Chemotherapeutic Stress Induces Transdifferentiation of Glioblastoma Cells to Endothelial Cells and Promotes Vascular Mimicry
Chemotherapeutic Stress Induces Transdifferentiation of Glioblastoma Cells to Endothelial Cells and Promotes Vascular Mimicry
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DOI：
10.1155/2019/6107456
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发表时间：
2019-06-18
影响因子：
4.3
通讯作者：
Ahmed, Atique U.
中科院分区：
文献类型：
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作者：
Baisiwala, Shivani;Auffinger, Brenda;Ahmed, Atique U.
胶质母细胞瘤（GBM）是影响成人的最常见和侵袭性的原发性恶性脑肿瘤，中位生存期约为21个月。当前治疗方式有限疗效的一个关键因素是GBM细胞表现出的显著可塑性，这使它们能够有效地适应抗癌治疗引起的变化。此外，GBM肿瘤是高度血管化的，异常血管使抗肿瘤药物的递送复杂化。最近的研究表明，GBM细胞具有转分化为内皮细胞（ECs）的能力，表明GBM细胞可能在血管化过程中使用可塑性，从而导致肿瘤源性血管的产生。然而，这种转分化背后的机制尚不清楚。在这里，我们发现替莫唑胺（TMZ）化疗诱导胶质瘤干细胞（GSCs）和未成熟和成熟的内皮细胞标志物的时间依赖性表达。此外，裸鼠原位异种移植物生长的GBM肿瘤在TMZ处理后，GSC和EC标记物的表达增加。体外FACS分析显示存在未成熟和成熟的EC群体。此外，免疫荧光分析显示tmz复发肿瘤中肿瘤源性血管增加。总体而言，本研究确定化疗应激是肿瘤细胞向内皮细胞转分化的新驱动因素，并强调细胞可塑性是治疗抵抗和肿瘤复发的关键因素。
Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor affecting adults, with a median survival of approximately 21 months. One key factor underlying the limited efficacy of current treatment modalities is the remarkable plasticity exhibited by GBM cells, which allows them to effectively adapt to changes induced by anticancer therapeutics. Moreover, GBM tumors are highly vascularized with aberrant vessels that complicate the delivery of antitumor agents. Recent research has demonstrated that GBM cells have the ability to transdifferentiate into endothelial cells (ECs), illustrating that GBM cells may use plasticity in concert with vascularization leading to the creation of tumor-derived blood vessels. The mechanism behind this transdifferentiation, however, remains unclear. Here, we show that treatment with temozolomide (TMZ) chemotherapy induces time-dependent expression of markers for glioma stem cells (GSCs) and immature and mature ECs. In addition, GBM tumors growing as orthotopic xenografts in nude mice showed increased expression of GSC and EC markers after TMZ treatment. Ex vivo FACS analysis showed the presence of immature and mature EC populations. Furthermore, immunofluorescence analysis revealed increased tumor-derived vessels in TMZ-recurrent tumors. Overall, this study identifies chemotherapeutic stress as a new driver of transdifferentiation of tumor cells to endothelial cells and highlights cellular plasticity as a key player in therapeutic resistance and tumor recurrence.