An apoptosis-driven 'onco-regenerative niche': roles of tumour-associated macrophages and extracellular vesicles.
An apoptosis-driven 'onco-regenerative niche': roles of tumour-associated macrophages and extracellular vesicles.
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DOI：
10.1098/rstb.2017.0003
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发表时间：
2018-01-05
期刊：
影响因子：
--
通讯作者：
Paterson M
中科院分区：
文献类型：
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作者：
Gregory CD;Paterson M
细胞死亡程序——细胞凋亡，已被确认为一种肿瘤抑制机制。然而矛盾的是，肿瘤中高水平的细胞凋亡却与不良预后密切相关。实际上，在已研究的案例中，细胞丢失是高级别癌症的一个显著特征，这表明将恶性疾病视为细胞增殖和细胞丢失之间有利于细胞增殖的失衡，而非仅仅是细胞增殖的单向紊乱是很重要的。除了协调细胞丢失外，细胞凋亡还能向邻近细胞发出再生反应的信号——例如代偿性增殖。越来越多的证据表明，正常的组织修复和再生过程在恶性组织微环境中被劫持，因此癌症可被比作一个“无法停止修复的伤口”。我们提出，恶性肿瘤成功生长、进展和复发的一个关键条件是一个复杂的环境，从概念上被称为“肿瘤再生微环境”，它除了由转化的肿瘤细胞组成外，还包括一个正常细胞网络以及仿佛在组织修复和再生过程中被激活的因子。我们的工作基于这样一个假设：肿瘤细胞凋亡、巨噬细胞激活和内皮细胞激活是肿瘤再生微环境的关键且相互关联的要素，并且凋亡肿瘤细胞衍生的细胞外囊泡是该微环境中关键的细胞间通讯载体。在侵袭性B细胞淋巴瘤中，肿瘤细胞凋亡促进淋巴瘤微环境中的血管生成以及促肿瘤巨噬细胞的聚集。此外，凋亡淋巴瘤衍生的细胞外囊泡具有强大的促肿瘤潜力。这些发现对于细胞凋亡在恶性疾病调控中的作用以及诱导细胞凋亡的抗癌疗法的疗效具有重要意义。
本文是“细胞外囊泡与肿瘤微环境”讨论会议议题的一部分。
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’.
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