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 E2 (PGE2)- 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 COL1A1 and SRC 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.

中文翻译：

---

慢循环，化学抗性癌细胞和成纤维细胞之间的相互作用为肿瘤的发展创造了促炎的生态位。

据信，静态癌细胞在化疗后通过未知机制引起癌症进展。我们在这里显示化学疗法后人类非小细胞肺癌（NSCLC）细胞系，静止状，慢循环癌细胞（SCC）和患者残留的异种移植（PDX）肿瘤经历了转录因子6（ATF6）的激活）介导的各种细胞因子的上调，这些因子以旁分泌的方式募集成纤维细胞。癌症相关的成纤维细胞（CAF）经历了COX2和I型胶原（Col-I）的转录上调，随后通过前列腺素E2（PGE2）和整联蛋白/ Src介导的信号传导途径触发了SCC中缓慢活跃的循环切换，导致癌症进展。对ATF6的拮抗作用和对Src / COX2的共同靶向都有效地抑制了SCC中细胞因子的产生和慢至活跃的细胞周期转变，从而阻止了癌症的发展。在接受化疗的NSCLC患者中观察到COX2和Col-I的表达以及Src的激活。公开数据分析显示，COL1A1和SRC表达与NSCLC复发之间存在显着关联。总体而言，这些发现表明，由SCC和CAF相互作用产生的促炎性利基会触发肿瘤进展。意义：共同靶向COX2和Src可能是预防化疗后癌症进展的有效策略。在接受化疗的NSCLC患者中观察到COX2和Col-I的表达以及Src的激活。公开数据分析显示，COL1A1和SRC表达与NSCLC复发之间存在显着关联。总体而言，这些发现表明，由SCC和CAF之间相互作用产生的促炎性利基会触发肿瘤进展。启示：共靶向COX2和Src可能是预防化疗后癌症进展的有效策略。在接受化疗的NSCLC患者中观察到COX2和Col-I的表达以及Src的激活。公开数据分析显示，COL1A1和SRC表达与NSCLC复发之间存在显着关联。总体而言，这些发现表明，由SCC和CAF相互作用产生的促炎性利基会触发肿瘤进展。意义：共同靶向COX2和Src可能是预防化疗后癌症进展的有效策略。