Department of Pharmacology and Toxicology, College of Pharmacy and The University of Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724-5024, USA.
Adv Exp Med Biol. 2013;754:179-94. doi: 10.1007/978-1-4419-9967-2_9.
Malignant cancer emerges from normal healthy cells in a multistep -process that involves both genetic and epigenetic lesions. Both genetic and environmental inputs participate in driving the epigenetic changes that occur during human carcinogenesis. The pathologic changes seen in DNA methylation and histone posttranslational modifications are complex, deeply intertwined, and act in concert to produce malignant transformation. To better understand the causes and consequences of the pathoepigenetic changes in cancer formation, a variety of experimentally tractable human cell line model systems that accurately reflect the molecular alterations seen in the clinical disease have been developed. Results from studies using these cell line model systems suggest that early critical epigenetic events occur in a stepwise fashion prior to cell immortalization. These epigenetic steps coincide with the cell's transition through well-defined cell proliferation barriers of stasis and telomere dysfunction. Following cell immortalization, stressors, such as environmental toxicants, can induce malignant transformation in a process in which the epigenetic changes occur in a smoother progressive fashion, in contrast to the stark stepwise epigenetic changes seen prior to cell immortalization. It is hoped that developing a clearer understanding of the identity, timing, and consequences of these epigenetic lesions will prove useful in future clinical applications that range from early disease detection to therapeutic intervention in malignant cancer.
恶性肿瘤是从正常健康细胞多步骤演变而来的，这个过程既涉及遗传改变，也涉及表观遗传改变。遗传和环境因素都参与了驱动人类癌症发生过程中发生的表观遗传改变。在 DNA 甲基化和组蛋白翻译后修饰中观察到的病理变化是复杂的、深度交织的，并协同作用产生恶性转化。为了更好地理解癌症形成中病理表观遗传改变的原因和后果，已经开发了多种可在实验中处理的、准确反映临床疾病中分子改变的人类细胞系模型系统。使用这些细胞系模型系统进行的研究结果表明，早期关键的表观遗传事件以前细胞永生化的方式逐步发生。这些表观遗传步骤与细胞通过静止和端粒功能障碍的明确细胞增殖障碍的过渡相吻合。在细胞永生化之后，应激源，如环境毒素，可以在一个过程中诱导恶性转化，在这个过程中，表观遗传变化以更平滑的渐进方式发生，与细胞永生化之前观察到的明显逐步的表观遗传变化形成对比。希望对这些表观遗传损伤的性质、时间和后果有更清晰的认识，将有助于未来的临床应用，从早期疾病检测到恶性癌症的治疗干预。
