文章：

超越遗传学：用肿瘤微环境驱动癌症

Beyond genetics: driving cancer with the tumour microenvironment behind the wheel

原文发布日期：2024-02-12

DOI: 10.1038/s41568-023-00660-9

类型: Review Article

开放获取: 否

英文摘要：

Cancer has long been viewed as a genetic disease of cumulative mutations. This notion is fuelled by studies showing that ageing tissues are often riddled with clones of complex oncogenic backgrounds coexisting in seeming harmony with their normal tissue counterparts. Equally puzzling, however, is how cancer cells harbouring high mutational burden contribute to normal, tumour-free mice when allowed to develop within the confines of healthy embryos. Conversely, recent evidence suggests that adult tissue cells expressing only one or a few oncogenes can, in some contexts, generate tumours exhibiting many of the features of a malignant, invasive cancer. These disparate observations are difficult to reconcile without invoking environmental cues triggering epigenetic changes that can either dampen or drive malignant transformation. In this Review, we focus on how certain oncogenes can launch a two-way dialogue of miscommunication between a stem cell and its environment that can rewire downstream events non-genetically and skew the morphogenetic course of the tissue. We review the cells and molecules of and the physical forces acting in the resulting tumour microenvironments that can profoundly affect the behaviours of transformed cells. Finally, we discuss possible explanations for the remarkable diversity in the relative importance of mutational burden versus tumour microenvironment and its clinical relevance.

摘要翻译： 

癌症长期以来被视为一种由突变累积导致的遗传性疾病。这一观点得到了以下研究的支持：衰老组织常常充斥着具有复杂致癌背景的克隆，这些克隆与正常组织成分看似和谐共存。然而同样令人费解的是，当携带高突变负荷的癌细胞在健康胚胎环境中发育时，却能形成正常、无肿瘤的小鼠。相反，最新证据表明，仅表达一个或少数几个癌基因的成体组织细胞在某些情境下，能够产生表现出恶性侵袭性癌症多种特征的肿瘤。若不引入能够抑制或驱动恶性转化的表观遗传变化的环境信号，这些迥异的观察结果难以得到统一解释。本综述重点关注某些癌基因如何启动干细胞与其环境之间的双向错误对话，从而以非遗传方式重编程下游事件并扭曲组织的形态发生进程。我们探讨了由此产生的肿瘤微环境中的细胞、分子及物理力量，这些因素能深刻影响转化细胞的行为。最后，我们对突变负荷与肿瘤微环境相对重要性之间存在显著差异的可能解释及其临床意义进行了讨论。

原文链接：

Beyond genetics: driving cancer with the tumour microenvironment behind the wheel