Withaferin A (WFA) inhibits tumor growth and metastasis by targeting ovarian cancer stem cells.
Withaferin A (WFA) inhibits tumor growth and metastasis by targeting ovarian cancer stem cells.
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DOI：
10.18632/oncotarget.20170
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发表时间：
2017-09-26
期刊：
影响因子：
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通讯作者：
Ratajczak MZ
中科院分区：
文献类型：
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作者：
Kakar SS;Parte S;Carter K;Joshua IG;Worth C;Rameshwar P;Ratajczak MZ
卵巢癌是美国女性癌症死亡的第五大原因。 2017年，预计将有22,440名女性被诊断出患有卵巢癌，14,080名女性将死于卵巢癌。目前使用的化疗（顺铂或铂/紫杉烷组合）以癌细胞为目标，但不影响癌症干细胞（CSC），而癌症干细胞是导致肿瘤复发并导致癌症复发的原因。乙醛脱氢酶I（ALDH1）阳性癌症干细胞是卵巢肿瘤的主要群体之一，与肿瘤的进展和转移有关。在我们的研究中，我们观察到 ALDH1 在卵巢表面上皮 (OSE) 和皮质中表达，与交界性 (BL) 和高级别 (HG) 卵巢肿瘤相比，正常卵巢和良性 (BN) 肿瘤中 OSE 的表达水平较高。相反，与正常卵巢和 BN 肿瘤相比，BL 和 HG 肿瘤的皮质中观察到高水平的 ALDH1 表达。与对照组相比，单独使用或与顺铂 (CIS) 联合使用的 Withaferin A (WFA) 可显着抑制体外分离的 ALDH1 CSC 的球状体形成（致瘤潜力），并显着降低其在从患有原位卵巢肿瘤的小鼠收集的肿瘤中的表达。单独用 CIS 治疗动物可显着增加肿瘤中 ALDH1 CSC 的数量，这表明 CIS 靶向癌细胞，但不影响进行扩增的癌症干细胞。 WFA 和 CIS 组合抑制了“癌基因”securin 的表达，表明 securin 可能作为下游信号基因介导 WFA 的抗肿瘤作用。
Ovarian cancer is the fifth leading cause of deaths due to cancer among women in the United States. In 2017, 22,440 women are expected to be diagnosed with ovarian cancer and 14,080 women will die with it. Currently used chemotherapies (Cisplatin or platinum/taxane combination) targets cancer cells, but spares cancer stem cells (CSCs), which are responsible for tumor relapse leading to recurrence of cancer. Aldehyde dehydrogenase I (ALDH1) positive cancer stem cells are one of the major populations in ovarian tumor and have been related to tumor progression and metastasis. In our studies, we observed expression of ALDH1 in both ovarian surface epithelium (OSE) and cortex with high levels of expression in OSE in normal ovary and benign (BN) tumor, compared to borderline (BL) and high grade (HG) ovarian tumors. In contrast, high levels of expression of ALDH1 were observed in cortex in BL and HG tumors compared to normal ovary and BN tumor. Withaferin A (WFA) alone or in combination with cisplatin (CIS) significantly inhibited the spheroid formation (tumorigenic potential) of isolated ALDH1 CSCs in vitro and significantly reduced its expression in tumors collected from mice bearing orthotopic ovarian tumor compared to control. Treatment of animals with CIS alone significantly increased the ALDH1 CSC population in tumors, suggesting that CIS targets cancer cells but spares cancer stem cells, which undergo amplification. WFA and CIS combination suppresses the expression of securin an “oncogene”, suggesting that securin may serve as a downstream signaling gene to mediate the antitumor effects of WFA.
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影响因子：
7.2
作者：
Hirohashi Y;Torigoe T;Inoda S;Morita R;Kochin V;Sato N
通讯作者：
Sato N
影响因子：
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作者：
Dyall S;Gayther SA;Dafou D
通讯作者：
Dafou D
影响因子：
13.5
作者：
Jung, CR;Yoo, J;Iml, DS
通讯作者：
Iml, DS
影响因子：
3.7
作者：
Deng S;Yang X;Lassus H;Liang S;Kaur S;Ye Q;Li C;Wang LP;Roby KF;Orsulic S;Connolly DC;Zhang Y;Montone K;Bützow R;Coukos G;Zhang L
通讯作者：
Zhang L
DOI：
10.1038/modpathol.2009.35
发表时间：
2009-06
期刊：
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
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