文章：

肿瘤发生：需要一个村庄

Tumorigenesis: it takes a village

原文发布日期：2015-07-02

DOI: 10.1038/nrc3971

类型: Review Article

开放获取: 否

要点：

1. Most human cancers exhibit a high degree of intratumour heterogeneity that arises from heritable and stochastic genetic and epigenetic changes, as well as environmental variations within the tumour. Heterogeneous subpopulations that exist within close proximity and compete for limited resources can engage in complex interactions that affect tumorigenesis, disease progression and therapeutic outcomes.
2. Phenotypic changes that arise from subclonal interactions in heterogeneous tumours were observed by cancer biologists very early on. However, as studies mostly focused on cell-autonomous oncogenes and tumour suppressors, investigations into clonal interactions went under the radar for almost three decades. With the increasing recognition of intratumour heterogeneity fuelled by advances in technology, dissecting the mechanistic basis of clonal interactions is now gaining more attention.
3. In addition to the more traditional models that explore clonal interactions strictly from the competitive angle, newer studies are investigating cooperative interactions among subclones that could give rise to novel characteristics and that potentially increase the growth and progression of the tumour.
4. In the absence of proper tools to directly study clonal interactions in patient samples, studies in D. melanogaster, rodents and xenograft systems (using both established cell lines and patient-derived cells) are providing us with mechanistic insights into interclonal crosstalk.
5. Theoretical and mathematical modelling are being used to simulate clonal dynamics under variable circumstances. Although currently far from perfect, these in silico cancer models have already been useful for the design of optimized cancer therapies for the more effective eradication of tumours.
6. Cooperation can be metabolically costly but evolution and survival are more efficient, especially in a changing environment, when diversity and heterogeneity are high. Insights from patient tumours have revealed the presence of multiple independent neoplastic driver subclones that could re-establish tumour heterogeneity after therapy and lead to disease relapse. Furthermore, there is increasing evidence of transient clonal cooperation between neoplastic and benign subclones, which can also lead to tumour recurrence.
7. In order to tackle the ever-evolving populations of tumour cells more effectively and to devise more lasting cures in patients, we must use ecological approaches that take advantage of cooperative tumour-promoting interactions and strategically eliminate them instead of targeting each individual subpopulation.

要点翻译：

1. 大多数人类癌症表现出高度的肿瘤内异质性，这种异质性源于可遗传的随机性遗传和表观遗传改变，以及肿瘤内部的环境变异。在有限空间内共存并竞争有限资源的异质性亚群之间可能发生复杂相互作用，这些相互作用会影响肿瘤发生、疾病进展和治疗效果。
2. 癌症生物学家很早就观察到异质性肿瘤中亚克隆相互作用导致的表型变化。然而，由于研究主要集中在细胞自主性癌基因和肿瘤抑制因子，对克隆相互作用的研究近三十年来一直未被重视。随着技术进步推动了对肿瘤内异质性认识的深化，解析克隆相互作用的机制基础正获得越来越多关注。
3. 除了严格从竞争角度探索克隆相互作用的传统模型外，新的研究正在调查亚克隆间的协同相互作用——这种作用可能产生新特征，并潜在促进肿瘤的生长和进展。
4. 由于缺乏直接研究患者样本中克隆相互作用的合适工具，通过黑腹果蝇、啮齿动物和异种移植系统（使用已建立的细胞系和患者来源细胞）的研究正在为我们提供关于克隆间相互作用的机制性见解。
5. 理论和数学模型正被用于模拟不同情况下的克隆动态。虽然目前远非完美，但这些计算机癌症模型已有助于设计优化癌症治疗方案，以更有效地根除肿瘤。
6. 协同合作可能在代谢层面代价高昂，但在多样性和异质性较高的变化环境中，进化与生存效率更高。对患者肿瘤的研究发现，存在多个独立的肿瘤驱动亚克隆，这些亚克隆可在治疗后重建肿瘤异质性并导致疾病复发。此外，越来越多证据表明肿瘤性亚克隆与良性亚克隆之间存在短暂的克隆合作，这也可能导致肿瘤复发。
7. 为了更有效地应对不断进化的肿瘤细胞群体并设计更持久的治疗方案，我们必须采用生态学方法，利用促进肿瘤的协同相互作用并战略性消除它们，而非单独靶向每个亚群。

英文摘要：

Although it is widely accepted that most cancers exhibit some degree of intratumour heterogeneity, we are far from understanding the dynamics that operate among subpopulations within tumours. There is growing evidence that cancer cells behave as communities, and increasing attention is now being directed towards the cooperative behaviour of subclones that can influence disease progression. As expected, these interactions can add a greater layer of complexity to therapeutic interventions in heterogeneous tumours, often leading to a poor prognosis. In this Review, we highlight studies that demonstrate such interactions in cancer and postulate ways to overcome them with better-designed therapeutic strategies.

摘要翻译： 

尽管人们普遍接受大多数肿瘤存在一定程度的瘤内异质性，我们对肿瘤亚群之间动态变化的理解仍十分有限。越来越多的证据表明，癌细胞以‘群体’方式行事，研究者的注意力正逐渐转向能影响疾病进展的亚克隆间协同行为。正如预期，这些相互作用为异质性肿瘤的治疗干预增添了更大层次的复杂性，并常导致预后不良。在本综述中，我们重点介绍展示此类癌症相互作用的研究，并设想通过更优设计的治疗策略来克服它们。

原文链接：

Tumorigenesis: it takes a village