文章：

从转移抑制蛋白中学习治疗经验

Learning therapeutic lessons from metastasis suppressor proteins

原文发布日期：2009-02-01

DOI: 10.1038/nrc2594

类型: Review Article

开放获取: 否

要点：

1. Metastasis accounts for the preponderance of morbidity and mortality in cancer, and accumulating evidence suggests that dissemination of tumour cells may occur earlier in the development of cancer than previously appreciated.
2. Metastasis is regulated either positively or negatively by proteins that promote steps in the metastatic cascade or those that suppress them.
3. Metastasis suppressor genes encode proteins that prevent or reduce the development of metastases in vivo, without simultaneously affecting primary tumour growth. This is in contrast to tumour suppressors, which affect primary tumorigenesis.
4. Metastasis suppressor proteins are lost primarily during cancer progression and not during transformation.
5. Until recently, relatively few metastasis suppressor genes had been characterized. However, expanding genomic technology has made possible in recent years the description of many metastasis suppressor genes impinging on a wide variety of cellular processes.
6. Although metastasis suppressor genes have been shown to work at multiple steps in the process of metastasis, several have been recently demonstrated to specifically suppress the colonization step of metastasis, the process by which solitary or small clusters of tumour cells living in a second organ site (micrometastases) grow to form clinically apparent and lethal macrometastases.
7. Recent work has shown techniques that restore metastasis suppressor function. These include re-expression of the gene from the endogenous locus or by exogenous gene therapy, direct administration of the protein itself and targeting important metastasis mediators downstream of the suppressor that are reciprocally induced with metastasis suppressor protein losses.

要点翻译：

1. 转移在癌症的发病率和死亡率中占据主要部分，且越来越多的证据表明，肿瘤细胞的播散可能发生在癌症发展的较早阶段，比以往所认知的更早。
2. 转移受到蛋白质的正向或负向调控，这些蛋白质要么促进转移级联的步骤，要么抑制这些步骤。
3. 转移抑制基因编码的蛋白质可在不影响原发性肿瘤生长的同时，预防或减少体内转移灶的发展。这与影响原发性肿瘤发生的肿瘤抑制基因形成对比。
4. 转移抑制蛋白主要在癌症进展过程中丢失，而非在转化过程中丢失。
5. 直到最近，相对较少的转移抑制基因得到鉴定。然而，随着基因组技术的扩展，近年来已有许多转移抑制基因被描述，这些基因涉及多种细胞过程。
6. 尽管转移抑制基因已被证明在转移过程的多个步骤中发挥作用，但最近研究表明，其中一些基因特别抑制转移的定植步骤，即生活在第二器官部位的单个或小簇肿瘤细胞（微转移）生长形成临床上明显且致命的大转移的过程。
7. 最近的研究展示了恢复转移抑制功能的技术。这些技术包括通过内源性基因位点重新表达基因或通过外源性基因治疗、直接施用蛋白质本身，以及靶向抑制因子下游的重要转移介质，这些介质在转移抑制蛋白丢失时被相互诱导。

英文摘要：

Metastasis suppressor proteins regulate multiple steps in the metastatic cascade, including cancer cell invasion, survival in the vascular and lymphatic circulation, and colonization of distant organ sites. Understanding the biology of metastasis suppressors provides valuable mechanistic insights that may translate to therapeutic opportunities. Several reports have explored novel strategies for restoring metastasis suppressor function, including gene transfer, induction of previously suppressed gene expression and exogenous administration of gene product. Pathways activated downstream of metastasis suppressor loss can also be targeted. Although none of these strategies are yet in routine clinical use, several are being tested preclinically and in clinical trials.

摘要翻译： 

转移抑制蛋白可调控转移级联反应的多个环节，包括癌细胞侵袭、在血管和淋巴循环中的存活，以及在远处器官部位的定植。深入理解转移抑制因子的生物学机制，可为治疗提供宝贵的理论依据。已有若干研究探索恢复转移抑制功能的创新策略，如基因转移、诱导此前被抑制的基因重新表达，以及外源性给予基因产物。也可针对转移抑制因子缺失后激活的下游通路进行干预。尽管这些策略尚未进入常规临床应用，但部分正处于临床前和临床试验阶段。

原文链接：

Learning therapeutic lessons from metastasis suppressor proteins