Cancer research (Chicago, Ill.), 2011-02, Vol.71 (4), p.1474-1485
2011
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- Autor(en) / Beteiligte
- Titel
- VEGFR-1 Expressed by Malignant Melanoma- Initiating Cells Is Required for Tumor Growth
- Ist Teil von
- Cancer research (Chicago, Ill.), 2011-02, Vol.71 (4), p.1474-1485
- Ort / Verlag
- Philadelphia, PA: American Association for Cancer Research
- Erscheinungsjahr
- 2011
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0008-5472eISSN: 1538-7445DOI: 10.1158/0008-5472.can-10-1660Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3083845
- Format
- –
- Schlagworte
- Animals, Antineoplastic agents, Biological and medical sciences, Cell Proliferation, Cells, Cultured, Dermatology, Gene Expression Profiling, Gene Expression Regulation, Neoplastic - physiology, Gene Knockdown Techniques, Humans, Medical sciences, Melanoma - drug therapy, Melanoma - genetics, Melanoma - pathology, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Mice, SCID, Microarray Analysis, Neoplastic Stem Cells - metabolism, Neoplastic Stem Cells - pathology, Pharmacology. Drug treatments, RNA, Small Interfering - pharmacology, RNA, Small Interfering - therapeutic use, Skin Neoplasms - drug therapy, Skin Neoplasms - genetics, Skin Neoplasms - pathology, Tumors, Tumors of the skin and soft tissue. Premalignant lesions, Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors, Vascular Endothelial Growth Factor Receptor-1 - genetics, Vascular Endothelial Growth Factor Receptor-1 - metabolism, Vascular Endothelial Growth Factor Receptor-1 - physiology, Xenograft Model Antitumor Assays