title: VEGFR-1 expressed by malignant melanoma-initiating cells is required for tumor growth.
abstract: Melanoma growth is driven by malignant melanoma-initiating cells (MMIC) identified by expression of the ATP-binding cassette (ABC) member ABCB5. ABCB5(+) melanoma subpopulations have been shown to overexpress the vasculogenic differentiation markers CD144 (VE-cadherin) and TIE1 and are associated with CD31(-) vasculogenic mimicry (VM), an established biomarker associated with increased patient mortality. Here we identify a critical role for VEGFR-1 signaling in ABCB5(+) MMIC-dependent VM and tumor growth. Global gene expression analyses, validated by mRNA and protein determinations, revealed preferential expression of VEGFR-1 on ABCB5(+) tumor cells purified from clinical melanomas and established melanoma lines. In vitro, VEGF induced the expression of CD144 in ABCB5(+) subpopulations that constitutively expressed VEGFR-1 but not in ABCB5(-) bulk populations that were predominantly VEGFR-1(-). In vivo, melanoma-specific shRNA-mediated knockdown of VEGFR-1 blocked the development of ABCB5(+) VM morphology and inhibited ABCB5(+) VM-associated production of the secreted melanoma mitogen laminin. Moreover, melanoma-specific VEGFR-1 knockdown markedly inhibited tumor growth (by > 90%). Our results show that VEGFR-1 function in MMIC regulates VM and associated laminin production and show that this function represents one mechanism through which MMICs promote tumor growth.
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Natasha Y
authors.initials: NY
authors.lastname: Frank
authors.forename: Tobias
authors.initials: T
authors.lastname: Schatton
authors.forename: Soo
authors.initials: S
authors.lastname: Kim
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhan
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Wilson
authors.forename: Jie
authors.initials: J
authors.lastname: Ma
authors.forename: Karim R
authors.initials: KR
authors.lastname: Saab
authors.forename: Veronika
authors.initials: V
authors.lastname: Osherov
authors.forename: Hans R
authors.initials: HR
authors.lastname: Widlund
authors.forename: Martin
authors.initials: M
authors.lastname: Gasser
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Waaga-Gasser
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kupper
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.forename: Markus H
authors.initials: MH
authors.lastname: Frank
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D046228:Microarray Analysis; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D034741:RNA, Small Interfering; D040281:Vascular Endothelial Growth Factor Receptor-1