A tumor-selective biotherapy with prolonged impact on established metastases based on cytokine gene-engineered MSCs
A tumor-selective biotherapy with prolonged impact on established metastases based on cytokine gene-engineered MSCs
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DOI：
10.1038/mt.2008.3
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发表时间：
2008-04-01
影响因子：
12.4
通讯作者：
Zhao, Xia
中科院分区：
文献类型：
--
作者：
Chen, Xiancheng;Lin, Xiaojuan;Zhao, Xia
晚期恶性肿瘤患者预后较差的部分原因是无法逆转癌症转移。在这项研究中，我们研究了一种针对B16黑色素瘤、4T1乳腺癌和HCA肝癌等三种晚期癌症模型中预先建立的转移的综合免疫治疗方法。在经过20天的静脉免疫治疗后，转移到多步骤淋巴结(LN)和内脏的进展明显受阻，并在终末期逆转[使用白介素12(IL-12)基因工程间充质干细胞(MSCs)，每5天一次(P<；0.05)]；该治疗没有全身毒性。作为对照，游离ADIL-12组有明显的全身毒性，但转移仅在中期部分延迟，而在终末期没有。酶联免疫吸附试验(ELISA)显示，在终末期，细胞因子工程MSCs组瘤内IL-12的表达水平比游离ADIL-12组高10倍；相反，在中期，游离ADIL-12组的血清IL-12水平升高，但瘤内IL-12水平无明显变化。此外，组织形态计量学分析显示，工程化MSC组肿瘤相关淋巴芽逆转的趋势减少，肿瘤细胞凋亡指数增加(P<；0.05)。这些数据表明，细胞因子工程的MSCs有可能被认为是针对晚期恶性肿瘤的综合治疗武器。
The poor prognosis for patients with advanced malignancy relates partly to the inability to reverse cancer metastasis. In this study we have investigated an integrated immunotherapy method against pre-established metastases in three kinds of advanced cancer models including B16 melanoma, 4T1 breast tumor, and Hca hepatoma. The progression of metastases into multistep lymph nodes (LN) and internal organs was, markedly impeded in the midway stage and reversed in the ultimate stage following a 20-day course of intravenous immunotherapy [with interleukin-12 (IL-12) gene-engineered mesenchymal stem cells (MSCs), administered once every 5 days (P < 0.05)]; the therapy was without systemic toxic effects. As the control, obvious systemic toxicity was observed in the free AdIL-12 group, yet metastasis was partly delayed only in the midway stage but not in the ultimate stage. Enzyme-linked immunosorbent assay (ELISA) showed that the intratumoral expression levels of IL-12 were enhanced by cytokine-engineered MSCs to be tenfold greater than that of free AdIL-12 groups in the ultimate stage; conversely, free AdIL-12 groups showed elevated serum, but not intratumoral levels of IL-12, during the midway stage. Furthermore, histomorphometric analysis revealed a reductive tendency toward reversion of tumor-associated lymphatic sprouts and an increased tumor apoptosis index in engineered MSC groups (P < 0.05). These data indicate the potential of cytokine-engineered MSCs to be considered as an integrated therapeutic weapon for targeting advanced malignancies.