Antibody against CD44s inhibits pancreatic tumor initiation and postradiation recurrence in mice.
Antibody against CD44s inhibits pancreatic tumor initiation and postradiation recurrence in mice.
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DOI：
10.1053/j.gastro.2013.12.035
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发表时间：
2014-04
期刊：
影响因子：
29.4
通讯作者：
Xu L
中科院分区：
文献类型：
--
作者：
Li L;Hao X;Qin J;Tang W;He F;Smith A;Zhang M;Simeone DM;Qiao XT;Chen ZN;Lawrence TS;Xu L
CD 44 s是肿瘤起始细胞（TIC）的表面标志物;高肿瘤水平与转移和复发以及患者的不良结局相关。抗CD 44的单克隆抗体可能以最小的毒性消除TIC。这种策略对于胰腺癌的治疗尚不清楚，关于抗CD 44如何影响胰腺癌的发生或放射治疗后的复发也知之甚少。从接受手术的患者中收集192对人胰腺癌和邻近的非肿瘤胰腺组织。我们通过免疫组化、实时PCR和免疫印迹法测量了组织样本和胰腺癌细胞系中的CD 44水平; CD 44水平与患者的生存时间相关。我们研究了抗CD 44在人胰腺肿瘤异种移植小鼠中的作用，并使用流式细胞术测定对TIC的作用。通过实时PCR、免疫印迹、报告基因测定和体外肿瘤球形成测定来检查CD 44 s信号传导的变化。胰腺癌组织中CD 44 s的表达水平明显高于癌旁组织。肿瘤表达高水平CD 44的患者的中位生存期为10个月，而低水平的患者为43个月。抗-CD 44 s减少小鼠胰腺异种移植肿瘤的生长、转移和放射后复发。该抗体减少了培养的胰腺癌细胞和异种移植肿瘤中TIC的数量，以及它们的致瘤性。在培养的胰腺癌细胞系中，抗CD 44下调干细胞自我更新基因Nanog、Sox-2和雷克斯-1，并抑制STAT 3介导的细胞增殖和存活信号。TIC标志物CD 44 s在人胰腺肿瘤中上调，并与患者生存时间相关。CD 44 s是小鼠异种移植肿瘤发生、生长、转移和放射后复发所必需的。抗CD 44从肿瘤中消除了大量肿瘤细胞以及TIC。靶向CD 44的策略可能会被开发出来，以阻断胰腺肿瘤的形成和患者放疗后的复发。
CD44s is a surface marker of tumor-initiating cells (TICs); high tumor levels correlate with metastasis and recurrence, as well as poor outcomes of patients. Monoclonal antibodies against CD44s might eliminate TICs with minimal toxicity. This strategy is unclear for treatment of pancreatic cancer, and little is known about how anti-CD44s affect pancreatic cancer initiation or recurrence after radiotherapy. 192 pairs of human pancreatic adenocarcinoma and adjacent non-tumor pancreatic tissues were collected from patients undergoing surgery. We measured CD44s levels in tissue samples and pancreatic cancer cell lines by immunohistochemistry, real-time PCR and immunoblot; levels were correlated with patient survival times. We studied the effects of anti-CD44s in mice with human pancreatic tumor xenografts, and used flow cytometry to determine effects on TICs. Changes in CD44s signaling were examined by real-time PCR, immunoblot, reporter assay, and in vitro tumorsphere formation assays. Levels of CD44s were significantly higher in pancreatic cancer than adjacent non-tumor tissues. Patients whose tumors expressed high levels of CD44s had a median survival of 10 months, compared to 43 months for those with low levels. Anti-CD44s reduced growth, metastasis, and post-radiation recurrence of pancreatic xenograft tumors in mice. The antibody reduced the number of TICs in cultured pancreatic cancer cells and in xenograft tumors, as well as their tumorigenicity. In cultured pancreatic cancer cell lines, anti-CD44s downregulated the stem cell self-renewal genes Nanog, Sox-2, and Rex-1 and inhibited STAT3-mediated cell proliferation and survival signaling. The TIC marker CD44s is upregulated in human pancreatic tumors and associated with patient survival time. CD44s is required for initiation, growth, metastasis, and post-radiation recurrence of xenograft tumors in mice. Anti-CD44s eliminated bulk tumor cells as well as TICs from the tumors. Strategies to target CD44s might be developed to block pancreatic tumor formation and post-radiotherapy recurrence in patients.
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