RIKEN Center for Developmental Biology, Kobe, Japan.
Anticancer Agents Med Chem. 2010 Jul;10(6):471-80. doi: 10.2174/1871520611009060471.
Both stem cells and cancer cells are thought to be capable of unlimited self-renewal. Moreover, a small number of cancer cells express stem cell markers, including CD133 and ATP-binding cassette transporters through which the cells can pump out anti-cancer drugs or specific fluorescence dyes such as Hoechst33342, suggesting that either cancer cells resemble stem cells or that cancers contain stem cell-like cancer cells, called cancer-initiating cells (CICs) or cancer stem cells. Using the common characteristics of tissue-specific stem cells, malignant tumors and cancer cell lines were shown to contain CICs, which self-renew and are tumorigenic. CICs are also resistant to both irradiation and chemotherapy. These findings suggest that CICs are critical targets for successful therapy. However, CICs have not been well characterized, due to a lack of specific markers. We recently established mouse glioma-initiating cell (GIC) lines by overexpressing oncogenic HRas(L)⁶¹ in p53-deficient neural cells. These cells form transplantable glioblastoma multiforme (GBM) with features of human GBM when as few as 10 cells are transplanted in vivo, suggesting that these GIC-like cells are enriched in CICs. Characterization of these GICs showed that they expressed little or no Sox11. The overexpression of exogenous Sox11 in GICs blocked their tumorigenesis by inducing their neuronal differentiation, which was accompanied by decreased levels of a novel oncogene, plagl1. These findings suggest that Sox11 and Plagl1 work as a tumor suppressor and oncogene, respectively, in GBM and are potential therapeutic targets.
干细胞和癌细胞都被认为具有无限自我更新的能力。此外，少数癌细胞表达干细胞标志物，包括 CD133 和 ATP 结合盒转运蛋白，通过这些蛋白，细胞可以将抗癌药物或特定的荧光染料（如 Hoechst33342）泵出，这表明癌细胞类似于干细胞，或者癌症中含有干细胞样癌细胞，称为癌症起始细胞（CICs）或癌症干细胞。利用组织特异性干细胞的共同特征，已经表明恶性肿瘤和癌细胞系含有能够自我更新并致瘤的 CICs。CICs 也对放疗和化疗具有抗性。这些发现表明 CICs 是成功治疗的关键靶点。然而，由于缺乏特异性标志物，CICs 尚未得到很好的表征。我们最近通过在 p53 缺陷的神经细胞中过表达致癌 HRas(L)⁶¹，建立了小鼠神经胶质瘤起始细胞（GIC）系。这些细胞在体内移植 10 个细胞时即可形成可移植的多形性胶质母细胞瘤（GBM），具有人类 GBM 的特征，这表明这些 GIC 样细胞富含 CICs。对这些 GICs 的特征分析表明，它们表达很少或不表达 Sox11。在 GIC 中过表达外源性 Sox11 通过诱导其神经元分化来阻断其致瘤性，同时伴随一种新的癌基因 plagl1 的水平降低。这些发现表明 Sox11 和 Plagl1 在 GBM 中分别作为肿瘤抑制基因和癌基因发挥作用，是潜在的治疗靶点。
