Synovial Sarcoma Is a Stem Cell Malignancy
Synovial Sarcoma Is a Stem Cell Malignancy
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DOI：
10.1002/stem.452
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发表时间：
2010-07-01
期刊：
影响因子：
5.2
通讯作者：
Itoh, Kazuyuki
中科院分区：
文献类型：
--
作者：
Naka, Norifumi;Takenaka, Satoshi;Itoh, Kazuyuki
滑膜肉瘤（Synovial sarcoma，SS）是一种以t（X;18）（p11;q11）染色体易位导致SS 18-SSX融合基因形成为特征的恶性软组织肿瘤。所得到的融合蛋白产物被认为是作为异常转录因子发挥作用，并通过干扰靶细胞的基因表达程序来转化靶细胞。然而，SS的细胞起源是高度争议的。我们建立了两种新的人SS细胞系Yamato-SS和Aska-SS，并研究了它们的生物学特性。我们发现这些细胞的自我更新能力，以产生肉瘤球，形成肿瘤在系列异种移植和重建肿瘤表型没有任何表面标志物的分级。SS细胞以及来自15名患者的临床组织标本均表达标记基因相关干细胞身份Oct 3/4、Nanog和Sox 2。我们还发现，这两个SS细胞显示有限的分化潜力，间充质谱系成骨细胞和软骨细胞，尽管与早期间充质和造血谱系基因的表达。在用序列特异性siRNA沉默SS 18-SSX后，这些SS细胞表现出从悬浮液中的球形生长到单层中的贴壁生长的形态学转变，后期间充质和造血谱系基因的额外表达，以及在适当的分化混合物中向骨细胞、软骨细胞、脂肪细胞和巨噬细胞的更广泛的分化潜力。总的来说，这些数据表明，人多能间充质干细胞可以作为SS的起源细胞，并且SS是由SS 18-SSX融合蛋白驱动的自我更新和分化能力失调引起的干细胞恶性肿瘤。干细胞2010：28：1119-1131
Synovial sarcoma (SS) is a malignant soft tissue tumor characterized by its unique t(X;18)(p11;q11) chromosomal translocation leading to the formation of the SS18-SSX fusion gene. The resulting fusion protein product is considered to play as an aberrant transcription factor and transform target cells by perturbing their gene expression program. However, the cellular origin of SS is highly debated. We herein established two novel human SS cell lines, named Yamato-SS and Aska-SS, and investigated their biological properties. We found the self-renewal ability of these cells to generate sarcospheres, to form tumors in serial xenotransplantation and reconstitute the tumor phenotypes without fractionation by any surface markers. Both SS cells as well as clinical tissue specimens from 15 patients expressed the marker genes-associated stem cell identity, Oct3/4, Nanog, and Sox2. We also found that both SS cells displayed limited differentiation potentials for mesenchymal lineages into osteocytes and chondrocytes albeit with the expression of early mesenchymal and hematopoietic lineage genes. Upon SS18-SSX silencing with sequence-specific siRNAs, these SS cells exhibited morphological transition from spherical growth in suspension to adherent growth in monolayer, additional expression of later mesenchymal and hematopoietic lineage genes, and broader differentiation potentials into osteocytes, chondrocytes, adipocytes, and macrophages in appropriate differentiation cocktails. Collectively, these data suggest that a human multipotent mesenchymal stem cell can serve as a cell of origin for SS and SS is a stem cell malignancy resulting from dysregulation of self-renewal and differentiation capacities driven by SS18-SSX fusion protein. STEM CELLS 2010:28:1119-1131