Hunter Kent W
Laboratory of Population Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 41, Room D702, 41 Library Drive, Bethesda, MD 20892-5060, USA.
Cancer Lett. 2003 Oct 28;200(2):97-105. doi: 10.1016/s0304-3835(03)00420-8.
Metastasis, the spread and growth of tumors at secondary sites, is an extremely important clinical event, since the majority of cancer mortality is associated with the metastatic tumors rather than the primary tumor. In spite of the importance of metastasis in the clinical setting, the actual process is extremely inefficient. Millions of tumor cells can be shed into the vasculature daily yet few secondary tumors are formed. To successfully colonize a distant site tumor cells must overcome a series of barriers. Failure to complete any single step in the metastatic cascade abrogates the ability to form a secondary lesion. A variety of theories have been proposed to explain the inefficiency of the metastatic process. The most commonly accepted, the progression theory, posits a series of random mutational occurs within a primary tumor to generate a small subpopulation that acquires full metastatic capability. While significant evidence supports this model, recent discoveries demonstrating the ability to predict metastatic propensity from gene expression profiles in bulk tumor tissue are not consistent with only a small subpopulation of cells in the primary tumor acquiring metastatic ability. A second theory of metastatic inefficiency, the transient compartment theory, is more consistent with the microarray data, but does not completely explain observations like metastasis associated loss-of-heterozygosity events. To reconcile the observed results additional variables need to be added to the model of metastatic inefficiency. One possible variable that might explain the discrepancies is genetic background effects. Studies have demonstrated that the genetic background a tumor arises on can have significant affects on the ability of the tumor to metastasize and on gene expression profiles. Thus the observations could be reconciled by combining the theories, with genetic background influencing both metastatic efficiency and predictive gene expression profiles, upon which subsequently occur metastasis-promoting mutational and epigenetic events. If the genetic background is an important determinant of metastatic efficiency it would have significant implications for the clinical prediction and treatment of metastatic disease, as well as for the design of potential prevention strategies.
转移，即肿瘤在继发部位的扩散和生长，是一个极其重要的临床事件，因为大多数癌症死亡与转移性肿瘤而非原发性肿瘤相关。尽管转移在临床环境中很重要，但其实际过程效率极低。每天有数百万肿瘤细胞进入脉管系统，但形成的继发性肿瘤却很少。为了成功在远处部位定植，肿瘤细胞必须克服一系列障碍。转移级联反应中任何一个步骤未能完成都会消除形成继发性病变的能力。人们提出了各种理论来解释转移过程的低效率。最被广泛接受的进展理论认为，原发性肿瘤内会发生一系列随机突变，产生一小部分具有完全转移能力的亚群。虽然有大量证据支持这一模型，但最近发现从大块肿瘤组织的基因表达谱预测转移倾向的能力与只有原发性肿瘤中的一小部分细胞获得转移能力并不一致。转移低效率的第二种理论，即瞬时隔室理论，与微阵列数据更一致，但不能完全解释诸如转移相关杂合性缺失事件等观察结果。为了协调观察结果，需要在转移低效率模型中加入其他变量。一个可能解释这些差异的变量是遗传背景效应。研究表明，肿瘤发生的遗传背景会对肿瘤转移能力和基因表达谱产生重大影响。因此，可以通过结合这些理论来协调观察结果，即遗传背景影响转移效率和预测性基因表达谱，随后发生促进转移的突变和表观遗传事件。如果遗传背景是转移效率的重要决定因素，那么它将对转移性疾病的临床预测和治疗以及潜在预防策略的设计产生重大影响。
