Department of Cellular and Molecular Medicine, Centre for Biological Disease Analysis and Danish Stem Cell Centre, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6124-9. doi: 10.1073/pnas.1203203109. Epub 2012 Mar 27.
The majority of human breast cancers exhibit luminal epithelial differentiation. However, most aggressive behavior, including invasion and purported cancer stem cell activity, are considered characteristics of basal-like cells. We asked the following questions: Must luminal-like breast cancer cells become basal-like to initiate tumors or to invade? Could luminally differentiated cells within a basally initiated hierarchy also be tumorigenic? To answer these questions, we used rare and mutually exclusive lineage markers to isolate subsets of luminal-like and basal-like cells from human breast tumors. We enriched for populations with or without prominent basal-like traits from individual tumors or single cell cloning from cell lines and recovered cells with a luminal-like phenotype. Tumor cells with basal-like traits mimicked phenotypic and functional behavior associated with stem cells assessed by gene expression, mammosphere formation and lineage markers. Luminal-like cells without basal-like traits, surprisingly, were fully capable of initiating invasive tumors in NOD SCID gamma (NSG) mice. In fact, these phenotypically pure luminal-like cells generated larger and more invasive tumors than their basal-like counterparts. The tumorigenicity and invasive potential of the luminal-like cancer cells relied strongly on the expression of the gene GCNT1, which encodes a key glycosyltransferase controlling O-glycan branching. These findings demonstrate that basal-like cells, as defined currently, are not a requirement for breast tumor aggressiveness, and that within a single tumor there are multiple "stem-like" cells with tumorigenic potential casting some doubt on the hypothesis of hierarchical or differentiative loss of tumorigenicity.
大多数人类乳腺癌表现出腔上皮分化。然而，大多数侵袭行为和所谓的癌症干细胞活性被认为是基底样细胞的特征。我们提出了以下问题：腔样乳腺癌细胞必须变成基底样才能起始肿瘤或侵袭吗？在基底起始的分级中，腔分化细胞也可能具有致瘤性吗？为了回答这些问题，我们使用罕见且相互排斥的谱系标志物从人乳腺癌肿瘤中分离出腔样和基底样细胞亚群。我们从单个肿瘤或细胞系的单细胞克隆中富集具有或不具有明显基底样特征的群体，并回收具有腔样表型的细胞。具有基底样特征的肿瘤细胞模拟了通过基因表达、类器官形成和谱系标志物评估与干细胞相关的表型和功能行为。令人惊讶的是，没有基底样特征的腔样细胞完全能够在 NOD SCID gamma (NSG) 小鼠中起始侵袭性肿瘤。事实上，这些表型纯的腔样细胞生成的肿瘤比其基底样对应物更大且更具侵袭性。腔样癌细胞的致瘤性和侵袭性潜力强烈依赖于基因 GCNT1 的表达，该基因编码控制 O-聚糖分支的关键糖基转移酶。这些发现表明，目前定义的基底样细胞不是乳腺癌侵袭性的必需条件，并且在单个肿瘤中存在具有致瘤潜力的多个“干细胞样”细胞，这对肿瘤发生的分级或分化丧失假说提出了一些质疑。
