CANCER RES：致命的皮肤癌如何全身扩散

　　弗吉尼亚联邦大学梅西癌症中心的科学家Paul B. Fisher博士1月3号发表在《癌症》杂志上的一项研究表明：在肿瘤新血管的形成过程中，mda-9/syntenin是调节血管生成的关键因子。

　　这是科学家继成功在实验室试验中消除黑色素瘤转移后，又取得的又一项重要发现：黑色素瘤分化相关基因-9（mda-9/syntenin）导致了转移的恶性黑色素瘤（皮肤癌的扩散）和其他可能癌症的发生。

　　研究让人类更进一步清晰地了解这种高度侵略性、治疗抵抗性、全身转移性的转移性黑色素瘤。人类基因组的分析表明，大多数的癌症中mda-9/syntenin的值升高，这意味着新药物的靶基因也可广谱适用于其他致命的癌症。

　　研究小组发现，mda-9/syntenin可调控血管蛋白质的表达，包括对胰岛素样生长因子结合蛋白-2（IGFBP-2）和白细胞介素-8（IL-8）的调控。这项研究是第一个证明IGFBP-2在人类黑色素瘤发展中具有促血管生成的功能。

　　在体内和体外实验中，科学家证实mda-9/syntenin与细胞外基质（ECM）发生一系列生物进程，最终使血管内皮细胞分泌IGFBP-2。ECM是细胞分泌并在其中嵌入的物质。内皮细胞是贯穿整个循环系统血管内表面的细胞。IGFBP-2分泌反馈给内皮细胞，使其产生和分泌血管内皮生长因子-A（VEGF-A），一种介导新的血管形成和生长的蛋白质。

　　研究人员还指出，IGFBP-2有望成为一个新的生物标志物，用于监测黑色素瘤患者的疾病进展。IGFBP-2在了解血管生成及其在黑色素瘤转移的影响中具有重大作用。科学家目前正专门针对mda-9/syntenin和IGFBP-2，研究可以抵抗的药物来治疗黑色素瘤和潜在的许多其他癌症。

与黑色素瘤相关的拓展阅读：

• JCO:索拉非尼对转移性黑色素瘤无益
• 澳研究出黑色素瘤新疗法
• JAMA：SPECT/CT成像技术有助黑色素瘤前哨淋巴结活检
• JCO：白介素-21治疗转移性黑色素瘤
• Cancer Res：转移性黑色素瘤患者在肿瘤微环境免疫细胞被激活
• J Invest Dermatol：抑制GSK3β阻断黑色素瘤细胞转移
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MDA-9/Syntenin and IGFBP-2 Promote Angiogenesis in Human Melanoma

Melanoma differentiation associated gene-9 (mda-9/syntenin) encodes an adapter scaffold protein whose expression correlates with and mediates melanoma progression and metastasis. Tumor angiogenesis represents an integral component of cancer metastasis prompting us to investigate a possible role of mda-9/syntenin in inducing angiogenesis. Genetic (gain-of-function and loss-of-function) and pharmacological approaches were employed to modify mda-9/syntenin expression in normal immortal melanocytes, early radial growth phase melanoma and metastatic melanoma cells. The consequence of modifying mda-9/syntenin expression on angiogenesis was evaluated using both in vitro and in vivo assays, including tube formation assays using human vascular endothelial cells, CAM assays and xenograft tumor animal models. Gain-of-function and loss-of-function experiments confirm that MDA-9/syntenin induces angiogenesis by augmenting expression of several pro-angiogenic factors/genes. Experimental evidence is provided for a model of angiogenesis induction by MDA-9/syntenin in which MDA-9/syntenin interacts with the ECM activating Src and FAK resulting in activation by phosphorylation of Akt, which induces HIF-1α. The HIF-1α activates transcription of Insulin Growth Factor Binding Protein-2 (IGFBP-2), which is secreted thereby promoting angiogenesis and further induces endothelial cells to produce and secrete VEGF-A augmenting tumor angiogenesis. Our studies delineate an unanticipated cell non-autonomous function of MDA-9/syntenin in the context of angiogenesis, which may directly contribute to its metastasis-promoting properties. As a result, targeting MDA-9/syntenin or its downstream-regulated molecules may provide a means of simultaneously impeding metastasis by both directly inhibiting tumor cell transformed properties (autonomous) and indirectly by blocking angiogenesis (non-autonomous).