Gowing Stephen D, Chow Simon C, Cools-Lartigue Jonathan J, Chen Crystal B, Najmeh Sara, Jiang Henry Y, Bourdeau France, Beauchamp Annie, Mancini Ugo, Angers Isabelle, Giannias Betty, Spicer Jonathan D, Rousseau Simon, Qureshi Salman T, Ferri Lorenzo E
Deparment of Surgery, L.D. MacLean Surgical Research Laboratories, McGill University Health Centre, McGill University, Montreal, QC, Canada.
Department of Critical Care and Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada.
Int J Cancer. 2017 Aug 1;141(3):561-571. doi: 10.1002/ijc.30734. Epub 2017 May 15.
Surgical resection of early stage nonsmall cell lung cancer (NSCLC) is necessary for cure. However, rates of postoperative bacterial pneumonias remain high and may confer an increased risk for metastasis. Toll-like receptors (TLRs) mediate the inflammatory cascade by recognizing microbial products at the surface of numerous cell types in the lung; however, little is known about how host TLRs influence NSCLC metastasis. TLR2 recognizes gram-positive bacterial cell wall components activating innate immunity. We demonstrate that lower respiratory tract infection with Streptococcus pneumonia augments the formation of murine H59 NSCLC liver metastases in C57BL/6 mice through host TLR2 activation. Infected mice demonstrate increased H59 and human A549 NSCLC adhesion to hepatic sinusoids in vivo compared with noninfected controls, a response that is significantly diminished in TLR2 knock-out mice. Intra-tracheal injection of purified TLR2 ligand lipoteichoic acid into mice similarly augments in vivo adhesion of H59 cells to hepatic sinusoids. Additionally, H59 and A549 NSCLC cells incubated with bronchoepithelial conditioned media show increased cell adhesion to extracellular matrix components in vitro and hepatic sinusoids in vivo in a manner that is dependent on bronchoepithelial TLR2 activation and interleukin-6 secretion. TLR2 is therefore a potential therapeutic target for gram-positive pneumonia-driven NSCLC metastasis.
早期非小细胞肺癌（NSCLC）的手术切除是治愈所必需的。然而，术后细菌性肺炎的发生率仍然很高，并且可能增加转移风险。Toll样受体（TLR）通过识别肺中多种细胞类型表面的微生物产物来介导炎症级联反应；然而，关于宿主TLR如何影响NSCLC转移知之甚少。TLR2识别革兰氏阳性细菌细胞壁成分，激活先天免疫。我们证明，肺炎链球菌引起的下呼吸道感染通过宿主TLR2激活增强了C57BL/6小鼠中鼠源H59 NSCLC肝转移的形成。与未感染的对照相比，感染的小鼠在体内表现出H59和人A549 NSCLC对肝血窦的粘附增加，在TLR2基因敲除小鼠中这种反应明显减弱。向小鼠气管内注射纯化的TLR2配体脂磷壁酸同样增强了H59细胞在体内对肝血窦的粘附。此外，用支气管上皮条件培养基培养的H59和A549 NSCLC细胞在体外对细胞外基质成分的粘附增加，在体内对肝血窦的粘附增加，其方式依赖于支气管上皮TLR2激活和白细胞介素-6分泌。因此，TLR2是革兰氏阳性肺炎驱动的NSCLC转移的潜在治疗靶点。
