CD133+ tumor initiating cells in a syngenic murine model of pancreatic cancer respond to Minnelide.
CD133+ tumor initiating cells in a syngenic murine model of pancreatic cancer respond to Minnelide.
复制标题
CD133+肿瘤在胰腺癌的合成鼠模型中启动细胞对Minnelide有反应。
DOI：
10.1158/1078-0432.ccr-13-2947
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发表时间：
2014-05-01
期刊：
影响因子：
--
通讯作者：
Saluja A
中科院分区：
文献类型：
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作者：
Banerjee S;Nomura A;Sangwan V;Chugh R;Dudeja V;Vickers SM;Saluja A
胰腺癌是癌症相关死亡率的第四大原因，生存率低于5%。晚期诊断和缺乏有效的化疗方案有助于这些严峻的生存统计。任何肿瘤的复发在很大程度上归因于肿瘤起始细胞（TIC）或癌症干细胞（CSC）的存在。这些细胞被认为是癌症治疗的障碍，因为没有已知的化疗化合物被报道靶向它们。因此，迫切需要开发针对胰腺癌的TIC靶向疗法。我们从自发性PDAC小鼠模型中分离出CD 133+细胞，并研究了胰腺TIC的表面表达和分子标志物。我们还通过在免疫活性小鼠中植入少量CD 133+细胞研究了肿瘤起始特性。研究了目前正在进行I期临床试验的药物Minnelide对CD 133+细胞来源的肿瘤的作用。我们的研究首次表明，CD 133+群体展示了胰腺TIC的所有分子标志物。这些细胞在免疫活性小鼠模型中引发肿瘤，与CD 133-non-TIC群体相比，这些细胞显示出促生存和促侵袭蛋白的表达增加。我们的研究进一步表明，Minnelide在下调肿瘤中的CD 133 −和CD 133+群体方面非常有效，与未经治疗的肿瘤相比，肿瘤体积减少了60%。由于Minnelide目前正在进行I期临床试验，其通过降低TIC以及非TIC人群来降低肿瘤负荷的评价表明其作为有效治疗的潜力。
Pancreatic adenocarcinoma is the fourth leading cause for cancer-related mortality with a survival rate of less than 5%. Late diagnosis and lack of effective chemotherapeutic regimen contribute to these grim survival statistics. Relapse of any tumor is largely attributed to the presence of tumor-initiating cells (TIC) or cancer stem cells (CSC). These cells are considered as hurdles to cancer therapy as no known chemotherapeutic compound is reported to target them. Thus, there is an urgent need to develop a TIC-targeted therapy for pancreatic cancer. We isolated CD133+ cells from a spontaneous PDAC mouse model and studied both surface expression, molecular markers of pancreatic TICs. We also studied tumor initiation properties by implanting low numbers of CD133+ cells in immune competent mice. Effect of Minnelide, a drug currently under Phase I clinical trial, was studied on the tumors derived from the CD133+ cells. Our study showed for the first time that CD133+ population demonstrated all the molecular markers for pancreatic TIC. These cells initiated tumors in immunocompetent mouse models and showed increased expression of pro-survival and pro-invasive proteins compared to the CD133− non-TIC population. Our study further showed that Minnelide, was very efficient in downregulating both CD133− and CD133+ population in the tumors, resulting in a 60% decrease in tumor volume compared to the untreated ones. As Minnelide is currently under Phase I clinical trial, its evaluation in reducing tumor burden by decreasing TIC as well as non-TIC population suggests its potential as an effective therapy.