Thenappan Arun, Li Ying, Shetty Kirti, Johnson Lynt, Reddy E P, Mishra Lopa
Curr Colorectal Cancer Rep. 2009 Oct 1;5(4):209. doi: 10.1007/s11888-009-0029-2.
The recent identification of tumor-initiating colorectal cancer (CRC) stem cells in the pathogenesis of CRC has provided a potential target for novel therapeutics. Many details about CRC stem cells, however, remain poorly understood. Several potential markers of CRC stem cells have been proposed, including CD133, CD44, and, recently, Lgr5. Attention also has been drawn to control of stem cell self-renewal, proliferation, and differentiation by the Wnt and transforming growth factor (TGF)-β pathways. Disruption of Wnt signaling, via loss of APC (adenomatous polyposis coli), is among the earliest events in the multistage progression of CRC and likely occurs in basal crypt stem cells, generating a neoplastic cell population that then expands upward to occupy the rest of the crypt. TGF-β signaling is a key tumor suppressor pathway, and mutations in the type II receptor and Smad4 are observed in CRC specimens and are associated with more aggressive disease in tumors with disrupted Wnt signaling. Loss of the TGF-β adaptor protein β(2)-spectrin is associated with loss of colonic cell polarity and architecture, and its expression parallels that of Smad4. This review suggests rational approaches to target CRC stem cells as a novel and effective way to treat advanced and difficult-to-treat CRC.
最近在结直肠癌（CRC）发病机制中发现的肿瘤起始性结直肠癌干细胞为新型治疗方法提供了一个潜在靶点。然而，关于结直肠癌干细胞的许多细节仍知之甚少。已经提出了几种结直肠癌干细胞的潜在标志物，包括CD133、CD44，以及最近发现的Lgr5。Wnt和转化生长因子（TGF）-β信号通路对干细胞自我更新、增殖和分化的调控也受到了关注。通过APC（腺瘤性息肉病 coli）缺失导致的Wnt信号通路破坏是结直肠癌多阶段进展中最早出现的事件之一，可能发生在隐窝基底干细胞中，产生一个肿瘤细胞群体，然后向上扩展占据隐窝的其余部分。TGF-β信号通路是一条关键的肿瘤抑制通路，在结直肠癌标本中观察到II型受体和Smad4的突变，并且在Wnt信号通路被破坏的肿瘤中与更具侵袭性的疾病相关。TGF-β衔接蛋白β(2)-血影蛋白的缺失与结肠细胞极性和结构的丧失有关，其表达与Smad4的表达平行。本综述提出了靶向结直肠癌干细胞的合理方法，作为治疗晚期和难治性结直肠癌的一种新颖且有效的方式。
