Serpine2和Slpi——恶性肿瘤转移的关键分子（Nature文章）

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$ M6 Z& p9 k* f  J肿瘤可以释放大量的肿瘤细胞进入到循环系统（淋巴和血液系统），这些细胞中的一小部分可以进入到远处的器官并存活下来，形成癌症转移灶。之前，已经有文章表明，复杂细胞群内个体细胞形成继发性病变的能力，表现出了异质性。近日,来自冷泉港霍华德休斯医学研究所的研究组发现, Serpine2和Slpi可以使肿瘤细胞形成血管样的网状结构，从而促进了肿瘤细胞的渗透和转移。此研究结果近日在线发表在Nauture杂志上。
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研究人员首先建立了一种多克隆的老鼠乳腺癌异质性模型，即利用逆转录病毒条码方法标记4T1细胞系中的不同细胞克隆，然后将细胞用乳腺脂肪垫注射的方法打入老鼠体内，形成老鼠乳腺癌模型。之后，研究人员检测了这些老鼠体内不同组织器官中，例如，淋巴结，肺，肝，脑和血液中，这些细胞克隆的相对比例。他们发现，在混合的细胞群中的不同克隆表现出了特异性，例如，主导原发肿瘤，促进了转移细胞群，或者是有进入淋巴和血液系统的趋向性。接着，研究人员将这些稳定的特性和不同的基因表达谱对应了起来。他们发现，能高效进入血管系统的克隆表达了两种分泌性蛋白，Serpine2和Slpi，这两种蛋白是使这些细胞形成血管拟态的必要和充分条件。数据表明，这两种蛋白不但促进了血管外网络的形成，而且通过抗凝作用确保了这些血管的渗透性。
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研究人员认为，血管拟态的生成提高了一些乳腺癌细胞促进远处转移的能力，同时，也满足了原发肿瘤细胞对血管供给的迫切需要。在人类乳腺癌细胞系上过表达SERPINE2和SLPI同样可以使这些细胞形成血管拟态。而且，在有肺部转移的复发患者身上，这两种蛋白的表达量也是增高的。
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% F8 l) a& z6 _  x因此，Serpine2和Slpi，这两种分泌型蛋白和它们所引起的表型，可能和人类肿瘤转移进程的驱动，有很大的相关性。（转载自生物谷)
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( W+ k# F1 b; a; o0 Q6 W7 R8 [2 c* ~原文检索：doi: 10.1038/ncomms7426
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6 M/ \- n. \) i/ {# rA model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis
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) U/ h! v) V" ^  g$ ~Elvin Wagenblast,et al.
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1 P1 h. E1 \- ZCancer metastasis requires that primary tumour cells evolve the capacity to intravasate into the lymphatic system or vasculature, and extravasate into and colonize secondary sites1. Others have demonstrated that individual cells within complex populations show heterogeneity in their capacity to form secondary lesions2, 3, 4, 5. Here we develop a polyclonal mouse model of breast tumour heterogeneity, and show that distinct clones within a mixed population display specialization, for example, dominating the primary tumour, contributing to metastatic populations, or showing tropism for entering the lymphatic or vasculature systems. We correlate these stable properties to distinct gene expression profiles. Those clones that efficiently enter the vasculature express two secreted proteins, Serpine2 and Slpi, which were necessary and sufficient to program these cells for vascular mimicry. Our data indicate that these proteins not only drive the formation of extravascular networks but also ensure their perfusion by acting as anticoagulants. We propose that vascular mimicry drives the ability of some breast tumour cells to contribute to distant metastases while simultaneously satisfying a critical need of the primary tumour to be fed by the vasculature. Enforced expression of SERPINE2 and SLPI in human breast cancer cell lines also programmed them for vascular mimicry, and SERPINE2 and SLPI were overexpressed preferentially in human patients that had lung-metastatic relapse. Thus, these two secreted proteins, and the phenotype they promote, may be broadly relevant as drivers of metastatic progression in human cancer.
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