Peritoneal Spread of Ovarian Cancer Harbors Therapeutic Vulnerabilities Regulated by FOXM1 and EGFR/ERBB2 Signaling.
Peritoneal Spread of Ovarian Cancer Harbors Therapeutic Vulnerabilities Regulated by FOXM1 and EGFR/ERBB2 Signaling.
复制标题
FOXM1和EGFR/ERBB2信号传导调节的卵巢癌腹膜范围内的治疗脆弱性。
DOI：
10.1158/0008-5472.can-19-3717
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发表时间：
2020-12-15
期刊：
影响因子：
11.2
通讯作者：
Chaluvally-Raghavan P
中科院分区：
文献类型：
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作者：
Parashar D;Nair B;Geethadevi A;George J;Nair A;Tsaih SW;Kadamberi IP;Gopinadhan Nair GK;Lu Y;Ramchandran R;Uyar DS;Rader JS;Ram PT;Mills GB;Pradeep S;Chaluvally-Raghavan P
腹膜扩散是卵巢癌转移的主要机制，并且卵巢癌细胞在腹膜腔中作为非粘附球体存活并粘附到远处器官的间皮导致癌症进展、转移和死亡。然而，卵巢癌细胞中控制这种转移过程的机制仍然知之甚少。在这项研究中，我们培养的卵巢癌细胞系在贴壁（AD）和非贴壁（NAD）的条件下，在体外和分析mRNA和蛋白质水平的变化，以确定肿瘤细胞的生存和增殖的机制，在AD和NAD细胞。EGFR或ERBB 2上调NAD细胞中的ZEB 1，这引起对细胞死亡的抵抗并增加肿瘤起始能力。相反，叉头盒M1（FOXM 1）是诱导整合素β 1（ITGB 1）、整合素-α V（ITGAV）和整合素-α 5（ITGA 5）粘附癌细胞所必需的。FOXM 1还上调ZEB 1，ZEB 1可作为FOXM 1的反馈抑制剂，引起AD细胞向NAD细胞的转变。引人注目的是，拉帕替尼（EGFR（ERBB 1）和ERBB 2的双重激酶抑制剂）和硫丝菌素（FOXM 1抑制剂）的组合治疗比体内单一药物治疗更有效地减少卵巢癌细胞的生长和腹膜扩散。总之，这些结果表明，FOXM 1和EGFR/ERBB 2途径是治疗卵巢癌细胞破坏腹膜扩散和粘附的关键点。
Peritoneal spread is the primary mechanism of metastasis of ovarian cancer, and survival of ovarian cancer cells in the peritoneal cavity as non-adherent spheroids and their adherence to the mesothelium of distant organs lead to cancer progression, metastasis and mortality. However, the mechanisms that govern this metastatic process in ovarian cancer cells remain poorly understood. In this study, we cultured ovarian cancer cell lines in adherent (AD) and in non-adherent (NAD) conditions in vitro and analyzed changes in mRNA and protein levels to identify mechanisms of tumor cell survival and proliferation in AD and NAD cells. EGFR or ERBB2 upregulated ZEB1 in NAD cells, which caused resistance to cell death and increased tumor-initiating capacity. Conversely, Forkhead box M1 (FOXM1) was required for the induction of Integrin Beta 1 (ITGB1), Integrin-α V (ITGAV), and Integrin-α 5 (ITGA5) for adhesion of cancer cells. FOXM1 also upregulated ZEB1, which could act as a feedback inhibitor of FOXM1 and caused the transition of AD cells to NAD cells. Strikingly, the combinatorial treatment with Lapatinib (dual kinase inhibitor of EGFR (ERBB1) and ERBB2) and Thiostrepton (FOXM1 inhibitor) reduced growth and peritoneal spread of ovarian cancer cells more effectively than either single agent treatment in vivo. In conclusion, these results demonstrate that FOXM1 and EGFR/ERBB2 pathways are key points of vulnerability for therapy to disrupt peritoneal spread and adhesion of ovarian cancer cells.