MRC Centre for Inflammation Research, University of Edinburgh College of Medicine and Veterinary Medicine, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
MRC Centre for Inflammation Research, University of Edinburgh College of Medicine and Veterinary Medicine, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Philos Trans R Soc Lond B Biol Sci. 2018 Jan 5;373(1737). doi: 10.1098/rstb.2017.0003.
The cell-death programme, apoptosis, is well established as a tumour suppressor mechanism. Paradoxically, high levels of apoptosis in tumours are closely coupled with poor prognosis. Indeed, where it has been studied, cell loss is a striking feature of high-grade cancers, illustrating the importance of considering malignant disease as an imbalance between cell gain and cell loss that favours cell gain rather than as a unidirectional disorder of cell gain alone. In addition to orchestrating cell loss, apoptosis can signal regenerative responses-for example compensatory proliferation-in neighbouring cells. Accumulating evidence suggests that normal tissue repair and regenerative processes are hijacked in the malignant tissue microenvironment such that cancer may be likened to a 'wound that fails to stop repairing'. We have proposed that a critical requirement for the successful growth, progression and re-growth of malignant tumours is a complex milieu, conceptually termed the 'onco-regenerative niche', which is composed, in addition to transformed neoplastic cells, of a network of normal cells and factors activated as if in tissue repair and regeneration. Our work is based around the hypothesis that tumour cell apoptosis, macrophage activation and endothelial activation are key, interlinked elements of the onco-regenerative niche and that apoptotic tumour cell-derived extracellular vesicles provide critical intercellular communication vehicles of the niche. In aggressive B-cell lymphoma, tumour cell apoptosis promotes both angiogenesis and the accumulation of pro-tumour macrophages in the lymphoma microenvironment. Furthermore, apoptotic lymphoma-derived extracellular vesicles have potent pro-tumour potential. These findings have important implications for the roles of apoptosis in regulation of malignant diseases and for the efficacy of apoptosis-inducing anti-cancer therapies.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'.
细胞死亡程序，即细胞凋亡，作为一种肿瘤抑制机制已得到充分证实。具有讽刺意味的是，肿瘤中高水平的细胞凋亡与预后不良密切相关。事实上，在已经研究过的地方，细胞丢失是高级别癌症的一个显著特征，这说明了考虑恶性疾病作为细胞获得和细胞丢失之间的不平衡是很重要的，这种不平衡有利于细胞获得，而不仅仅是细胞获得的单向紊乱。除了协调细胞丢失外，细胞凋亡还可以发出再生反应的信号，例如相邻细胞中的代偿性增殖。越来越多的证据表明，正常组织修复和再生过程在恶性组织微环境中被劫持，以至于癌症可能被比作“无法停止修复的伤口”。我们提出，恶性肿瘤成功生长、进展和再生长的关键要求是一个复杂的环境，概念上称为“肿瘤再生生态位”，除了转化的肿瘤细胞外，还由正常细胞网络和作为组织修复和再生而激活的因素组成。我们的工作基于这样一个假设，即肿瘤细胞凋亡、巨噬细胞激活和内皮细胞激活是肿瘤再生生态位的关键、相互关联的元素，而凋亡的肿瘤细胞衍生的细胞外囊泡提供了生态位的关键细胞间通讯载体。在侵袭性 B 细胞淋巴瘤中，肿瘤细胞凋亡促进了血管生成和肿瘤微环境中促肿瘤巨噬细胞的积累。此外，凋亡的淋巴瘤衍生的细胞外囊泡具有很强的促肿瘤潜力。这些发现对凋亡在调节恶性疾病中的作用以及凋亡诱导抗癌治疗的疗效具有重要意义。本文是“细胞外囊泡和肿瘤微环境”讨论会议的一部分。
