Tsao J L, Zhang J, Salovaara R, Li Z H, Järvinen H J, Mecklin J P, Aaltonen L A, Shibata D
Department of Pathology, Norris Cancer Center, University of Southern California School of Medicine, Los Angeles, USA.
Am J Pathol. 1998 Oct;153(4):1189-200. doi: 10.1016/S0002-9440(10)65663-5.
Occult aspects of tumor proliferation are likely recorded genetically as their microsatellite (MS) loci become polymorphic. However, MS mutations generated by division may also be eliminated with death as noncoding MS loci lack selective value. Therefore, highly polymorphic MS loci cannot exist unless mutation rates are high, or unless mutation losses are inherently minimized. Mutations accumulate differently when cell fates are determined intrinsically before or extrinsically after division. Stem cell (asymmetrical division as in intestinal crypts) and random (asymmetrical and symmetrical division) proliferation, respectively, represent simulated cell fates determined before or after division. Whereas mutations regardless of selection systematically persist once inherited with stem cell proliferation, mutations are eliminated by the symmetrical losses of both daughter cells with random proliferation. Therefore, greater genetic diversity or MS variance accumulate with stem cell compared with random proliferation. MS loci in normal murine intestinal mucosa and xenografts of cancer cell lines accumulated mutations, respectively, consistent with stem cell and random proliferation. Tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) demonstrated polymorphic MS loci. Overall, three of five adenomas and one of six cancers exhibited high MS variances. Assuming mutation rates are not significantly greater in adenomas than in cancers, these studies suggest the stem cell proliferation and hierarchy of normal intestines persists in many HNPCC adenomas and some cancers. An adenoma stem cell architecture can explain the complex polymorphic MS loci observed in HNPCC adenomas and account for many adenoma features. In contrast, cancers may lose intrinsic control of cell fate. These studies illustrate a feasible phylogenetic approach to unravel and describe occult aspects of human tumor proliferation. The switch from predominantly stem cell to random proliferation may be a critical and defining characteristic of malignancy.
肿瘤增殖的隐匿方面可能会通过其微卫星（MS）位点的多态性被遗传记录下来。然而，由于非编码MS位点缺乏选择价值，分裂产生的MS突变也可能随着细胞死亡而被消除。因此，除非突变率很高，或者除非突变损失本身被最小化，否则高度多态的MS位点不可能存在。当细胞命运在分裂前内在地或分裂后外在地被决定时，突变的积累方式是不同的。干细胞增殖（如肠道隐窝中的不对称分裂）和随机增殖（不对称和对称分裂）分别代表在分裂前或分裂后决定的模拟细胞命运。虽然无论选择如何，突变一旦通过干细胞增殖遗传下来就会系统地持续存在，但在随机增殖中，两个子细胞的对称损失会消除突变。因此，与随机增殖相比，干细胞增殖会积累更多的遗传多样性或MS变异。正常小鼠肠道黏膜和癌细胞系异种移植中的MS位点分别积累了与干细胞增殖和随机增殖一致的突变。遗传性非息肉病性结直肠癌（HNPCC）患者的肿瘤表现出多态性MS位点。总体而言，五个腺瘤中有三个和六个癌症中有一个表现出高MS变异。假设腺瘤中的突变率并不显著高于癌症，这些研究表明正常肠道的干细胞增殖和层级结构在许多HNPCC腺瘤和一些癌症中持续存在。腺瘤干细胞结构可以解释在HNPCC腺瘤中观察到的复杂多态性MS位点，并解释许多腺瘤特征。相比之下，癌症可能会失去对细胞命运的内在控制。这些研究说明了一种可行的系统发育方法，用于揭示和描述人类肿瘤增殖的隐匿方面。从主要的干细胞增殖转变为随机增殖可能是恶性肿瘤的一个关键且决定性的特征。
