Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts.
Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts.
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DOI：
10.1186/s13287-017-0516-3
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发表时间：
2017-03-09
影响因子：
7.5
通讯作者：
Pallini R
中科院分区：
文献类型：
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作者：
Pacioni S;D'Alessandris QG;Giannetti S;Morgante L;Coccè V;Bonomi A;Buccarelli M;Pascucci L;Alessandri G;Pessina A;Ricci-Vitiani L;Falchetti ML;Pallini R
间充质干细胞/基质细胞（MSCs）是基于细胞的癌症治疗的一个有吸引力的工具，主要是因为它们能够迁移到肿瘤并释放生物活性分子。然而，间充质干细胞对肿瘤生长的影响尚未完全确定。我们之前证明了小鼠间充质干细胞对胶质母细胞瘤（GBM）脑异种移植物表现出强烈的趋向性，并且这些细胞能够摄取和释放化疗药物紫杉醇（PTX），保持其对肿瘤的趋向性。在这里，我们解决了在原位GBM模型中使用来自人类供体的间充质干细胞（hMSCs）进行局部或全身给药的治疗相关问题，包括患者来源的胶质瘤干细胞（GSCs）的异种移植。将表达绿色荧光蛋白（GFP）的U87MG或GSC1细胞移植到免疫抑制大鼠纹状体上。用mCherry蛋白荧光标记的脂肪hMSCs （Ad-hMSCs）接种于肿瘤附近或肿瘤内。在移植U87MG的大鼠中，通过股静脉或颈动脉全身注射Ad-hMSCs或骨髓(BM)-hMSCs。在每个实验中，分别使用ptx加载或未加载的hMSCs。为了描述hMSCs对肿瘤生长的影响，我们分析了存活、肿瘤体积、肿瘤细胞增殖和微血管密度。总体而言，AD-hMSCs对肿瘤表现出显著的趋向性。脑内注射Ad-hMSCs可显著提高U87MG异种移植大鼠的存活率。这种效果与肿瘤生长、肿瘤细胞增殖和微血管密度的减少有关。在GSC1异种移植物中，瘤内注射Ad-hMSCs减少了肿瘤细胞群，并诱导了原位小胶质细胞的迁移。总的来说，PTX负载并没有显著增强hMSCs的抗肿瘤潜能。全身注射的Ad-和BM-hMSCs归巢到肿瘤异种移植物。hMSC归巢的效率在注射细胞的0.02 - 0.5%之间，这取决于细胞注射的途径和来源。重要的是，全身注射了ptx负载的hMSCs，其归巢到异种移植物诱导周围肿瘤细胞的细胞毒性损伤。hMSCs在GBM脑异种移植物中具有治疗潜力，这种潜力也针对GSC群体表达。在这种情况下，hMSCs的PTX负载似乎起着次要作用。本文的在线版本（doi:10.1186/s13287-017-0516-3）包含补充材料，仅供授权用户使用。
Mesenchymal stem/stromal cells (MSCs) represent an attractive tool for cell-based cancer therapy mainly because of their ability to migrate to tumors and to release bioactive molecules. However, the impact of MSCs on tumor growth has not been fully established. We previously demonstrated that murine MSCs show a strong tropism towards glioblastoma (GBM) brain xenografts and that these cells are able to uptake and release the chemotherapeutic drug paclitaxel (PTX), maintaining their tropism towards the tumor. Here, we address the therapy-relevant issue of using MSCs from human donors (hMSCs) for local or systemic administration in orthotopic GBM models, including xenografts of patient-derived glioma stem cells (GSCs). U87MG or GSC1 cells expressing the green fluorescent protein (GFP) were grafted onto the striatum of immunosuppressed rats. Adipose hMSCs (Ad-hMSCs), fluorescently labeled with the mCherry protein, were inoculated adjacent to or into the tumor. In rats bearing U87MG xenografts, systemic injections of Ad-hMSCs or bone marrow (BM)-hMSCs were done via the femoral vein or carotid artery. In each experiment, either PTX-loaded or unloaded hMSCs were used. To characterize the effects of hMSCs on tumor growth, we analyzed survival, tumor volume, tumor cell proliferation, and microvascular density. Overall, the AD-hMSCs showed remarkable tropism towards the tumor. Intracerebral injection of Ad-hMSCs significantly improved the survival of rats with U87MG xenografts. This effect was associated with a reduction in tumor growth, tumor cell proliferation, and microvascular density. In GSC1 xenografts, intratumoral injection of Ad-hMSCs depleted the tumor cell population and induced migration of resident microglial cells. Overall, PTX loading did not significantly enhance the antitumor potential of hMSCs. Systemically injected Ad- and BM-hMSCs homed to tumor xenografts. The efficiency of hMSC homing ranged between 0.02 and 0.5% of the injected cells, depending both on the route of cell injection and on the source from which the hMSCs were derived. Importantly, systemically injected PTX-loaded hMSCs that homed to the xenograft induced cytotoxic damage to the surrounding tumor cells. hMSCs have a therapeutic potential in GBM brain xenografts which is also expressed against the GSC population. In this context, PTX loading of hMSCs seems to play a minor role. The online version of this article (doi:10.1186/s13287-017-0516-3) contains supplementary material, which is available to authorized users.