CELLULAR-ORIGIN OF CANCER - DEDIFFERENTIATION OR STEM-CELL MATURATION ARREST
CELLULAR-ORIGIN OF CANCER - DEDIFFERENTIATION OR STEM-CELL MATURATION ARREST
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DOI：
10.2307/3431838
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发表时间：
1993-12-01
影响因子：
10.4
通讯作者：
SELL, S
中科院分区：
文献类型：
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作者：
SELL, S
鉴于癌症必须起源于具有分裂潜力的细胞这一基本原则，关于癌症细胞起源的两个主要非排他性假设是，恶性肿瘤起源于：a）由于成熟停滞而源自干细胞；b）源自保留增殖能力的成熟细胞的去分化。干细胞在癌变中的作用在畸胎癌中得到了清楚的证明。畸胎癌的恶性干细胞来源于正常的多能干细胞，具有分化为正常良性成熟组织的潜力。一个广泛研究的支持去分化的模型被认为是肝癌起源于化学物质在大鼠肝脏中诱导的“癌前”病灶和结节。然而，肝癌发生的去分化概念受到最近的解释的挑战，这些解释表明肝细胞癌是由确定的干细胞的异常分化引起的成熟停滞引起的。这两种假设都得到了不同肝癌治疗方案后啮齿动物肝脏中发生的细胞变化的支持。改变的肝细胞形成病灶和结节支持去分化；具有分化成胆管或肝细胞潜力的小卵圆细胞的增殖支持了确定的干细胞的成熟停滞。现在假设病灶和结节变化反映了致癌物毒性作用的适应性变化，而不是癌症的“肿瘤前”阶段。干细胞模型预测，基因毒性化学物质会诱导所确定的干细胞发生突变，这些突变可能会在其后代中表达。起始细胞的增殖是通过促进事件来诱导的，这也允许发生额外的突变。
Given the fundamental principle that cancer must arise from a cell that has the potential to divide, two major nonexclusive hypotheses of the cellular origin of cancer are that malignancy arises a) from stem cells due to maturation arrest or b) from dedifferentiation of mature cells that retain the ability to proliferate. The role of stem cells in carcinogenesis is clearly demonstrated in teratocarcinomas. The malignant stem cells of teratocarcinomas are derived from normal multipotent stem cells and have the potential to differentiate into normal benign mature tissue. A widely studied model supporting dedifferentiation has been the putative origin of hepatocarcinomas from ''premalignant'' foci and nodules induced in the rat liver by chemicals. However, the dedifferentiation concept for hepatocarcinogenesis is challenged by more recent interpretations indicating that hepatocellular carcinoma arises from maturation arrest caused by abherrant differentiation of determined stem cells. Either hypothesis is supported by the cellular changes that occur in the rodent liver after different hepatocarcinogenic regimens. The formation of foci and nodules from altered hepatocytes supports dedifferentiation; the proliferation of small oval cells with the potential to differentiate into either biliary ducts or hepatocytes supports arrested maturation of determined stem cells. It is now postulated that foci and nodular change reflect adaptive changes to the toxic effects of carcinogens and not ''preneoplastic'' stages to cancer. The stem cell model predicts that genotoxic chemicals induce mutations in the determined stem cell which may be expressed in its progeny. Proliferation of initiated cells is induced by promoting events which also allow additional mutations to occur.