National Centre for Cell Science, NCCS Complex, Pune University Campus, Ganeshkhind, Pune, India.
Cancer Res. 2009 Dec 15;69(24):9245-53. doi: 10.1158/0008-5472.CAN-09-2802.
Tumor formation involves substantial cell division and genetic instability, but the relationship between quiescent cancer stem cells (CSC) and dividing progenitors in these events is poorly understood. Likewise, the implication of aneuploid cells in solid tumors is uncertain. CSCs are postulated to contribute to tumor dormancy and present a formidable obstacle in limiting treatment outcomes for a majority of cancers, whereas the genetic heterogeneity conjured by aneuploid cells may influence tumor drug resistance. However, direct confirmation of these events remains forthcoming. In the present study, we addressed the identification of tumor dormancy in terms of isolation of therapy-refractory residual tumor cells from tumors that persist in a state of quiescence as label-retaining cells. The choices of label were PKH67/PKH26 dyes that irreversibly bind to the lipid bilayer on cell membranes and get equally partitioned among daughter cells subsequent to each cell division. Consequent characterization revealed that label-retaining cells encompass two different populations capable of remaining in a state of quiescence, i.e., stem-like cells and aneuploid cells. The former express a reversibility of quiescence through retention of functionality and also exhibit therapeutic refractoriness; the latter seem to be either quiescent or proliferation-arrested at steady-state. Subsequent to exposure to selective pressure of chemotherapy, a fraction of these cells may acquire the potential to proliferate in a drug-refractory manner and acquire stem-like characteristics. Collectively, the findings of the present study reveal that tumor-derived CSCs and aneuploid populations contribute to drug resistance and tumor dormancy in cancer progression.
肿瘤的形成涉及大量的细胞分裂和遗传不稳定性，但静止的癌症干细胞（CSC）与这些事件中分裂的祖细胞之间的关系还知之甚少。同样，非整倍体细胞在实体瘤中的意义也不确定。CSC 被认为有助于肿瘤休眠，并在限制大多数癌症的治疗效果方面构成了一个巨大的障碍，而非整倍体细胞引起的遗传异质性可能会影响肿瘤的药物耐药性。然而，这些事件的直接证实仍然有待进一步研究。在本研究中，我们通过从处于静止状态的肿瘤中分离出对治疗有抗药性的残留肿瘤细胞，来研究肿瘤休眠的鉴定。标记物的选择是 PKH67/PKH26 染料，它们不可逆地结合在细胞膜的脂质双层上，并在每次细胞分裂后在子细胞之间均等分配。随后的特征分析表明，标记保留细胞包括两种不同的群体，能够保持静止状态，即干细胞样细胞和非整倍体细胞。前者通过保留功能来实现静止的可逆性，并且表现出治疗抗性；后者似乎处于静止或增殖停滞的稳定状态。随后暴露于化疗的选择性压力下，这些细胞中的一部分可能会获得以耐药方式增殖的潜力，并获得干细胞样特征。总之，本研究的结果表明，肿瘤来源的 CSC 和非整倍体群体有助于癌症进展中的药物耐药性和肿瘤休眠。
