Jinushi Masahisa, Nakazaki Yukoh, Carrasco Daniel R, Draganov Dobrin, Souders Nicholas, Johnson Matthew, Mihm Martin C, Dranoff Glenn
Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Cancer Res. 2008 Nov 1;68(21):8889-98. doi: 10.1158/0008-5472.CAN-08-2147.
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.
恶性黑色素瘤的发病机制涉及肿瘤细胞与正常宿主成分之间的相互作用，但其潜在机制尚未完全明确。在此，我们发现乳脂肪球表皮生长因子8（MFG-E8），一种在黑色素瘤垂直生长期高水平表达的分泌蛋白，通过在肿瘤微环境中协调α(v)β(3)整合素信号促进疾病进展。在黑色素瘤小鼠模型中，MFG-E8通过Akt依赖和Twist依赖途径增强致瘤性和转移能力。MFG-E8增强黑色素瘤细胞对凋亡的抗性，引发上皮-间质转化（EMT），并刺激侵袭和免疫抑制。在人黑色素瘤细胞中，MFG-E8基因敲低减弱了Akt和Twist信号，从而损害肿瘤细胞存活、EMT和侵袭能力。MFG-E8缺陷的人黑色素瘤细胞对胰岛素样生长因子I受体和c-Met的小分子抑制剂也表现出更高的敏感性。总之，这些发现阐明了MFG-E8在肿瘤微环境中的多效性作用，并提出全身性MFG-E8阻断可能对黑色素瘤患者具有治疗作用的可能性。
