Mesenchymal stem cell targeting of microscopic tumors and tumor stroma development monitored by noninvasive in vivo positron emission tomography imaging
Mesenchymal stem cell targeting of microscopic tumors and tumor stroma development monitored by noninvasive in vivo positron emission tomography imaging
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DOI：
10.1158/1078-0432.ccr-05-0876
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发表时间：
2005-11-01
影响因子：
11.5
通讯作者：
Gelovani, JG
中科院分区：
文献类型：
--
作者：
Hung, SC;Deng, WP;Gelovani, JG
本研究的目的是评估人间充质干细胞（hMSC）靶向显微肿瘤和自杀基因或细胞因子基因治疗的疗效。免疫缺陷小鼠皮下移植。用HT-29 Inv 2或CCS系的人结肠癌细胞，并且3至4天后，静脉内用表达单纯疱疹病毒1型胸苷激酶（HSV 1-TK）和增强的绿色荧光蛋白（EGFP）报告基因的“示踪剂”hMSC。随后，通过使用F-18标记的9-（4-氟-3-羟甲基丁基）-鸟嘌呤（[F-18]-FHBG）的体内正电子发射断层扫描（PET），检查这些肿瘤中肿瘤基质中HSV 1-TK+、EGFP（+）干细胞植入和增殖的特异性和幅度。生长4周的肿瘤的体内PET图像显示存在HSV 1-TK+肿瘤基质，平均0.36 +/-0.24%ID/g [F-18]-FHBG积累。通过原位相关组织化学、免疫荧光和细胞计数分析验证了体内成像结果，显示EGFP在毛细血管和大血管的vWF（+）和CD 31（+）内皮细胞、真皮的生发层和靠近s.c.的毛囊中表达。肿瘤部位。这些分化的HSV 1-TK+、GFP（+）内皮细胞具有有限的增殖能力，并且在移植到第二宿主的肿瘤碎片中的寿命短于2周。我们的结论是，hMSCs可以靶向微观肿瘤，随后增殖和分化，并有助于形成一个显着的肿瘤基质的一部分。PET成像应促进临床翻译的干细胞为基础的抗癌基因治疗方法，通过提供在体内非侵入性全身监测的运输，肿瘤靶向，和增殖的HSV 1-tk表达的“示踪剂”的hMSCs在肿瘤基质。
The aim of this study was to assess the efficacy human mesenchymal stem cells (hMSC) for targeting microscopic tumors and suicide gene or cytokine gene therapy. Immunodeficient mice were transplanted s.c. with human colon cancer cells of HT-29 Inv2 or CCS line, and 3 to 4 days later, i.v. with "tracer" hMSCs expressing herpes simplex virus type 1 thymidine kinase (HSV1-TK) and enhanced green fluorescent protein (EGFP) reporter genes. Subsequently, these tumors were examined for specificity and magnitude of HSV1-TK+, EGFP(+) stem cell engraftment and proliferation in tumor stroma by in vivo positron emission tomography (PET) with F-18-labeled 9-(4-fluoro-3-hydroxymethylbutyl)-guanine ([F-18]-FHBG). In vivo PET images of tumors growing for 4 weeks showed the presence of HSV1-TK+ tumor stroma with an average of 0.36 +/- 0.24% ID/g [F-18]-FHBG accumulation. In vivo imaging results were validated by in situ correlative histochemical, immunofluorescent, and cytometric analyses, which revealed EGFP expression in vWF(+) and CD31(+) endothelial cells of capillaries and larger blood vessels, in germinal layer of dermis and hair follicles proximal to the s.c. tumor site. These differentiated HSV1-TK+, GFP(+) endothelial cells had limited proliferative capacity and a short life span of < 2 weeks in tumor fragments transplanted into secondary hosts. We conclude that hMSCs can target microscopic tumors, subsequently proliferate and differentiate, and contribute to formation of a significant portion of tumor stroma. PET imaging should facilitate clinical translation of stem cell-based anticancer gene therapeutic approaches by providing the means for in vivo noninvasive whole-body monitoring of trafficking, tumor targeting, and proliferation of HSV1-tk-expressing "tracer" hMSCs in tumor stroma.