Sell S
Department of Pathology and Laboratory Medicine, Medical School, University of Texas Health Science Center at Houston 77225.
Environ Health Perspect. 1993 Dec;101 Suppl 5(Suppl 5):15-26. doi: 10.1289/ehp.93101s515.
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 aberrant 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.
鉴于癌症必定起源于具有分裂潜力的细胞这一基本原理，关于癌症细胞起源的两个主要且并非相互排斥的假说是：恶性肿瘤的产生，一是源于干细胞因成熟停滞，二是源于保留增殖能力的成熟细胞的去分化。干细胞在致癌过程中的作用在畸胎瘤中得到了明确证明。畸胎瘤的恶性干细胞源自正常的多能干细胞，并且有分化为正常良性成熟组织的潜力。一个被广泛研究的支持去分化的模型是，肝癌被认为起源于化学物质诱导大鼠肝脏产生的“癌前”灶和结节。然而，肝癌发生的去分化概念受到了最近一些解释的挑战，这些解释表明肝细胞癌起源于特定干细胞异常分化导致的成熟停滞。两种假说都得到了不同肝癌致癌方案处理后啮齿动物肝脏中发生的细胞变化的支持。由改变的肝细胞形成灶和结节支持去分化；具有分化为胆管或肝细胞潜力的小卵圆形细胞的增殖支持特定干细胞的成熟停滞。现在推测，灶和结节性变化反映了对致癌物毒性作用的适应性变化，而不是癌症的“癌前”阶段。干细胞模型预测，遗传毒性化学物质会在特定干细胞中诱导突变，这些突变可能在其后代中表达。引发细胞的增殖由促进事件诱导，这些促进事件也会导致额外的突变发生。
