Differential regulation of the sphere formation and maintenance of cancer-initiating cells of malignant mesothelioma via CD44 and ALK4 signaling pathways.
Differential regulation of the sphere formation and maintenance of cancer-initiating cells of malignant mesothelioma via CD44 and ALK4 signaling pathways.
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DOI：
10.1038/s41388-018-0405-y
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发表时间：
2018-12
期刊：
影响因子：
8
通讯作者：
Tanaka T
中科院分区：
文献类型：
--
作者：
Ohno Y;Shingyoku S;Miyake S;Tanaka A;Fudesaka S;Shimizu Y;Yoshifuji A;Yamawaki Y;Yoshida S;Tanaka S;Sakura K;Tanaka T
恶性间皮瘤（Malignant mesothelioma， MM）预后差，且对标准治疗有很大的耐药性，因此寻求新的治疗策略是很重要的。癌症启动细胞（CICs）先前在MM中使用干细胞相关标记物与球体培养物结合鉴定。然而，在MM中诱导和维持CICs的机制仍有待充分探索。在这里，我们发现具有高醛脱氢酶（ALDHbright）水平和干细胞相关基因的CICs在球形条件下培养的MM细胞中扩增。在免疫缺陷小鼠中，MM球体也比传统的贴壁MM细胞更有效地引发肿瘤。在MM球体中，透明质酸（HA）合成酶的表达上调。通过基因敲低或中和抗体抑制HA合成或CD44功能，可消除大球体的形成和ALDHbright CICs的扩增。激活素- a在球体中的表达也增加，激活素- a受体I型亚基（ALK4）在ALDHbright CICs中表达上调。激活素- a的中和或ALK4的功能失活降低了ALDHbright CICs，但不影响球体的形成。CD44或ALK4的敲低能明显抑制免疫缺陷小鼠的肿瘤生长。这些结果共同提示HA-CD44和激活素- a - alk4通路对MM细胞中ALDHbright CICs的球形形成和维持有不同的调节作用，这两种通路在免疫缺陷宿主的肿瘤生长中都起着关键作用。我们的研究结果为MM提供了一种新的治疗选择，即靶向通过CD44和ALK4促进CIC室的信号通路。
Malignant mesothelioma (MM) has a poor prognosis and is largely resistant to standard treatments, so it is important to seek novel therapeutic strategies for this disease. Cancer-initiating cells (CICs) were previously identified in MM using stem cell-associated markers in combination with spheroid cultures. However, the mechanisms underlying the induction and maintenance of CICs in MM remain to be fully explored. Here we showed that the CICs, which had high aldehyde dehydrogenase levels (ALDHbright) and stem cell-associated genes, were expanded in MM cells cultured under sphere-forming conditions. The MM spheroids also initiated tumors in immunodeficient mice more efficiently than did conventional adherent MM cells. In the MM spheroids, the expression of hyaluronan (HA) synthases was upregulated. Inhibiting the HA synthesis or CD44 functions by gene knockdown or neutralizing antibody abolished the formation of large-sized spheroids and the expansion of ALDHbright CICs. The expression of activin-A was also increased in the spheroids, and type I activin-A receptor subunit (ALK4) was upregulated in the ALDHbright CICs. The neutralization of activin-A or functional inactivation of ALK4 diminished the ALDHbright CICs without affecting spheroid formation. The knockdown of CD44 or ALK4 strongly suppressed the tumor growth in immunodeficient mice. These results together suggest that the HA–CD44 and activin-A–ALK4 pathways differentially regulate the spheroid formation and maintenance of ALDHbright CICs in MM cells, and that both pathways play critical roles in tumor growth in immunodeficient hosts. Our findings provide a novel therapeutic option for MM that targets signaling pathways that promote the CIC compartment through CD44 and ALK4.
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影响因子：
5.8
作者：
Cortes-Dericks L;Schmid RA
通讯作者：
Schmid RA
影响因子：
21.3
作者：
Lin KC;Moroishi T;Meng Z;Jeong HS;Plouffe SW;Sekido Y;Han J;Park HW;Guan KL
通讯作者：
Guan KL
影响因子：
5.2
作者：
Loomans HA;Andl CD
通讯作者：
Andl CD
影响因子：
8.4
作者：
Hoda, Mir Alireza;Dong, Yawen;Hegedus, Balazs
通讯作者：
Hegedus, Balazs
影响因子：
8
作者：
Tajima, K.;Ohashi, R.;Takahashi, K.
通讯作者：
Takahashi, K.