Mesenchymal stem cells modified with a single-chain antibody against EGFRvIII successfully inhibit the growth of human xenograft malignant glioma.
Mesenchymal stem cells modified with a single-chain antibody against EGFRvIII successfully inhibit the growth of human xenograft malignant glioma.
复制标题
DOI：
10.1371/journal.pone.0009750
复制
发表时间：
2010-03-18
期刊：
影响因子：
3.7
通讯作者：
Lesniak MS
中科院分区：
文献类型：
--
作者：
Balyasnikova IV;Ferguson SD;Sengupta S;Han Y;Lesniak MS
多形性胶质母细胞瘤是最致命的脑肿瘤，治疗方法有限。在恶性细胞表面表达的抗原是抗体介导的基因/药物传递的潜在靶点。在这项研究中，我们研究了在其表面表达单链抗体（scFv）的转基因人间充质干细胞（hMSCs）对抗肿瘤特异性抗原EGFRvIII的能力，以增强体内表达EGFRvIII的胶质瘤细胞的治疗能力。在与hMSC-scFvEGFRvIII共培养时，U87-EGFRvIII的生长被特异性延迟。与对照组相比，在hMSC-scFvEGFRvIII培养的表达EGFRvIII的胶质瘤细胞中，以及在体内共注射hMSC-scFvEGFRvIII的脑肿瘤中表达EGFRvIII的胶质瘤细胞中，pAkt的表达均显著下调。与对照hMSCs相比，表达scFvEGFRvIII的hMSC在表达EGFRvIII的侧翼和颅内胶质瘤异种移植物中的保留率也提高了几倍。hMSC-scFvEGFRvIII对U87-EGFRvIII侧翼异种移植物生长的抑制作用为50% （p<0.05）。此外，与单独注射U87-EGFRvIII胶质瘤细胞或对照hMSCs相比，颅内注射U87-EGFRvIII和hMSC-scFvEGFRvIII胶质瘤细胞的动物的存活率显著提高。当相同的动物在初始肿瘤植入两周后接受额外剂量的hMSC-scFvEGFRvIII时，这种存活率进一步提高。值得注意的是，与对照肿瘤相比，与hMSCs共注射表达EGFRvIII的脑肿瘤具有较低的表达CD31的血管密度，这表明可能在肿瘤血管生成中起作用。本研究的结果表明，转基因间充质干细胞可能作为恶性脑肿瘤的一种新的治疗载体。
Glioblastoma multiforme is the most lethal brain tumor with limited therapeutic options. Antigens expressed on the surface of malignant cells are potential targets for antibody-mediated gene/drug delivery. In this study, we investigated the ability of genetically modified human mesenchymal stem cells (hMSCs) expressing a single-chain antibody (scFv) on their surface against a tumor specific antigen, EGFRvIII, to enhance the therapy of EGFRvIII expressing glioma cells in vivo. The growth of U87-EGFRvIII was specifically delayed in co-culture with hMSC-scFvEGFRvIII. A significant down-regulation was observed in the expression of pAkt in EGFRvIII expressing glioma cells upon culture with hMSC-scFvEGFRvIII vs. controls as well as in EGFRvIII expressing glioma cells from brain tumors co-injected with hMSC-scFvEGFRvIII in vivo. hMSC expressing scFvEGFRvIII also demonstrated several fold enhanced retention in EGFRvIII expressing flank and intracranial glioma xenografts vs. control hMSCs. The growth of U87-EGFRvIII flank xenografts was inhibited by 50% in the presence of hMSC-scFvEGFRvIII (p<0.05). Moreover, animals co-injected with U87-EGFRvIII and hMSC-scFvEGFRvIII intracranially showed significantly improved survival compared to animals injected with U87-EGFRvIII glioma cells alone or with control hMSCs. This survival was further improved when the same animals received an additional dosage of hMSC-scFvEGFRvIII two weeks after initial tumor implantation. Of note, EGFRvIII expressing brain tumors co-injected with hMSCs had a lower density of CD31 expressing blood vessels in comparison with control tumors, suggesting a possible role in tumor angiogenesis. The results presented in this study illustrate that genetically modified MSCs may function as a novel therapeutic vehicle for malignant brain tumors.
登录
查看更多内容
DOI：
10.1634/stemcells.2008-0831
发表时间：
2009-03
期刊：
Stem cells (Dayton, Ohio)
影响因子：
--
作者：
Compte M;Cuesta AM;Sánchez-Martín D;Alonso-Camino V;Vicario JL;Sanz L;Alvarez-Vallina L
通讯作者：
Alvarez-Vallina L
影响因子：
5.2
作者：
Honczarenko, Marek;Le, Yi;Silberstein, Leslie E.
通讯作者：
Silberstein, Leslie E.
影响因子：
64.8
作者：
Karnoub, Antoine E.;Dash, Ajeeta B.;Weinberg, Robert A.
通讯作者：
Weinberg, Robert A.
影响因子：
3.5
作者：
Kucerova, Lucia;Matuskova, Miroslava;Altaner, Cestmir
通讯作者：
Altaner, Cestmir
影响因子：
3.7
作者：
Frank, Richard T.;Edmiston, Marissa;Aboody, Karen S.
通讯作者：
Aboody, Karen S.