Barcellos-Hoff M H, Brooks A L
Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720, USA.
Radiat Res. 2001 Nov;156(5 Pt 2):618-27. doi: 10.1667/0033-7587(2001)156[0618:esttma]2.0.co;2.
Cell growth, differentiation and death are directed in large part by extracellular signaling through the interactions of cells with other cells and with the extracellular matrix; these interactions are in turn modulated by cytokines and growth factors, i.e. the microenvironment. Here we discuss the idea that extracellular signaling integrates multicellular damage responses that are important deterrents to the development of cancer through mechanisms that eliminate abnormal cells and inhibit neoplastic behavior. As an example, we discuss the action of transforming growth factor beta (TGFB1) as an extracellular sensor of damage. We propose that radiation-induced bystander effects and genomic instability are, respectively, positive and negative manifestations of this homeostatic process. Bystander effects exhibited predominantly after a low-dose or a nonhomogeneous radiation exposure are extracellular signaling pathways that modulate cellular repair and death programs. Persistent disruption of extracellular signaling after exposure to relatively high doses of ionizing radiation may lead to the accumulation of aberrant cells that are genomically unstable. Understanding radiation effects in terms of coordinated multicellular responses that affect decisions regarding the fate of a cell may necessitate re-evaluation of radiation dose and risk concepts and provide avenues for intervention.
细胞的生长、分化和死亡在很大程度上是由细胞与其他细胞以及细胞外基质相互作用产生的细胞外信号所引导的；这些相互作用又受到细胞因子和生长因子（即微环境）的调节。在此，我们探讨这样一种观点，即细胞外信号整合了多细胞损伤反应，这些反应通过消除异常细胞和抑制肿瘤行为的机制，成为癌症发展的重要阻碍。例如，我们讨论转化生长因子β（TGFB1）作为损伤的细胞外传感器的作用。我们提出，辐射诱导的旁观者效应和基因组不稳定性分别是这种稳态过程的正向和负向表现。低剂量或非均匀辐射暴露后主要表现出的旁观者效应是调节细胞修复和死亡程序的细胞外信号通路。暴露于相对高剂量的电离辐射后，细胞外信号的持续破坏可能导致基因组不稳定的异常细胞积累。从影响细胞命运决策的协调多细胞反应角度理解辐射效应，可能需要重新评估辐射剂量和风险概念，并提供干预途径。
