Platelet-derived growth factor receptor-α and -β promote cancer stem cell phenotypes in sarcomas.
Platelet-derived growth factor receptor-α and -β promote cancer stem cell phenotypes in sarcomas.
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DOI：
10.1038/s41389-018-0059-1
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发表时间：
2018-06-19
期刊：
影响因子：
6.2
通讯作者：
Yoon SS
中科院分区：
文献类型：
--
作者：
Chang KK;Yoon C;Yi BC;Tap WD;Simon MC;Yoon SS
肉瘤是来源于间充质组织的恶性肿瘤，并且可能含有具有癌症干细胞样细胞（CSC）特性的细胞亚群。血小板源性生长因子受体α和β（PDGFR-α/β）在间充质干细胞的维持中起重要作用。在这里，我们研究了PDGFR-α/β在肉瘤CSC中的作用。使用体外试验和小鼠异种移植模型在3种人肉瘤细胞系中检查PDGFR-α/β活性和PDGFR-α/β抑制的作用。在所有三种细胞系中，PDGFR-α/β活性在生长为球状体（以富集CSC）的细胞和针对CD 133表达（肉瘤CSC的标志物）分选的细胞中显著更高。自我更新转录因子Nanog、Oct 4和Slug以及上皮-间质转化（EMT）蛋白Snail、Slug和Zeb 1在球状体细胞和CD 133（+）细胞中也显著较高。球形细胞和CD 133（+）细胞表现出2.9至4.2倍的迁移和侵袭能力，并对阿霉素化疗产生耐药性。使用shRNA或药理学抑制剂抑制CSC中的PDGFR-α/β可降低某些自我更新和EMT蛋白的表达，使球状体形成减少74- 82%，使迁移和侵袭减少73- 80%，并逆转化疗耐药性。在小鼠异种移植模型中，PDGFR-α/β抑制（使用shRNA或伊马替尼）与多柔比星联合使用在阻断肿瘤生长方面具有超过累加的效果，并增强了细胞凋亡，特别是在CD 133（+）细胞中。这些结果表明，PDGFR-α/β活性在肉瘤CSC中上调，并促进CSC表型，包括迁移、侵袭和化疗抗性。因此，PDGFR-α/β通路代表了降低转移潜能和增加化疗敏感性的新的潜在治疗靶点。
Sarcomas are malignant tumors derived from mesenchymal tissues and may harbor a subset of cells with cancer stem-like cell (CSC) properties. Platelet-derived growth factor receptors α and β (PDGFR-α/β) play an important role in the maintenance of mesenchymal stem cells. Here we examine the role of PDGFR-α/β in sarcoma CSCs. PDGFR-α/β activity and the effects of PDGFR-α/β inhibition were examined in 3 human sarcoma cell lines using in vitro assays and mouse xenograft models. In all three cell lines, PDGFR-α/β activity was significantly higher in cells grown as spheroids (to enrich for CSCs) and in cells sorted for CD133 expression (a marker of sarcoma CSCs). Self-renewal transcription factors Nanog, Oct4, and Slug and epithelial-to-mesenchymal transition (EMT) proteins Snail, Slug, and Zeb1 were also significantly higher in spheroids cells and CD133(+) cells. Spheroid cells and CD133(+) cells demonstrated 2.9- to 4.2-fold greater migration and invasion and resistance to doxorubicin chemotherapy. Inhibition of PDGFR-α/β in CSCs using shRNA or pharmacologic inhibitors reduced expression of certain self-renewal and EMT proteins, reduced spheroid formation by 74–82%, reduced migration and invasion by 73–80%, and reversed chemotherapy resistance. In mouse xenograft models, combining PDGFR-α/β inhibition (using shRNA or imatinib) with doxorubicin had a more-than-additive effect in blocking tumor growth, with enhanced apoptosis, especially in CD133(+) cells. These results indicate that PDGFR-α/β activity is upregulated in sarcoma CSCs and promote CSC phenotypes including migration, invasion, and chemotherapy resistance. Thus, the PDGFR-α/β pathway represents a new potential therapeutic target to reduce metastatic potential and increase chemosensitivity.
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DOI：
10.1097/pai.0b013e3181b77451
发表时间：
2010-03-01
影响因子：
1.6
作者：
Terry, Jefferson;Nielsen, Torsten
通讯作者：
Nielsen, Torsten
影响因子：
3.6
作者：
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通讯作者：
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影响因子：
3.6
作者：
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通讯作者：
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影响因子：
5.2
作者：
Fujii, Hiromasa;Honoki, Kanya;Takakura, Yoshinori
通讯作者：
Takakura, Yoshinori
影响因子：
254.7
作者：
Siegel, Rebecca;Ma, Jiemin;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin