肿瘤基质衍生的 TGF-β 通过 Suv39h1 依赖性衰老限制了 Myc 驱动的淋巴瘤发生。

Tumor stroma-derived TGF-beta limits myc-driven lymphomagenesis via Suv39h1-dependent senescence.

机构信息

Charité - Universitätsmedizin Berlin/Molekulares Krebsforschungszentrum der Charité - MKFZ, 13353 Berlin, Germany.

出版信息

Cancer Cell. 2010 Mar 16;17(3):262-72. doi: 10.1016/j.ccr.2009.12.043.

DOI:10.1016/j.ccr.2009.12.043

PMID:20227040

Abstract

Activated RAS/BRAF oncogenes induce cellular senescence as a tumor-suppressive barrier in early cancer development, at least in part, via an oncogene-evoked DNA damage response (DDR). In contrast, Myc activation-although producing a DDR as well-is known to primarily elicit an apoptotic countermeasure. Using the Emu-myc transgenic mouse lymphoma model, we show here in vivo that apoptotic lymphoma cells activate macrophages to secrete transforming growth factor beta (TGF-beta) as a critical non-cell-autonomous inducer of cellular senescence. Accordingly, neutralization of TGF-beta action, like genetic inactivation of the senescence-related histone methyltransferase Suv39h1, significantly accelerates Myc-driven tumor development via cancellation of cellular senescence. These findings, recapitulated in human aggressive B cell lymphomas, demonstrate that tumor-prompted stroma-derived signals may limit tumorigenesis by feedback senescence induction.

摘要

激活的 RAS/BRAF 癌基因通过癌基因诱发的 DNA 损伤反应（DDR）诱导细胞衰老作为早期癌症发展中的肿瘤抑制屏障，至少在部分程度上是这样。相比之下，尽管 Myc 的激活也会产生 DDR，但已知其主要引发细胞凋亡的对策。使用 Emu-myc 转基因小鼠淋巴瘤模型，我们在此体内显示凋亡的淋巴瘤细胞激活巨噬细胞分泌转化生长因子-β（TGF-β）作为细胞衰老的关键非细胞自主诱导物。因此，中和 TGF-β作用，就像遗传失活与衰老相关的组蛋白甲基转移酶 Suv39h1 一样，通过消除细胞衰老，显著加速 Myc 驱动的肿瘤发展。这些在人类侵袭性 B 细胞淋巴瘤中得到的发现表明，肿瘤诱导的基质衍生信号可能通过反馈性衰老诱导来限制肿瘤发生。