Department of Experimental Pathology and Oncology, University of Florence, Florence, Italy.
Cell Cycle. 2013 Jan 15;12(2):353-64. doi: 10.4161/cc.23200. Epub 2012 Jan 15.
One undisputed milestone of traditional oncology is neoplastic progression, which consists of a progressive selection of dedifferentiated cells driven by a chance sequence of genetic mutations. Recently it has been demonstrated that the overexpression of well-defined transcription factors reprograms somatic cells to the pluripotent stem status. The demonstration raises crucial questions as to whether and to what extent this reprogramming contributes to tumorigenesis, and whether the epigenetic changes involved in it are reversible. Here, we show for the first time that a tumor produced in vivo by a chemical carcinogen is the product of the interaction between neoplastic progression and reprogramming. The experimental model employed the prototype of ascites tumors, the Yoshida AH130 hepatoma and other neoplasias, including human melanoma. AH130 hepatoma was started in the liver by the carcinogen o-aminoazotoluene. This compound binds to and abolishes the p53 protein, producing a genomic instability that promotes both the neoplastic progression and the hepatoma reprogramming. Eventually this tumor contained 100% CD133(+) elements and pO(2)-dependent percentages of the three embryonic transcription factors Nanog, Klf4 and c-Myc. Once transferred into aerobic cultures, the minor cellular fraction expressing this triad generates various types of adherent cells, which are progressively substituted by non-tumorigenic elements committed to fibromuscular, neuronal and glial differentiation. This reprogramming appears to be accomplished stepwise, with the assembly of the triad into a sophisticated transcriptional, oxygen-dependent circuitry, in which Nanog and Klf4 antagonistically regulate c-Myc, and hence, cell hypoxia survival and cell cycle activation.
传统肿瘤学无可争议的里程碑之一是肿瘤进展，它由遗传突变的偶然序列驱动的去分化细胞的渐进选择组成。最近已经证明，定义明确的转录因子的过度表达将体细胞重编程为多能干细胞状态。这一证明提出了至关重要的问题，即这种重编程是否以及在多大程度上促进了肿瘤发生，以及涉及其中的表观遗传变化是否可逆。在这里，我们首次表明，化学致癌剂在体内产生的肿瘤是肿瘤进展和重编程相互作用的产物。所采用的实验模型是腹水肿瘤的原型，即 Yoshida AH130 肝癌和其他肿瘤，包括人类黑色素瘤。AH130 肝癌由致癌剂邻氨基偶氮甲苯在肝脏中引发。这种化合物与 p53 蛋白结合并使其失活，产生基因组不稳定性，从而促进肿瘤进展和肝癌重编程。最终，这个肿瘤包含 100%的 CD133(+)细胞和依赖 pO2 的三种胚胎转录因子 Nanog、Klf4 和 c-Myc 的比例。一旦转移到需氧培养中，表达这三联体的少量细胞亚群会产生各种类型的贴壁细胞，这些细胞逐渐被向纤维肌、神经元和神经胶质分化的非肿瘤性细胞所取代。这种重编程似乎是逐步完成的，三联体组装成一个复杂的转录、氧依赖性电路，其中 Nanog 和 Klf4 拮抗地调节 c-Myc，从而调节细胞缺氧存活和细胞周期激活。
