Charité-Universitätsmedizin Berlin/Molekulares Krebsforschungszentrum der Charité-MKFZ, 13353 Berlin, Germany.
Semin Cancer Biol. 2011 Dec;21(6):377-84. doi: 10.1016/j.semcancer.2011.10.002. Epub 2011 Oct 13.
Ras/Raf-prototypic oncogenes induce cellular senescence, a terminal cell-cycle arrest, as a default cellular safeguard program, while oncogenic Myc is known to rather promote apoptosis as the prime failsafe mechanism. We review and discuss here evidence for Myc-induced senescence - which is detectable to a limited degree as a cell-autonomous, direct response to Myc action, but occurs predominantly in a non-cell-autonomous fashion via crosstalk of the oncogene-driven cell population with non-neoplastic bystanders, namely cells of the host immune system, prompting them to release pro-senescent cytokines that strike back onto adjacent proliferating tumor cells. In particular, we discuss how Myc-evoked apoptosis serves as a signal for macrophage attraction and activation, followed by the secretion of TGF-β as a cytokine that is capable of terminally arresting Myc-driven lymphoma cells without causing further DNA damage and without launching a senescence-associated, pro-inflammatory, and, therefore, potentially detrimental cytokine response in the target population. In essence, non-cell-autonomous but still oncogene-orchestrated senescence is a functionally relevant, robustly tumor-suppressive principle with critical implications for conceptually novel anti-cancer therapies in the clinic.
Ras/Raf 原型致癌基因诱导细胞衰老，这是一种细胞周期的终末阻滞，作为一种默认的细胞保护程序，而致癌 Myc 已知更倾向于促进细胞凋亡作为主要的失效安全机制。在这里，我们回顾和讨论了 Myc 诱导的衰老的证据——这是一种可以在一定程度上检测到的、对 Myc 作用的细胞自主的直接反应，但主要是以非细胞自主的方式发生的，通过致癌基因驱动的细胞群体与非肿瘤旁观者（即宿主免疫系统的细胞）的串扰，促使它们释放促衰老细胞因子，这些细胞因子反过来作用于相邻的增殖肿瘤细胞。特别是，我们讨论了 Myc 诱导的凋亡如何作为巨噬细胞吸引和激活的信号，随后 TGF-β作为一种细胞因子被分泌出来，它能够终止 Myc 驱动的淋巴瘤细胞而不造成进一步的 DNA 损伤，也不会在靶细胞群中引发与衰老相关的、促炎的、因此可能有害的细胞因子反应。从本质上讲，非细胞自主但仍然是癌基因协调的衰老，是一种具有功能相关性的、强有力的肿瘤抑制原则，对临床上概念新颖的抗癌疗法具有重要意义。
