Department of Cell Biology, RIMLS, Radboud University Medical Center, Nijmegen, Netherlands.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nat Rev Cancer. 2022 Mar;22(3):157-173. doi: 10.1038/s41568-021-00427-0. Epub 2022 Jan 10.
Resistance to therapeutic treatment and metastatic progression jointly determine a fatal outcome of cancer. Cancer metastasis and therapeutic resistance are traditionally studied as separate fields using non-overlapping strategies. However, emerging evidence, including from in vivo imaging and in vitro organotypic culture, now suggests that both programmes cooperate and reinforce each other in the invasion niche and persist upon metastatic evasion. As a consequence, cancer cell subpopulations exhibiting metastatic invasion undergo multistep reprogramming that - beyond migration signalling - supports repair programmes, anti-apoptosis processes, metabolic adaptation, stemness and survival. Shared metastasis and therapy resistance signalling are mediated by multiple mechanisms, such as engagement of integrins and other context receptors, cell-cell communication, stress responses and metabolic reprogramming, which cooperate with effects elicited by autocrine and paracrine chemokine and growth factor cues present in the activated tumour microenvironment. These signals empower metastatic cells to cope with therapeutic assault and survive. Identifying nodes shared in metastasis and therapy resistance signalling networks should offer new opportunities to improve anticancer therapy beyond current strategies, to eliminate both nodular lesions and cells in metastatic transit.
治疗抵抗和转移进展共同决定了癌症的致命结局。癌症转移和治疗抵抗传统上被视为两个独立的领域，采用的是不重叠的策略。然而，包括体内成像和体外器官型培养在内的新证据表明，这两个程序在侵袭龛中相互合作和加强，并在转移逃避后持续存在。因此，表现出转移侵袭能力的癌细胞亚群经历了多步重编程，除了迁移信号外，还支持修复程序、抗凋亡过程、代谢适应、干性和存活。共同的转移和治疗抵抗信号转导由多种机制介导，例如整合素和其他上下文受体的参与、细胞间通讯、应激反应和代谢重编程，这些机制与激活的肿瘤微环境中存在的自分泌和旁分泌趋化因子和生长因子线索引发的效应协同作用。这些信号使转移性细胞能够应对治疗攻击并存活。确定转移和治疗抵抗信号转导网络中共享的节点，应该为超越当前策略改善抗癌治疗提供新的机会，以消除结节性病变和转移过程中的细胞。
