Komarova Natalia L, Wang Liming
Departmentof Mathematics, Rutgers University, Piscataway, New Jersey, USA.
Cell Cycle. 2004 Dec;3(12):1558-65. doi: 10.4161/cc.3.12.1186. Epub 2004 Dec 1.
It is widely believed that stem cells are of special importance for colorectal cancer initiation. The earliest event being the inactivation of both alleles of the Adenomatous Polyposis Coli (APC) gene, it is thought that the stem cells are the most likely target for these two first hits. Indeed, at the first glance, short-lived differentiated cells cannot sustain a mutation long enough for the second hit to occur, because of the constant apoptosis/renewal process in epithelial tissues. Using a straightforward calculation, we show that this intuitive argument is incorrect. Our model based on the conventional view of colon crypt architecture, suggests that at least one of the two hits may occur in the migrating compartment. We suggest that a possible role of differentiating cells in cancer initiation cannot be discarded simply based on the fact that they are short-lived. More evidence is needed to understand the cellular origins of cancer and to identify whether or not a double hit in a daughter cell can be "immortalizing". In this study we discuss several scenarios and propose some experiments which can shed light on these questions.
人们普遍认为干细胞在结直肠癌的起始过程中具有特殊重要性。最早的事件是腺瘤性息肉病基因（APC）的两个等位基因均失活，人们认为干细胞最有可能是这两个首次打击的靶点。确实，乍一看，由于上皮组织中持续的凋亡/更新过程，寿命短暂的分化细胞无法维持突变足够长的时间以使第二次打击发生。通过一个简单的计算，我们表明这个直观的论点是不正确的。我们基于结肠隐窝结构的传统观点建立的模型表明，这两次打击中至少有一次可能发生在迁移区室。我们认为，不能仅仅因为分化细胞寿命短暂就排除它们在癌症起始中可能发挥的作用。需要更多证据来了解癌症的细胞起源，并确定子细胞中的双重打击是否能够“永生化”。在本研究中，我们讨论了几种情况并提出了一些实验，这些实验可以阐明这些问题。
