McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA.
PLoS One. 2011 Apr 26;6(4):e19310. doi: 10.1371/journal.pone.0019310.
There is a paradox offered up by the cancer stem cell hypothesis. How are the mixed populations that are characteristic of heterogeneous solid tumors maintained at constant proportion, given their high, and different, mitotic indices? In this study, we evaluate a well-characterized mouse model of human basaloid tumors (induced by the oncogene Wnt1), which comprise mixed populations of mammary epithelial cells resembling their normal basal and luminal counterparts. We show that these cell types are substantially inter-dependent, since the MMTV LTR drives expression of Wnt1 ligand in luminal cells, whereas the functional Wnt1-responsive receptor (Lrp5) is expressed by basal cells, and both molecules are necessary for tumor growth. There is a robust tumor initiating activity (tumor stem cell) in the basal cell population, which is associated with the ability to differentiate into luminal and basal cells, to regenerate the oncogenic paracrine signaling cell pair. However, we found an additional tumor stem cell activity in the luminal cell population. Knowing that tumors depend upon Wnt1-Lrp5, we hypothesized that this stem cell must express Lrp5, and found that indeed, all the stem cell activity could be retrieved from the Lrp5-positive cell population. Interestingly, this reflects post-transcriptional acquisition of Lrp5 protein expression in luminal cells. Furthermore, this plasticity of molecular expression is reflected in plasticity of cell fate determination. Thus, in vitro, Wnt1-expressing luminal cells retro-differentiate to basal cell types, and in vivo, tumors initiated with pure luminal cells reconstitute a robust basal cell subpopulation that is indistinguishable from the populations initiated by pure basal cells. We propose this is an important proof of concept, demonstrating that bipotential tumor stem cells are essential in tumors where oncogenic ligand-receptor pairs are separated into different cell types, and suggesting that Wnt-induced molecular and fate plasticity can close paracrine loops that are usually separated into distinct cell types.
癌症干细胞假说提出了一个悖论。考虑到异质实体瘤的混合群体具有较高且不同的有丝分裂指数，它们如何保持恒定的比例？在这项研究中，我们评估了一个经过充分表征的人类基底细胞瘤小鼠模型（由癌基因 Wnt1 诱导），该模型由类似于正常基底和腔细胞的乳腺上皮细胞的混合群体组成。我们表明，这些细胞类型是相互依存的，因为 MMTV LTR 在腔细胞中驱动 Wnt1 配体的表达，而功能性 Wnt1 反应性受体（Lrp5）由基底细胞表达，并且这两种分子对于肿瘤生长都是必需的。在基底细胞群体中存在强大的肿瘤起始活性（肿瘤干细胞），这与分化为腔细胞和基底细胞的能力、再生致癌旁分泌信号细胞对有关。然而，我们在腔细胞群体中发现了额外的肿瘤干细胞活性。鉴于肿瘤依赖于 Wnt1-Lrp5，我们假设这种干细胞必须表达 Lrp5，并发现确实可以从 Lrp5 阳性细胞群体中获得所有的干细胞活性。有趣的是，这反映了腔细胞中 Lrp5 蛋白表达的转录后获得。此外，这种分子表达的可塑性反映在细胞命运决定的可塑性上。因此，在体外，表达 Wnt1 的腔细胞逆行分化为基底细胞类型，在体内，用纯腔细胞起始的肿瘤重新构成了一个强大的基底细胞亚群，与用纯基底细胞起始的肿瘤群无法区分。我们提出这是一个重要的概念证明，表明在致癌配体-受体对被分离到不同细胞类型的肿瘤中，双潜能肿瘤干细胞是必不可少的，并表明 Wnt 诱导的分子和命运可塑性可以关闭通常分离到不同细胞类型的旁分泌环。
