Pancreatic cancer stem cells in patient pancreatic xenografts are sensitive to drozitumab, an agonistic antibody against DR5.
Pancreatic cancer stem cells in patient pancreatic xenografts are sensitive to drozitumab, an agonistic antibody against DR5.
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DOI：
10.1186/s40425-016-0136-y
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发表时间：
2016
影响因子：
10.9
通讯作者：
Hylander BL
中科院分区：
文献类型：
--
作者：
Eng JW;Mace TA;Sharma R;Twum DYF;Peng P;Gibbs JF;Pitoniak R;Reed CB;Abrams SI;Repasky EA;Hylander BL
胰腺导管腺癌的耐药和肿瘤复发是其治疗的两大障碍。最近的研究结果表明，这两个属性都与胰腺肿瘤起始癌症干细胞（CSC）的一个小子集有关。在这里，我们证明了drozitumab，一种结合死亡受体DR 5的人激动性单克隆抗体，选择性地消除CSC，导致肿瘤生长抑制甚至胰腺肿瘤消退。为了检查drozitumab对胰腺CSC的功效，我们在免疫受损的SCID小鼠中处理患者来源的胰腺肿瘤异种移植物（PDX）并评估肿瘤控制。为了评估drozitumab治疗后的细胞凋亡，我们通过FACS分析将CSC鉴定为CD 24+、CD 44+和EpCAM+，并测量体内和体外切割的胱天蛋白酶-3水平。最后，使用分离的患者胰腺癌异种移植细胞沿着细胞系Panc-1进行DR 5再表达的体外评价。在用drozitumab处理后，在处理后8、24和48小时通过FACS分析评估剩余的DR 5-细胞在细胞表面的DR 5表达。通过双向Anova分析所有体内生长数据，使用Mantel-Cox分析发生率数据，并使用t检验进行体外研究统计。我们发现，虽然75- 100%的CSC表达DR 5，但在任何一个时间，只有25%的大部分肿瘤细胞表达死亡受体。因此，携带PDX的SCID小鼠的drozitumab治疗杀死的CSC百分比高于大量肿瘤细胞。此外，植入分离的CSC然后立即用drozitumab治疗的SCID小鼠从未发生肿瘤。体外研究表明，虽然drozitumab治疗减少了DR 5+细胞群，但剩余的肿瘤细胞开始表达DR 5，这表明了drozitumab连续给药最终导致肿瘤消退的机制，尽管最初DR 5+细胞的百分比较低。总的来说，我们的工作表明，用drozitumab治疗胰腺肿瘤可以通过靶向散装细胞和CSC来实现长期的肿瘤控制。本文的在线版本（doi：10.1186/s40425-016-0136-y）包含补充材料，可供授权用户使用。
Therapeutic resistance and tumor recurrence are two major hurdles in the treatment of pancreatic ductal adenocarcinoma. Recent findings suggest that both of these attributes are associated with a small subset of pancreatic tumor initiating cancer stem cells (CSCs). Here, we demonstrate that drozitumab, a human agonistic monoclonal antibody which binds the death receptor DR5, selectively eliminates CSCs, resulting in tumor growth inhibition and even regression of pancreatic tumors. To examine the efficacy of drozitumab against pancreatic CSCs, we treated patient-derived pancreatic tumor xenografts (PDX) in immunocompromised SCID mice and evaluated tumor control. To assess apoptosis following drozitumab treatment, we identified the CSCs as CD24+, CD44+, and EpCAM+ by FACS analysis, and measured in vivo and in vitro levels of cleaved caspase-3. Lastly, in vitro evaluation of DR5 re-expression was performed using isolated patient pancreatic cancer xenograft cells along with the cell line, Panc-1. After treatment with drozitumab, the remaining DR5- cells were assessed by FACS analysis for DR5 expression at the cell surface at 8, 24 and 48 h post-treatment. All in vivo growth data was analyzed by 2-way Anova, incidence data was analyzed using Mantel-Cox, and in vitro studies statistics were performed with a t-test. We find that while 75–100 % of CSCs express DR5, only 25 % of bulk tumor cells express the death receptors at any one time. Consequently, drozitumab treatment of SCID mice bearing PDX kills higher percentages of CSCs than bulk tumor cells. Additionally, SCID mice implanted with isolated CSCs and then immediately treated with drozitumab fail to ever develop tumors. In vitro studies demonstrate that while drozitumab treatment reduces the DR5+ cell population, the remaining tumor cells begin to express DR5, suggesting a mechanism by which continuous administration of drozitumab can ultimately result in tumor regression despite the initially low percentage of DR5+ cells. Overall, our work reveals that treatment of pancreatic tumors with the drozitumab can lead to long-term tumor control by targeting both bulk cells and CSCs. The online version of this article (doi:10.1186/s40425-016-0136-y) contains supplementary material, which is available to authorized users.