CEACAM1 and hyperplastic polyps: new links in the chain of events leading to colon cancer
CEACAM1 and hyperplastic polyps: new links in the chain of events leading to colon cancer
复制标题
CEACAM1 和增生性息肉：导致结肠癌的事件链中的新环节
作者：
J. Shively
Nittka等人报道的结肠增生性病变中肿瘤抑制蛋白的下调。在本期的《癌基因》杂志中，揭示了在已知导致结肠癌发生的基因改变之前发生的事件。下调的蛋白质是一种被称为CEACAM1的细胞黏附分子，最近被认为与产生凋亡信号有关，以确保乳腺管腔周围单层上皮细胞的发育和维持。Nittka等人也报道了诱导细胞凋亡的作用，并提出了由于CEACAM1表达缺失而导致的细胞凋亡减少，这是对增生和获得致癌突变的可能性增加的解释，例如APC基因的失活。结肠癌表现为从良性增生性组织到癌前腺瘤再到显性肿瘤的形态演变的最明显的例子之一，在从腺瘤到癌的转变过程中，基因突变逐渐积累。然而，虽然公认结肠最早的形态变化包括异常隐窝病灶(ACF)和增生性息肉(HPP)，但它们缺乏遗传变化，如腺瘤性息肉病(APC)基因突变或缺失，从而得出肿瘤不是来自这些细胞的结论。如果不是来自这些细胞，那么从哪里来？一种假设是，隐窝深处的干细胞在APC中积累了早期突变，随着它们积累更多的突变，如k-ras，失去了分化、持续分裂的能力，并逐渐形成肿瘤。与这一假设相反的是，没有APC突变的息肉经常与有APC突变的腺瘤一起被发现，而切除这些息肉可以降低结肠癌的发病率。在Nittka等人的论文中。在本期《癌基因》杂志中，提出了ACF和HPP细胞是癌前病变的证据。作者研究了ACF和HPP病变，这些病变代表了肿瘤抑制蛋白CEACAM1表达的最早形态异常阶段，发现这些病变的表达水平与腺瘤和腺癌相同。正如预期的那样，APC在这些皮损中的表达水平是正常的，b-连环蛋白的表达模式也是正常的。因此，CEACAM1表达的沉默先于守门人基因APC的变化，如果发生这种变化，细胞容易发生进一步的致癌突变。Nittka等人。认为CEACAM1的缺失会导致细胞凋亡水平降低，从而导致这些细胞增殖的净增加。虽然大多数过度增殖的细胞退化，但有一小部分但相当大的一部分继续积累致癌突变。现在我们将注意力转向CEACAM1在这一过程中的作用。出现了两个重要的问题：第一，CEACAM1沉默的机制是什么；第二，CEACAM1在结肠中的作用是什么？让我们从CEACAM1的功能开始。CEACAM1是CEA基因家族中的一员，在19号染色体上有28个基因。在正常结肠中表达的四个成员是CEA、CEACAM1、CEACAM6和CEACAM7。只有CEACAM1具有跨膜和胞质结构域(另外三个是GPI连接到膜上)，只有CEACAM1在啮齿动物中保守，这表明其他三个基因在肠道中具有新的功能。事实上，CEACAM1表达于整个胃肠道的上皮细胞以及其他形成管腔的器官，如肝脏、乳腺、胰腺、前列腺和肾脏。然而，尽管CEACAM1(以及在结肠中表达的其他三个基因)被称为细胞-细胞黏附分子，但它们在结肠(以及其他器官)中呈现出独有的顶端表达模式，这对这种功能分配提出了质疑。使用乳腺形态发生的体外模型，其中CEACAM1的表达模式可以在发育的每个阶段进行跟踪，我们已经证明，CEACAM1确实在器官发生早期的细胞之间被发现，并且在启动凋亡程序中是必不可少的，该程序消除了不与基底膜接触的中央细胞(Huang等人，1999；Kirshner等人，2003)。这不仅创造了管腔，还确保了单层上皮细胞将沿着基底膜保持。因此，CEACAM1是这一进程中的主要参与者，该进程声明：Cells*COMMICATION：je Shivelly；电子邮件：jshiful@coh.org Oncogene(2004)23,9303-9305&2004自然出版集团版权所有0950-9232/04$30.00
The downregulation of a tumor suppressor protein in hyperplastic lesions of the colon, as reported by Nittka et al. in this issue of Oncogene, sheds new light on the events that precede the genetic alterations known to contribute to the development of colon cancer. The downregulated protein is a cell adhesion molecule known as CEACAM1, recently implicated in generating apoptotic signals to ensure the development and maintenance of a single monolayer of epithelial cells around the lumena of the mammary gland. A role in inducing apoptosis is also reported by Nittka et al., and a reduction in apoptosis, due to loss of CEACAM1 expression proposed as an explanation for both the hyperplasia, and an increased likelihood of acquiring an oncogenic mutation, such as inactivation of the APC gene. Colon cancers exhibit one of the clearest examples of the morphological progression of benign hyperplastic tissue to premalignant adenomas to overt neoplasia with genetic mutations progressively accumulating in the transition from adenomas to carcinomas. However, while it is well recognized that the earliest morphological changes in the colon include aberrant crypt foci (ACF) and hyperplastic polyps (HPP), their lack of genetic alterations such as mutations or deletions in the adenomatous polyposis coli (APC) gene have led to the conclusion that tumors do not arise from these cells. If not from these cells, then from where? One hypothesis is that the stem cells deep in the crypts accumulate early