Purpose

Signaling by cancer stem cells (CSCs) is known to occur at least in part through conserved developmental pathways. Here, the role of one of these pathways, i.e., the hedgehog pathway, was evaluated in high-grade serous ovarian carcinoma (HGSOC).

Methods and results

We found that in HGSOC, hedgehog inhibitors (HHIs) GANT61, LDE225 and GDC0449 reduced or inhibited the formation of spheroids enriched in CSCs. Primary malignant cells (PMCs) in ascites from HGSOC patients cultured in the presence of HHIs showed significant reduction in CSCs. Sonic hedgehog (SHH) significantly increased the expression of ALDH1A1, which was inhibited by GANT61. In the presence of a SHH neutralizing antibody (5E1), a significant reduction in the number of spheroids was observed in HGSOC-derived cell lines. Further, the motility, migration and clonogenic growth of the cells were significantly reduced by HHIs. In the presence of GANT61, a reduction of cells from PMCs in the G0 phase of the cell cycle was observed. The magnitude of difference in expression of Gli1 in tumors from the same HGSOC patients at presentation and at interval debulking surgery was greater in patients who had a recurrence on follow up. GANT61 also significantly inhibited the growth of CSCs in nude mice. Finally, RNA sequencing of HGSOC cells treated with GANT61 showed a significantly reduced expression of CSC markers.

Conclusions

Our results indicate that the hedgehog pathway plays an important role in maintaining the integrity of CSCs in HGSOC and could be a potential therapeutic target.

中文翻译：

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刺猬通路调节卵巢浆液性腺癌中的癌症干细胞。

目的

已知癌干细胞（CSC）发出的信号至少部分通过保守的发育途径发生。在此，评估了这些途径之一（即刺猬途径）在高级浆液性卵巢癌（HGSOC）中的作用。

方法与结果

我们发现在HGSOC中，刺猬抑制剂（HHI）GANT61，LDE225和GDC0449减少或抑制了富含CSC的球体的形成。在HHI存在下培养的HGSOC患者腹水中的原发性恶性细胞（PMC）显示CSC显着降低。声波刺猬（SHH）显着增加了ALDH1A1的表达，这被GANT61抑制。在SHH中和抗体（5E1）的存在下，在HGSOC衍生的细胞系中观察到球状体数量的显着减少。此外，HHIs显着降低了细胞的运动性，迁移和克隆形成生长。在存在GANT61的情况下，观察到细胞周期G0期PMC中的细胞减少。Gli1表达差异的大小随访时复发的同一HGSOC患者在肿瘤表现及间隔期间进行减瘤手术的比例更高。GANT61还显着抑制裸鼠中CSC的生长。最后，用GANT61处理的HGSOC细胞的RNA测序显示CSC标记的表达显着降低。

结论

我们的结果表明，刺猬通路在维持HGSOC中CSC的完整性方面起着重要作用，并且可能成为潜在的治疗靶点。