Central Laboratories, Xuhui Central Hospital, Shanghai Clinical Research Center, Chinese Academy of Sciences, 966 Middle Huaihai Road, Shanghai 200031, China.
Future Oncol. 2014 May;10(7):1239-53. doi: 10.2217/fon.13.272.
The somatic mutation carcinogenesis theory has dominated for decades. The alternative theory, tissue organization field theory, argues that the development of cancer is determined by the surrounding microenvironment. However, neither theory can explain all features of cancer. As cancers share the features of uncontrolled proliferation and genomic instability, they are likely to have the same pathogenesis. It has been found that various DNA repair pathways within a cell crosstalk with one another, forming a DNA repair network. When one DNA repair pathways is defective, the others may work as compensatory backups. The latter pathways are explored for synthetic lethal anticancer therapy. In this article, we extend the concept of compensatory alternative DNA repair to unify the theories. We propose that the microenvironmental stress can activate low-fidelity compensatory alternative DNA repair, causing mutations. If the mutation occurs to a DNA repair gene, this secondarily mutated gene can lead to even more mutated genes, including those related to other DNA repair pathways, eventually destabilizing the genome. Therefore, the low-fidelity compensatory alternative DNA repair may mediate microenvironment-dependent carcinogenesis. The proposal seems consistent with the view of evolution: the environmental stress causes mutations to adapt to the changing environment.
体细胞突变致癌理论已经主导了几十年。替代理论——组织场理论认为，癌症的发展是由周围的微环境决定的。然而，这两种理论都不能解释癌症的所有特征。由于癌症具有不受控制的增殖和基因组不稳定性的特征，因此它们可能具有相同的发病机制。人们发现，细胞内的各种 DNA 修复途径相互交流，形成一个 DNA 修复网络。当一个 DNA 修复途径有缺陷时，其他途径可能作为补偿性备份工作。人们正在探索后者途径，以进行合成致死性抗癌治疗。在本文中，我们将补偿性替代 DNA 修复的概念扩展到统一理论中。我们提出，微环境压力可以激活低保真度补偿性替代 DNA 修复，导致突变。如果突变发生在一个 DNA 修复基因上，那么这个二次突变基因可能会导致更多的突变基因，包括与其他 DNA 修复途径相关的基因，最终使基因组不稳定。因此，低保真度补偿性替代 DNA 修复可能介导了依赖于微环境的致癌作用。这一假说似乎与进化观点一致：环境压力导致突变以适应不断变化的环境。
