| 摘要: |
| 虽然只有25%癌症的发生与病毒等病原体慢性感染直接相关,但是慢性炎症却与多数癌症的发生、发展和预后关系密切。根据我们在乙肝病毒致癌和胃肠道、泌尿系统癌症的发生、发展分子机制等中的系列研究,结合国内外研究进展,作者提出了"癌症进化发育假说"的基本概念和理论框架。该假说的核心学术思想是:由先天遗传因素和后天环境因素如病毒感染的交互作用导致的免疫平衡失调或功能失调维持了慢性非可控性炎症,后者促进癌症发生和发展并贯穿以"变异-选择-适应"为特征的癌症进化发育过程的始终。在非可控性炎症微环境条件下,促炎介质通过反式激活核酸编辑酶及其类似物表达,或引起氧化应激,促进病毒和宿主基因组变异。绝大部分变异细胞和变异病毒在生存竞争中被淘汰,少数变异细胞通过改变原有生存信号通路和模式,在炎症微环境中炎性介质通过表观遗传调控使上皮细胞向间质细胞转化,赋予了癌症起始细胞克服衰老、掠夺营养和无限繁殖等"干性"特征而被选择出来,促进癌症的发生和侵袭。癌症进化发育一般具有"逆向进化"和"去分化"特征,体现了"干性"信号通路在癌症进化发育中的不可或缺性。"癌症进化发育假说"不但在探索炎症促进癌症的本质方面有望具有可试验性,而且对预测、预防、个体化和大众参与性的"P4医学"癌症控制工作具有一定的指导作用。 |
| 关键词: 肿瘤 进化 发育 炎症 突变 选择(遗传学) 适应 |
| DOI：10.3724/SP.J.1008.2015.00349 |
| 投稿时间：2014-09-23修订日期：2015-01-27 |
| 基金项目:国家重点基础研究项目("973"计划,2015CB554000),国家自然科学基金重大研究计划重点项目(91129301),国家自然科学基金国家杰出青年科学基金(81025015). |
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| Hypothesis of cancer evolution and development (Evo-Dev) and its significance for specific prophylaxis and treatment of cancers |
| CAO Guang-wen |
| (Department of Epidemiology, Faculty of Tropical Medicine and Public Health, Second Military Medical University, Shanghai 200433, China) |
| Abstract: |
| Although chronic infection with various pathogens including viruses directly contributes to only approximately 25% of cancers worldwide, chronic inflammation is closely linked to the development, progression and prognosis of most human cancers. In this article the author bring forth a hypothesis termed as "Cancer Evolution-Development" (Cancer Evo-Dev), which is based on our series of studies on the molecular mechanisms of HBV infection-induced hepatocarcinogenesis, gastrointestinal and urological cancers, and world wide advances in this field. The core theory of this hypothesis is: the imbalance or dysfunction caused by the interactions of genetic predispositions and environmental exposures such as viral infection is responsible for the maintenance of chronic non-resolving inflammation. Then non-resolving inflammation promotes cancer occurrence and progression and persists throughout the cancer evolution, which is characterized by a process of "mutation-selection-adaptation". Under the microenvironment of non-resolving inflammation, pro-inflammatory factors promote mutations in viral or host genomes by trans-activating cytidine deaminases and their analogues or by inducing oxidative stress. The majority of cells acquired somatic mutations and mutated viruses are eliminated in survival competition; only a small percentage of the mutated cells are selected and function as cancer-initiating cells; these mutated cells have altered survival signaling pathways and undergo epithelial-to-mesenchymal transition via epigenetic modification by proinflammatory molecules in an inflammatory microenvironment. The selected cells exhibit the characteristics of "stemness" such as overcoming senescence, robbing nutrition, and proliferating immortally, thus promotes carcinogenesis and invasion. Cancers generally possess the properties of "backward evolution" and "retro-differentiation", suggesting the indispensability of stem-like signaling pathways in cancer Evo-Dev. This hypothesis of Cancer Evo-Dev is expected to be not only testable in understanding the inherent mechanisms by which inflammation promotes the development of cancers, but also instructive for the prophylaxis and control of cancers in the model of predictive, preventive, personalized, and participatory (P4) medicine. |
| Key words: neoplasms evolution development inflammation mutation selection (genetics) adaptation |
