Milk Fat Globule EGF-8 Promotes Melanoma Progression through Coordinated Akt and Twist Signaling in the Tumor Microenvironment
Milk Fat Globule EGF-8 Promotes Melanoma Progression through Coordinated Akt and Twist Signaling in the Tumor Microenvironment
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DOI：
10.1158/0008-5472.can-08-2147
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发表时间：
2008-11-01
期刊：
影响因子：
11.2
通讯作者：
Dranoff, Glenn
中科院分区：
文献类型：
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作者：
Jinushi, Masahisa;Nakazaki, Yukoh;Dranoff, Glenn
恶性黑色素瘤的发病机制涉及肿瘤细胞与正常宿主元素的相互作用，但其潜在机制尚不完全清楚。在这里，我们表明，乳脂球EGF-8（MFG-E8），在黑色素瘤的垂直生长期高水平表达的分泌蛋白，通过协调α（v）β（3）整合素信号在肿瘤微环境中促进疾病进展。在小鼠黑色素瘤模型中，MFG-E8通过Akt依赖性和Twist依赖性途径增强致瘤性和转移能力。MFG-E8增强了黑色素瘤细胞对凋亡的抵抗力，触发了上皮向间质转化（EMT），并刺激了侵袭和免疫抑制。在人黑色素瘤细胞中，MFG-E8敲低减弱了Akt和Twist信号传导，从而损害了肿瘤细胞存活、EMT和侵袭能力。MFG-E8缺陷型人黑色素瘤细胞也显示出对胰岛素样生长因子I受体和c-Met的小分子抑制剂的敏感性增加。总之，这些发现描绘了MFG-E8在肿瘤微环境中的多效性作用，并提高了全身性MFG-E8阻断可能证明对黑色素瘤患者具有治疗作用的可能性。[Cancer Res 2008;68（21.）：8889-98]
The pathogenesis of malignant melanoma involves the interplay of tumor cells with normal host elements, but the underlying mechanisms are incompletely understood. Here, we show that milk fat globule EGF-8 (MFG-E8), a secreted protein expressed at high levels in the vertical growth phase of melanoma, promotes disease progression through coordinated alpha(v)beta(3) integrin signaling in the tumor microenvironment. In a murine model of melanoma, MFG-E8 enhanced tumorigenicity and metastatic capacity through Akt-dependent and Twist-dependent pathways. MFG-E8 augmented melanoma cell resistance to apoptosis, triggered an epithelial-to-mesenchymal transition (EMT), and stimulated invasion and immune suppression. In human melanoma cells, MFG-E8 knockdown attenuated Akt and Twist signaling and thereby compromised tumor cell survival, EMT, and invasive ability. MFG-E8-deficient human melanoma cells also showed increased sensitivity to small molecule inhibitors of insulin-like growth factor I receptor and c-Met. Together, these findings delineate pleiotropic roles for MFG-E8 in the tumor microenvironment and raise the possibility that systemic MFG-E8 blockade might prove therapeutic for melanoma patients. [Cancer Res 2008;68(21.):8889-98]