The inhibitory effect of hypoxic cytotoxin on the expansion of cancer stem cells in ovarian cancer
The inhibitory effect of hypoxic cytotoxin on the expansion of cancer stem cells in ovarian cancer
复制标题
DOI：
10.1016/j.bbrc.2015.01.053
复制
发表时间：
2015-02-20
影响因子：
3.1
通讯作者：
Morishige, Ken-ichirou
中科院分区：
文献类型：
--
作者：
Nozawa-Suzuki, Noriko;Nagasawa, Hideko;Morishige, Ken-ichirou
虽然当血管生成抑制剂用于治疗高复发率卵巢癌时可以观察到无进展生存时间的增加，但它对总生存期的影响很小。对血管生成抑制剂的治疗抗性的一个可能原因是干细胞在通过血管生成抑制在肿瘤组织内建立的缺氧微环境中生长。本研究探讨了低氧细胞毒素TX-402对干细胞和肿瘤干细胞（CSC）增殖的抑制作用。TX-402是一种具有低氧选择性的前体药物，具有抑制HIF-1和血管生成的作用。我们认为TX-402作为一个可能的分子靶向药物候选人卵巢癌由于其抑制CSC的扩展。在本研究中，我们发现在缺氧条件下，HIF-1 α和HIF-2 α在浆液性卵巢癌细胞系中的表达增加。缺氧诱导的HIF-1 α和HIF-2 α的表达被TX-402以剂量依赖性方式抑制。接下来，我们研究了缺氧对干细胞因子Oct 4、Nanog、Sox 2和Lin 28表达水平的影响，并表明它们的表达是由缺氧诱导的。缺氧诱导了卵巢癌干细胞标志物CD 133和CD 44的表达。此外，TX-402还能剂量依赖性地抑制CSC标志物和干细胞因子的表达。HIF-2 α沉默可抑制Oct 4的表达，而HIF-1 α则不抑制Oct 4的表达，表明TX-402可能通过抑制HIF-2 α来抑制Oct 4的表达。其中内部缺氧区域含有表达Oct 4的CSC样细胞。缺氧可促进表达CD 133和CD 44的CSC扩增，并伴有干细胞因子的增加。其对缺氧诱导的CSC扩增的抑制使得TX-402有希望用于卵巢癌治疗的组合。(C)2015 Elsevier Inc. All rights reserved.
While an increase in progression free survival time is seen when an angiogenesis inhibitor is used in the treatment of high-relapse rate ovarian cancer, it has little effect on overall survival. A possible cause of treatment-resistance to angiogenesis inhibitors is the growth of stem cells in a hypoxic microenvironment built inside the tumor tissue by angiogenesis inhibition. In this study, we examined the possible suppression of stem cell and cancer stem cell (CSC) expansion by hypoxic cytotoxin, TX-402.TX-402, an analogue of tirapazamine, has been developed as a hypoxia selective prodrug with inhibitory effects of HIF-1 and angiogenesis. We considered TX-402 as a possible molecular-target drug candidate for ovarian cancer due to its inhibition of CSC expansion. In this study, we found that the expressions of HIF-1 alpha and HIF-2 alpha were increased under hypoxia in serous ovarian cancer cell lines. The expressions of HIF-1 alpha and HIF-2 alpha induced under hypoxia were repressed by TX-402 in a dose-dependent manner. Next, we investigated the effects of hypoxia on the expression levels of stem cell factors, Oct4, Nanog, Sox2 and Lin28, and showed that their expressions were induced by hypoxia. It was also observed that the expressions of putative ovarian cancer stem cell markers, CD133 and CD44 were induced under hypoxia. Furthermore, TX-402 was found to dose-dependently inhibit the expressions of CSC markers and stem cell factors.Oct4 expression was repressed by HIF-2 alpha silencing, but not by HIF-1 alpha silencing, indicating that TX-402 may repress the expression of Oct4 by inhibiting HIF-2 alpha.We constructed CaOV3 spheroids as a 3-dimensional hypoxia model, in which the internal hypoxic region contained CSC-like cells expressing Oct4. The internal hypoxic region, which contained Oct4 expressing cells, disappeared following TX-402 treatment.In conclusion, hypoxia promoted the expansion of CSCs expressing CD133 and CD44 accompanied by an increase of stem cell factors. Its inhibition of hypoxia-induced CSC expansion makes TX-402 promising agent usable in combination for ovarian cancer therapy. (C) 2015 Elsevier Inc. All rights reserved.