The Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, 02139, USA.
Cell. 2010 Oct 29;143(3):355-66. doi: 10.1016/j.cell.2010.09.043.
While numerous cell-intrinsic processes are known to play decisive roles in chemotherapeutic response, relatively little is known about the impact of the tumor microenvironment on therapeutic outcome. Here, we use a well-established mouse model of Burkitt's lymphoma to show that paracrine factors in the tumor microenvironment modulate lymphoma cell survival following the administration of genotoxic chemotherapy. Specifically, IL-6 and Timp-1 are released in the thymus in response to DNA damage, creating a "chemo-resistant niche" that promotes the survival of a minimal residual tumor burden and serves as a reservoir for eventual tumor relapse. Notably, IL-6 is released acutely from thymic endothelial cells in a p38-dependent manner following genotoxic stress, and this acute secretory response precedes the gradual induction of senescence in tumor-associated stromal cells. Thus, conventional chemotherapies can induce tumor regression while simultaneously eliciting stress responses that protect subsets of tumor cells in select anatomical locations from drug action.
虽然已知许多细胞内在过程在化疗反应中起决定性作用，但对于肿瘤微环境对治疗结果的影响知之甚少。在这里，我们使用已建立的伯基特淋巴瘤小鼠模型表明，肿瘤微环境中的旁分泌因子在接受遗传毒性化疗后调节淋巴瘤细胞的存活。具体而言，IL-6 和 Timp-1 会响应 DNA 损伤而在胸腺中释放，从而产生促进最小残留肿瘤负担存活的“化疗抵抗小生境”，并作为最终肿瘤复发的储备库。值得注意的是，IL-6 是在遗传毒性应激后以依赖 p38 的方式从胸腺内皮细胞中急性释放的，并且这种急性分泌反应先于肿瘤相关基质细胞中衰老的逐渐诱导。因此，传统化疗可以诱导肿瘤消退，同时引发应激反应，使特定解剖位置的肿瘤细胞亚群免受药物作用。
