Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
College of Pharmacy, Inje University, Gimhae, Gyungnam, Republic of Korea.
Cancer Res. 2020 Jun 1;80(11):2257-2272. doi: 10.1158/0008-5472.CAN-19-0631. Epub 2020 Mar 19.
Quiescent cancer cells are believed to cause cancer progression after chemotherapy through unknown mechanisms. We show here that human non-small cell lung cancer (NSCLC) cell line-derived, quiescent-like, slow-cycling cancer cells (SCC) and residual patient-derived xenograft (PDX) tumors after chemotherapy experience activating transcription factor 6 (ATF6)-mediated upregulation of various cytokines, which acts in a paracrine manner to recruit fibroblasts. Cancer-associated fibroblasts (CAF) underwent transcriptional upregulation of COX2 and type I collagen (Col-I), which subsequently triggered a slow-to-active cycling switch in SCC through prostaglandin E (PGE)- and integrin/Src-mediated signaling pathways, leading to cancer progression. Both antagonism of ATF6 and cotargeting of Src/COX2 effectively suppressed cytokine production and slow-to-active cell cycling transition in SCC, withholding cancer progression. Expression of COX2 and Col-I and activation of Src were observed in patients with NSCLC who progressed while receiving chemotherapy. Public data analysis revealed significant association between and expression and NSCLC relapse. Overall, these findings indicate that a proinflammatory niche created by the interplay between SCC and CAF triggers tumor progression. SIGNIFICANCE: Cotargeting COX2 and Src may be an effective strategy to prevent cancer progression after chemotherapy.
静止癌细胞被认为通过未知机制在化疗后导致癌症进展。我们在这里表明，人非小细胞肺癌（NSCLC）细胞系来源的静止样、缓慢循环癌细胞（SCC）和化疗后残留的患者来源异种移植（PDX）肿瘤经历激活转录因子 6（ATF6）介导的各种细胞因子的上调，这些细胞因子以旁分泌方式招募成纤维细胞。癌相关成纤维细胞（CAF）经历 COX2 和 I 型胶原（Col-I）的转录上调，随后通过前列腺素 E（PGE）和整合素/Src 介导的信号通路触发 SCC 的缓慢到活跃的循环转变，导致癌症进展。ATF6 的拮抗作用和 Src/COX2 的共同靶向作用均有效地抑制了 SCC 中的细胞因子产生和缓慢到活跃的细胞循环转变，从而阻止了癌症的进展。在接受化疗的 NSCLC 患者中观察到 COX2 和 Col-I 的表达和 Src 的激活，这些患者在接受化疗时发生了进展。公共数据分析显示 COX2 和 NSCLC 复发之间存在显著关联。总的来说，这些发现表明 SCC 和 CAF 之间的相互作用产生的促炎微环境触发了肿瘤进展。意义：靶向 COX2 和 Src 可能是预防化疗后癌症进展的有效策略。
