近日，著名国际学术期刊nature在线发表了芬兰科学家的一项最新研究进展，他们从进化的角度阐述了肿瘤转移的复杂性机制，并通过前列腺癌具体展示了不同转移灶之间是如何产生联系，促进癌症进展。这项研究对于从根本上理解肿瘤转移的机制提供了重要指导意义。
癌症是遵循达尔文进化论，经历了一个持续的进化过程出现的。在一个原发肿瘤中常会存在多个竞争性亚克隆，这种进化过程最终导致肿瘤转移的形成，同时也是90%癌症相关死亡的主要原因。
尽管这一进化过程具有临床重要性，但癌细胞向远端器官扩散的原则仍不清楚。虽然有假设说每个肿瘤转移都来自于单个肿瘤细胞，并且也有部分研究结果给与该假设以支持，但最近一些研究利用肿瘤小鼠模型发现肿瘤的形成存在多克隆萌发的情况并且在不同亚克隆之间存在克隆协同作用。
在该项研究中，研究人员发现了确凿证据，证明在人类恶性肿瘤中也存在多克隆萌发的情况，并以转移性前列腺癌为背景在不同癌转移之间建立了克隆遗传联系。利用全基因组测序的方法，研究人员对10位前列腺癌病人的不同转移灶进行了分析，在前所未有的细节方面揭示了肿瘤细胞亚克隆的转移扩散模式。结果发现从转移灶到转移灶的扩散模式普遍存在，既可以通过 "播种"的方式，建立全新的转移灶，也可以通过不同转移灶之间的多个肿瘤细胞克隆交换来实现扩散。抑癌基因的表达损伤通常作为单一事件发生，但参与AR信号通路的基因发生突变在不同转移灶中比较常见。
这项研究详细阐述了肿瘤转移扩散的复杂模式，进一步加深了我们对前列腺癌治疗抵抗的理解，具有非常重要的指导意义。
原文摘要：Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour1, 2, 3, 4. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths5. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported6, 7, 8, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones9, 10. Here we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, wheras mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer.
