TLR2 enhances ovarian cancer stem cell self-renewal and promotes tumor repair and recurrence
TLR2 enhances ovarian cancer stem cell self-renewal and promotes tumor repair and recurrence
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DOI：
10.4161/cc.23406
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发表时间：
2013-02-01
期刊：
影响因子：
4.3
通讯作者：
Mor, Gil
中科院分区：
文献类型：
--
作者：
Chefetz, Ilana;Alvero, Ayesha B.;Mor, Gil
原发性卵巢癌对治疗有反应，但大多数患者会出现化疗耐药的复发性疾病。最近令人信服的证据表明，特定的癌细胞群，即癌症干细胞，会引发并维持肿瘤。因此，该细胞群也可能是复发的原因。我们之前已经证明 CD44+/MyD88+ 上皮性卵巢癌干细胞（CD44+/MyD88+ EOC 干细胞）负责肿瘤的发生。在这项研究中，我们证明该人群在手术和化疗引起的肿瘤损伤后驱动肿瘤修复。使用体内和体外模型，我们还证明在肿瘤修复过程中，CD44+/MyD88+ EOC 干细胞会进行自我更新，干性相关基因的上调证明了这一点。更重要的是，我们发现 TLR2-MyD88-NF kappa B 通路创建的促炎微环境支持 EOC 干细胞驱动的修复和自我更新。总体而言，我们的研究结果表明，特定的癌细胞群 CD44+/MyD88+ EOC 干细胞和特定的促炎途径 TLR2-MyD88-NF kappa B 途径是促进肿瘤修复所需的两个参与者，而肿瘤修复与癌症干细胞负荷的增强有关。确定这些关键参与者是阐明预防 EOC 患者复发所需步骤的第一步。
Primary ovarian cancer is responsive to treatment, but chemoresistant recurrent disease ensues in majority of patients. Recent compelling evidence demonstrates that a specific population of cancer cells, the cancer stem cells, initiates and sustains tumors. It is therefore possible that this cell population is also responsible for recurrence. We have shown previously that CD44+/MyD88+ epithelial ovarian cancer stem cells (CD44+/MyD88+ EOC stem cells) are responsible for tumor initiation. In this study, we demonstrate that this population drives tumor repair following surgery- and chemotherapy-induced tumor injury. Using in vivo and in vitro models, we also demonstrate that during the process of tumor repair, CD44+/MyD88+ EOC stem cells undergo self-renewal as evidenced by upregulation of stemness-associated genes. More importantly, we show that a pro-inflammatory microenvironment created by the TLR2-MyD88-NF kappa B pathway supports EOC stem cell-driven repair and self-renewal. Overall, our findings point to a specific cancer cell population, the CD44+/MyD88+ EOC stem cells and a specific pro-inflammatory pathway, the TLR2-MyD88-NF kappa B pathway, as two of the required players promoting tumor repair, which is associated with enhanced cancer stem cell load. Identification of these key players is the first step in elucidating the steps necessary to prevent recurrence in EOC patients.