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作者:Eduard Batlle Hans Clevers



最近开发的世系追踪和细胞消融策略对CSC的可塑性、休眠、更新,和对治疗的反应 提供了见解。



(a) Left, a canonical hardwired stem cell/CSC hierarchy. In this type of cell hierarchy, stem cells/CSCs are rare, relatively quiescent and largely defined by intrinsic properties. Upon asymmetric division, they give rise to one stem cell and one transient amplifying (TA) cell. The latter divides rapidly, yet it is not capable of self-renewal and eventually undergoes differentiation. Nonstem cells are poorly tumorigenic and display limited functional plasticity. Right, novel features of stem cell/CSCs hierarchies; stem cells/CSCs are not necessarily rare or quiescent and are instructed by niche signals following neutral competition dynamics. TA cells and differentiated cells can be reprogrammed into stem cells by the niche through plasticity. (b) Modes of stem cell division. The outcome of asymmetric cell divisions is pre-established, whereas in neutral competition dynamics, the fate of (cancer) stem cell daughters is determined by niche signals, and therefore, stem cells can give rise to one, two, or no daughter stem cells, depending on the available niche space. Number of stem cells is determined by the size of the niche, i.e., in the example, the niche has available space for four stem cells, and thus stem cell progeny compete to occupy such space. Only cells that remain within the niche are specified as stem cells, whereas those that linger outside the niche undergo differentiation. (c) Stem cell niche factor dependency and tumor progression. In tissues such as the colon, tumor progression occurs through the acquisition of genetic alterations in the same signaling pathways that sustain self renewal of normal ISCs. This process has two consequences; first, as the tumor evolves, mutations render CSCs progressively independent of niche signals. Second, the autonomous CSC phenotype impedes differentiation, resulting in a shallow hierarchy with many CSCs and few non-CSCs.

In tumors displaying a unidirectional hardwired CSC hierarchy, elimination of CSCs is sufficient to cure the disease. In the case of CSCs having extensive cell plasticity, niche signals will re-instruct stem cell properties to progenitor or differentiated cells after CSC loss, which will result in tumor regeneration and therapy failure. Blocking niche signals that specify or sustain CSC identity will be more effective for this class of tumors and may improve therapeutic efficacy by preventing plasticity and CSC regeneration.