Reprogramming human cancer cells in the mouse mammary gland.
Reprogramming human cancer cells in the mouse mammary gland.
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DOI：
10.1158/0008-5472.can-10-0591
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发表时间：
2010-08-01
期刊：
影响因子：
11.2
通讯作者：
Smith GH
中科院分区：
文献类型：
--
作者：
Bussard KM;Boulanger CA;Booth BW;Bruno RD;Smith GH
组织微环境指导干/祖细胞行为。癌细胞也受到微环境的影响。已经表明，当置于胚泡中时，癌细胞对胚胎线索作出反应，并根据本体发育期间遇到的组织类型进行分化。以前，我们表明，小鼠乳腺能够重定向成年小鼠睾丸和神经干/祖细胞对乳腺上皮细胞的命运在腺体再生。在这里，我们报告，人胚胎癌细胞增殖，并产生分化的乳腺上皮细胞后代与小鼠乳腺上皮细胞混合，接种到无上皮细胞的无胸腺裸鼠乳腺脂肪垫。荧光原位杂交证实了人类细胞后代在人类着丝粒DNA的乳腺增生中的存在，以及人类特异性乳腺上皮细胞角蛋白和人类特异性乳蛋白在怀孕移植宿主中的免疫化学。结果发现，在乳腺上皮生长和扩张过程中，人细胞的数量增加了66至660倍，这是通过人细胞角蛋白表达确定的。在嵌合植入物的继发性生长中重现了在原发性生长中发现的所有特征。这些结果表明，人胚胎癌衍生的后代在乳腺再生过程中与小鼠乳腺细胞相互作用，并定向分化为表现出不同乳腺上皮细胞表型的细胞。这是第一次证明人类细胞能够识别体内腺体再生过程中存在的小鼠乳腺微环境产生的信号。
The tissue microenvironment directs stem/progenitor cell behavior. Cancer cells are also influenced by the microenvironment. It has been shown that, when placed into blastocysts, cancer cells respond to embryonic cues and differentiate according to the tissue type encountered during ontological development. Previously, we showed that the mouse mammary gland was capable of redirecting adult mouse testicular and neural stem/progenitor cells toward a mammary epithelial cell fate during gland regeneration. Here, we report that human embryonal carcinoma cells proliferate and produce differentiated mammary epithelial cell progeny when mixed with mouse mammary epithelial cells and inoculated into the epithelium-free mammary fat pads of athymic nude mice. Fluorescence in situ hybridization confirmed the presence of human cell progeny in the mammary outgrowths for human centromeric DNA, as well as immunochemistry for human-specific breast epithelial cytokeratins and human-specific milk proteins in impregnated transplant hosts. It was found that the number of human cells increased by 66- to 660-fold during mammary epithelial growth and expansion as determined by human cytokeratin expression. All features found in primary outgrowths were recapitulated in the secondary outgrowths from chimeric implants. These results show that human embryonal carcinoma–derived progeny interact with mouse mammary cells during mammary gland regeneration and are directed to differentiate into cells that exhibit diverse mammary epithelial cell phenotypes. This is the first demonstration that human cells are capable of recognizing the signals generated by the mouse mammary gland microenvironment present during gland regeneration in vivo.