1. Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
J Cancer. 2013 Jul 2;4(6):447-57. doi: 10.7150/jca.6896. Print 2013.
Stem-like cancer cells contribute to cancer initiation and maintenance. Stem cells can self-renew by asymmetric cell division (ACD). ACD with non-random chromosomal cosegregation (ACD-NRCC) is one possible self-renewal mechanism. There is a paucity of evidence supporting ACD-NRCC in human cancer. Our aim was to investigate ACD-NRCC and its potential interactions with the cancer niche (microenvironment) in gastrointestinal cancers.
We used DNA double and single labeling approaches with FACS to isolate live cells undergoing ACD-NRCC.
Gastrointestinal cancers contain rare subpopulations of cells capable of ACD-NRCC. ACD-NRCC was detected preferentially in subpopulations of cells previously suggested to be stem-like/tumor-initiating cancer cells. ACD-NRCC was independent of cell-to-cell contact, and was regulated by the cancer niche in a heat-sensitive paracrine fashion. Wnt pathway genes and proteins are differentially expressed in cells undergoing ACD-NRCC vs. symmetric cell division. Blocking the Wnt pathway with IWP2 (WNT antagonist) or siRNA-TCF4 resulted in suppression of ACD-NRCC. However, using a Wnt-agonist did not increase the relative proportion of cells undergoing ACD-NRCC.
Gastrointestinal cancers contain subpopulations of cells capable of ACD-NRCC. Here we show for the first time that ACD-NRCC can be regulated by the Wnt pathway, and by the cancer niche in a paracrine fashion. However, whether ACD-NRCC is exclusively associated with stem-like cancer cells remains to be determined. Further study of these findings might generate novel insights into stem cell and cancer biology. Targeting the mechanism of ACD-NRCC might engender novel approaches for cancer therapy.
肿瘤起始和维持是由肿瘤干细胞所贡献的。干细胞可以通过不对称细胞分裂（ACD）实现自我更新。非随机染色体共分离（ACD-NRCC）是一种可能的自我更新机制。目前，很少有证据支持人类癌症中的 ACD-NRCC。我们的目的是研究胃肠道癌症中的 ACD-NRCC 及其与肿瘤微环境（ niche）的潜在相互作用。
我们使用 DNA 双标记和单标记方法以及 FACS 来分离正在进行 ACD-NRCC 的活细胞。
胃肠道癌症中存在能够进行 ACD-NRCC 的罕见细胞亚群。ACD-NRCC 主要存在于先前被认为是具有干细胞样/肿瘤起始特性的肿瘤细胞的细胞亚群中。ACD-NRCC 独立于细胞间接触，并以热敏感的旁分泌方式受肿瘤微环境调节。ACD-NRCC 细胞中 Wnt 通路基因和蛋白的表达与对称细胞分裂细胞中不同。用 IWP2（Wnt 拮抗剂）或 siRNA-TCF4 阻断 Wnt 通路可抑制 ACD-NRCC。然而，使用 Wnt 激动剂并不能增加进行 ACD-NRCC 的细胞的相对比例。
胃肠道癌症中存在能够进行 ACD-NRCC 的细胞亚群。我们首次表明，ACD-NRCC 可受 Wnt 通路和旁分泌方式调节，受肿瘤微环境调节。然而，ACD-NRCC 是否仅与肿瘤干细胞相关仍有待确定。进一步研究这些发现可能为干细胞和癌症生物学提供新的见解。针对 ACD-NRCC 的机制可能会产生癌症治疗的新方法。
