VEGFR-1 Expressed by Malignant Melanoma- Initiating Cells Is Required for Tumor Growth

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-02, Vol.71 (4), p.1474-1485
• Main Authors: FRANK, Natasha Y, SCHATTON, Tobias, WAAGA-GASSER, Ana-Maria, KUPPER, Thomas S, MURPHY, George F, FRANK, Markus H, KIM, Soo, QIAN ZHAN, WILSON, Brian J, JIE MA, SAAB, Karim R, OSHEROV, Veronika, WIDLUND, Hans R, GASSER, Martin
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-1660

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.