials: SJ
authors.lastname: Lee
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Kim
authors.forename: Phil-Dong
authors.initials: PD
authors.lastname: Moon
authors.forename: Hyung-Min
authors.initials: HM
authors.lastname: Kim
authors.forename: Hyun-A
authors.initials: HA
authors.lastname: Oh
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006632:Histamine / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology*; D008545:Melanoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011969:Receptors, Histamine H1 / Q000737:chemistry / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D011969:Receptors, Histamine H1; D042461:Vascular Endothelial Growth Factor A; D006632:Histamine