VEGFR-1 expressed by malignant melanoma-initiating cells is required for tumor growth.
VEGFR-1 expressed by malignant melanoma-initiating cells is required for tumor growth.
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DOI：
10.1158/0008-5472.can-10-1660
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发表时间：
2011-02-15
期刊：
影响因子：
11.2
通讯作者：
Frank MH
中科院分区：
文献类型：
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作者：
Frank NY;Schatton T;Kim S;Zhan Q;Wilson BJ;Ma J;Saab KR;Osherov V;Widlund HR;Gasser M;Waaga-Gasser AM;Kupper TS;Murphy GF;Frank MH
黑色素瘤生长由恶性黑色素瘤起始细胞（MMIC）驱动，MMIC通过ATP结合盒（ABC）成员ABCB 5的表达来鉴定。ABCB 5+黑色素瘤亚群已被证明过表达血管生成分化标志物CD 144（VE-钙粘蛋白）和TIE 1，并与CD 31 −血管生成拟态（VM）相关，这是一种与患者死亡率增加相关的既定生物标志物。在此，我们确定了VEGFR-1信号在ABCB 5 + MMIC依赖性VM和肿瘤生长中的关键作用。通过mRNA和蛋白质测定验证的全局基因表达分析显示，从临床黑色素瘤和已建立的黑色素瘤细胞系纯化的ABCB 5+肿瘤细胞上优先表达VEGFR-1。在体外，VEGF在组成性表达VEGFR-1的ABCB 5+亚群中诱导CD 144的表达，但在主要为VEGFR-1-的ABCB 5-大群中不诱导CD 144的表达。在体内，黑色素瘤特异性shRNA介导的VEGFR-1敲低阻断了ABCB 5 + VM形态的发展，并抑制了分泌的黑色素瘤有丝分裂原层粘连蛋白的ABCB 5 + VM相关生产。此外，黑色素瘤特异性VEGFR-1敲低显著抑制肿瘤生长（>90%）。我们的研究结果表明，MMIC中的VEGFR-1功能调节VM和相关层粘连蛋白的产生，并表明这种功能代表MMIC促进肿瘤生长的一种机制。
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.