Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors
Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors
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DOI：
10.1158/0008-5472.can-06-4238
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发表时间：
2007-04-15
期刊：
影响因子：
11.2
通讯作者：
Kerbel, Robert S.
中科院分区：
文献类型：
--
作者：
Folkins, Chris;Man, Shan;Kerbel, Robert S.
血管内皮细胞已被确定为神经干细胞生态位的关键组成部分，这提高了脑肿瘤干细胞样细胞（TSLC）也可能依赖于与附近肿瘤血管的信号相互作用来维持其干细胞样状态的可能性。通过抗血管生成治疗破坏这种TSLC血管生态位可能导致与内在耐药性相关的严重度特征的丧失，从而优先使TSLC对化疗的影响敏感。考虑到这些可能性，我们研究了抗血管生成抗癌治疗对胶质瘤TSLC部分的影响。携带C6大鼠胶质瘤细胞系的s.c.肿瘤异种移植的胸腺裸鼠分别接受靶向抗血管生成药物、低剂量节律化疗的抗血管生成方案、抗血管生成药物和化疗的联合治疗，或者为了进行比较，采用常规的细胞毒性方案，即使用环磷酰胺的最大耐受剂量化疗。靶向抗血管生成治疗或细胞毒性化疗并没有降低肿瘤中肿瘤球形成单位（S]，U）的比例，而所有联合抗血管生成和细胞毒性药物作用的治疗组均可显著降低SFU。这项工作强调了选择性根除TSLC的可能性，可以通过靶向肿瘤微环境（以及潜在的支持性TSLC生态位）而不是直接靶向TSLC来实现。此外，本研究提示抗血管生成疗法可能具有新的作用，即作为TSLC的化疗增敏剂，从而代表了一种可能的新机制来解释抗血管生成疗法提高化疗疗效的能力。
Vascular endothelial cells have been identified as a critical component of the neural stem cell niche, raising the possibility that brain tumor stem-like cells (TSLC) may also rely on signaling interactions with nearby tumor vasculature to maintain their stem-like state. The disruption of such a TSLC vascular niche by an antiangiogenic therapy could result in loss of sternness characteristics associated with intrinsic drug resistance and, thus, preferentially sensitize TSLC to the effects of chemotherapy. Considering these possibilities, we investigated the impact of antiangiogenic anticancer therapy on the TSLC fraction of glioma tumors. Athymic nude mice bearing s.c. tumor xenografts of the C6 rat glioma cell line were treated with either a targeted antiangiogenic agent, antiangiogenic schedules of low-dose metronomic chemotherapy, combination therapies of antiangiogenic agents and chemotherapy, or, for the purpose of comparison, a conventional cytotoxic schedule of maximum tolerated dose chemotherapy using cyclophosphamide, Targeted antiangiogenic therapy or cytotoxic chemotherapy did not reduce the fraction of tumor sphere-forming units (S],U) in the tumor, whereas all treatment groups that combined both antiangiogenic and cytotoxic drug effects caused a significant reduction in SFU. This work highlights the possibility that selective eradication of TSLC may be achieved by targeting the tumor microenvironment (and potentially a supportive TSLC niche) rather than the TSLC directly. Furthermore, this work suggests a possible novel effect of antiangiogenic therapy, namely, as a chemosensitizer of TSLC, and thus represents a possible new mechanism to explain the ability of antiangitigenic therapy to enhance the efficacy of chemotherapy.