Heddle J A, Cosentino L, Dawod G, Swiger R R, Paashuis-Lew Y
Department of Biology, York University, Toronto, Canada.
Environ Mol Mutagen. 1996;28(4):334-41. doi: 10.1002/(SICI)1098-2280(1996)28:4<334::AID-EM6>3.0.CO;2-B.
Self-renewing tissues have a differentiation hierarchy such that the stem cells are the only permanent residents of the tissue, and it is in these cells that most cancerous mutations arise. The progeny of the stem cells either remain stem cells or enter a transient proliferating cell population that differentiates to produce the functional cells of the tissue. The reason that this differentiation hierarchy exists has not been established. We show here that alternative hierarchies, in which there would be no stem cells, are feasible and biologically plausible. We show that current evidence from somatic mutation frequencies at both transgenic and endogenous loci implicates cell division in the origin of most somatic mutations. We suggest, therefore, that the existence of stem cells is an evolutionary consequence of a selective pressure to avoid cancer by reducing the number of somatic mutations. The stem cell hierarchy reduces the number of cell divisions of those cells that reside permanently in the tissue, which reduces the number of somatic mutations and thus minimizes the cancer rate. In the small intestine, the existence of stem cells reduces the mutant frequency in the stem cells by about one order of magnitude. Since two or more mutations are required to transform a cell, the protective effect may be 100-fold or more. Similar factors may be expected in other tissues.
自我更新组织具有分化层次结构，使得干细胞是该组织中唯一的永久驻留细胞，并且大多数癌性突变就发生在这些细胞中。干细胞的后代要么仍然是干细胞，要么进入一个短暂增殖的细胞群体，该群体分化产生组织的功能细胞。这种分化层次结构存在的原因尚未确定。我们在此表明，不存在干细胞的替代层次结构是可行的且在生物学上是合理的。我们表明，来自转基因和内源性位点体细胞突变频率的当前证据表明，大多数体细胞突变的起源与细胞分裂有关。因此，我们认为干细胞的存在是通过减少体细胞突变数量来避免癌症的选择性压力的进化结果。干细胞层次结构减少了那些永久驻留在组织中的细胞的细胞分裂次数，从而减少了体细胞突变的数量，进而将癌症发生率降至最低。在小肠中，干细胞的存在使干细胞中的突变频率降低了约一个数量级。由于转化一个细胞需要两个或更多的突变，这种保护作用可能高达100倍或更多。在其他组织中可能也有类似的因素。