mutations in APC, lose their ability to differentiate, keep dividing, and gradually form tumors as they accumulate more mutations such as k-ras. Against this hypothesis is the finding that polyps free of APC mutations are frequently found together with adenomas that have APC mutations, and the fact that removal of these polyps decreases the incidence of colon cancer. In the paper by Nittka et al. in this issue of Oncogene, evidence that ACF and HPP cells are preneoplastic is presented. The authors have examined ACF and HPP lesions that represent the earliest stage of morphological abnormality for the expression of the tumor suppressor protein CEACAM1, and found that these lesions have the same reduced levels of expression as found in adenomas and adenocarcinomas. As expected, expression levels of APC were normal in these lesions, as was the expression pattern for b-catenin. Thus, silencing of CEACAM1 expression precedes changes in the gatekeeper gene APC, which, if they occur, predispose the cell to further oncogenic mutations. Nittka et al. propose that loss of CEACAM1 leads to reduced levels of apoptosis, thus leading to a net increase in proliferation in these cells. While the majority of the hyperproliferative cells regress, a small but significant portion go on to accumulate oncogenic mutations. Now we turn our attention to the role of CEACAM1 in this process. Two important questions arise: first, what is the mechanism of CEACAM1 silencing and second what is the function of CEACAM1 in the colon? Let us start with the function of CEACAM1. CEACAM1 is a member of the CEA gene family that includes 28 genes on chromosome 19. Four members of the family that are expressed in normal colon are CEA, CEACAM1, CEACAM6, and CEACAM7. Only CEACAM1 has transmembrane and cytoplasmic domains (the other three are GPI-linked to the membrane), and only CEACAM1 is conserved in rodents, suggesting that the other three genes have novel functions in the gut. In fact, CEACAM1 is expressed on epithelial cells throughout the GI tract and in other lumen-forming organs such as the liver, breast, pancreas, prostate and kidney. However, even though CEACAM1 (as well as the other three genes expressed in the colon) have been termed cell–cell adhesion molecules, they exhibit an exclusively apical expression pattern in the colon (as well as other organs), calling into question this functional assignment. Using an in vitro model of mammary morphogenesis, where the expression pattern of CEACAM1 can be followed at each stage of development, we have shown that CEACAM1 is indeed found between cells early in organogenesis, and is essential in the initiation of an apoptotic program that eliminates the central cells that are not in contact with the basement membrane (Huang et al., 1999; Kirshner et al., 2003). This not only creates a lumen, but also ensures that a monolayer of epithelial cells will be maintained along the basement membrane. Thus, CEACAM1 is a major player in the process termed anoikis that states that cells *Correspondence: JE Shively; E-mail: jshively@coh.org Oncogene (2004) 23, 9303–9305 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $30.00
影响因子：
11.2
作者：
Phan, D;Cheng, CJ;Lin, SH
通讯作者：
Lin, SH