Identification of tumorsphere- and tumor-initiating cells in HER2/Neu-Induced mammary tumors
Identification of tumorsphere- and tumor-initiating cells in HER2/Neu-Induced mammary tumors
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DOI：
10.1158/0008-5472.can-07-1486
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发表时间：
2007-09-15
期刊：
影响因子：
11.2
通讯作者：
Zacksenhaus, Eldad
中科院分区：
文献类型：
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作者：
Liu, Jeff C.;Deng, Tao;Zacksenhaus, Eldad
包括乳腺癌在内的各种人类恶性肿瘤被认为是以层次结构组织的，其中相对较少的肿瘤起始细胞（TIC）群体负责肿瘤生长，而绝大多数剩余细胞是非致瘤性的。在乳腺癌模型系统中分析TIC将提供统一和可获得的肿瘤细胞来源，以及小鼠遗传学的力量来解剖这些罕见的细胞。HER 2/Neu原癌基因在侵袭性人类乳腺癌中过度表达。小鼠乳腺肿瘤病毒（MMTV）-Neu转基因小鼠发生模拟人HER 2亚型乳腺癌的乳腺肿瘤。在这里，我们报告的功能鉴定小鼠HER 2/Neu TICs，可以诱导肿瘤移植到受体小鼠的乳腺后。注射MMTV-Neu TIC后形成的继发性肿瘤类似于原始转基因小鼠中的原发性肿瘤，并且以包含TIC及其非致瘤后代的层次结构组织。为了在体外研究MMTV-Neu TIC，我们在非贴壁培养条件下生长肿瘤球。能够产生肿瘤球的肿瘤球形成单位（TFU）保留了致瘤潜力，并且根据几项标准无法与TICs区分。有趣的是，当在体外诱导分化时，MMTV-Neu TIC和TFU致力于管腔细胞命运。我们的数据定义了MMTV-Neu TIC和TFU的可重复特征，这有助于解释HER 2阳性乳腺癌的标志物表达谱。此外，该系统中TIC和TFU之间的相似性为基于TFU的筛选靶向HER 2（+）乳腺癌中的肿瘤起始细胞提供了理论基础。
A variety of human malignancies, including breast cancer, are thought to be organized in a hierarchy, whereby a relatively minor population of tumor initiating cells (TIC) is responsible for tumor growth and the vast majority of remaining cells is nontumorigenic. Analysis of TICs in model systems of breast cancer would offer uniform and accessible source of tumor cells and the power of mouse genetics to dissect these rare cells. The HER2/Neu proto-oncogene is overexpressed in an aggressive form of human breast cancer. Mouse mammary tumor virus (MMTV)-Neu transgenic mice develop mammary tumors that mimic human HER2 subtype breast cancer. Here, we report on the functional identification of mouse HER2/Neu TICs that can induce tumors after transplantation into the mammary gland of recipient mice. Secondary tumors formed after injecting MMTV-Neu TICs resemble primary tumors in the original transgenic mice and are organized in a hierarchy containing TICs as well as their nontumorigenic descendants. To study MMTV-Neu TICs in vitro, we grew tumorspheres under nonadherent culture conditions. Tumorsphere forming units (TFU) capable of producing tumorspheres retained tumorigenic potential and were indistinguishable by several criteria from TICs. Interestingly, MMTV-Neu TICs and TFUs were committed to the luminal cell fate when induced to differentiate in vitro. Our data define reproducible characteristics of the MMTV-Neu TIC and TFU, which help to explain marker expression profiles of HER2-positive breast cancer. In addition, the similarity between TICs and TFUs in this system provides a rationale for TFU-based screens to target tumor-initiating cells in HER2(+) breast cancer.