In vivo fluorescence imaging reveals the promotion of mammary tumorigenesis by mesenchymal stromal cells.
In vivo fluorescence imaging reveals the promotion of mammary tumorigenesis by mesenchymal stromal cells.
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DOI：
10.1371/journal.pone.0069658
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hoffman RM
中科院分区：
文献类型：
--
作者：
Ke CC;Liu RS;Suetsugu A;Kimura H;Ho JH;Lee OK;Hoffman RM
间充质基质细胞（Mesenchymal stromal cells, MSCs）是一种多能成体干细胞，可被募集到肿瘤微环境（tumor microenvironment， TME）中，并通过多种机制影响肿瘤的进展。在这项研究中，我们检测了MSCs对4T1小鼠乳腺癌细胞的非致生能力的影响。结果发现，mscs条件培养基提高了体外4T1细胞的增殖、迁移和乳腺球形成效率。当与MSCs共注射到小鼠乳腺脂肪垫时，4T1细胞表现出肿瘤生长增强和自发性肺转移增加。利用体内荧光彩色编码成像技术，监测表达gfp的MSCs与表达rfp的4T1细胞之间的相互作用。与MSCs共注入小鼠乳腺脂肪垫时，4T1细胞最多可形成5个肿瘤，而单独注入5个或10个4T1细胞时，均未形成肿瘤。基因表达分析进一步支持了致瘤潜能的升高，表明当4T1细胞与MSCs接触时，几种致癌基因、癌症标志物和肿瘤启动子上调。此外，肿瘤发生的体内纵向荧光成像显示，MSCs创造了一个血管化的环境，增强了4T1细胞的定植和增殖能力。总之，本研究表明，MSCs促进乳腺癌进展是通过产生促癌微环境来增加致瘤潜力实现的。这些发现也提示了MSCs在临床细胞治疗中促进肿瘤进展的潜在风险。在考虑用间充质干细胞进行细胞治疗时，必须注意乳腺癌高危患者。
Mesenchymal stromal cells (MSCs) are multipotent adult stem cells which are recruited to the tumor microenvironment (TME) and influence tumor progression through multiple mechanisms. In this study, we examined the effects of MSCs on the tunmorigenic capacity of 4T1 murine mammary cancer cells. It was found that MSC-conditioned medium increased the proliferation, migration, and efficiency of mammosphere formation of 4T1 cells in vitro. When co-injected with MSCs into the mouse mammary fat pad, 4T1 cells showed enhanced tumor growth and generated increased spontaneous lung metastasis. Using in vivo fluorescence color-coded imaging, the interaction between GFP-expressing MSCs and RFP-expressing 4T1 cells was monitored. As few as five 4T1 cells could give rise to tumor formation when co-injected with MSCs into the mouse mammary fat pad, but no tumor was formed when five or ten 4T1 cells were implanted alone. The elevation of tumorigenic potential was further supported by gene expression analysis, which showed that when 4T1 cells were in contact with MSCs, several oncogenes, cancer markers, and tumor promoters were upregulated. Moreover, in vivo longitudinal fluorescence imaging of tumorigenesis revealed that MSCs created a vascularized environment which enhances the ability of 4T1 cells to colonize and proliferate. In conclusion, this study demonstrates that the promotion of mammary cancer progression by MSCs was achieved through the generation of a cancer-enhancing microenvironment to increase tumorigenic potential. These findings also suggest the potential risk of enhancing tumor progression in clinical cell therapy using MSCs. Attention has to be paid to patients with high risk of breast cancer when considering cell therapy with MSCs.
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影响因子：
11.2
作者：
Nakamizo, A;Marini, F;Lang, FF
通讯作者：
Lang, FF
影响因子：
11.2
作者：
Liu S;Ginestier C;Ou SJ;Clouthier SG;Patel SH;Monville F;Korkaya H;Heath A;Dutcher J;Kleer CG;Jung Y;Dontu G;Taichman R;Wicha MS
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5.2
作者：
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通讯作者：
Bieback, Karen
影响因子：
20.3
作者：
Lee, OK;Kuo, TK;Chen, TH
通讯作者：
Chen, TH
影响因子：
4
作者：
Suetsugu, Atsushi;Osawa, Yosuke;Hoffman, Robert M.
通讯作者：
Hoffman, Robert M.