Top-down morphogenesis of colorectal tumors
Top-down morphogenesis of colorectal tumors
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DOI：
10.1073/pnas.051629398
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发表时间：
2001-02-27
影响因子：
11.1
通讯作者：
Vogelstein, B
中科院分区：
文献类型：
--
作者：
Shih, LM;Wang, TL;Vogelstein, B
肿瘤学的基本原则之一是肿瘤起源于干细胞。在结肠中，干细胞被认为位于隐窝的底部。然而，在肿瘤发生的早期阶段，通常在隐窝的腔表面发现发育异常的细胞，而在这些相同隐窝的基部的细胞在形态上看起来正常。为了理解这种差异，我们评估了从小结直肠腺瘤中相同隐窝的基底和开口分离的细胞的分子特征。我们发现，在隐窝顶部的异型增生细胞往往表现出腺瘤性结肠息肉病（APC）和肿瘤相关的基因表达模式的遗传改变。相反，位于这些相同的隐窝底部的细胞不包含这样的改变，并且与它们上方的连续转化细胞没有克隆相关性。这些结果意味着腺瘤性息肉的发展是通过自上而下的机制进行的。粘膜表面部分的基因改变的细胞横向和向下扩散，形成新的隐窝，这些隐窝首先连接到先前存在的正常隐窝，并最终取代它们。
One of the fundamental tenets of oncology is that tumors arise from stem cells. In the colon, stem cells are thought to reside at the base of crypts. In the early stages of tumorigenesis, however, dysplastic cells are routinely found at the luminal surface of the crypts whereas the cells at the bases of these same crypts appear morphologically normal. To understand this discrepancy, we evaluated the molecular characteristics of cells isolated from the bases and orifices of the same crypts in small colorectal adenomas. We found that the dysplastic cells at the tops of the crypts often exhibited genetic alterations of adenomatous polyposis coli (APC) and neoplasia-associated patterns of gene expression. In contrast, cells located at the base of these same crypts did not contain such alterations and were not clonally related to the contiguous transformed cells above them. These results imply that development of adenomatous polyps proceeds through a top-down mechanism. Genetically altered cells in the superficial portions of the mucosae spread laterally and downward to form new crypts that first connect to preexisting normal crypts and eventually replace them.