Department of Thoracic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Aging (Albany NY). 2024 Sep 3;16(17):12225-12238. doi: 10.18632/aging.206057.
Tumor-associated macrophages (TAMs), present within the tumor microenvironment (TME), strictly modulate tumor angiogenesis and lymphangiogenesis. Nevertheless, the associated signaling networks and candidate drug targets for these events remains to be elucidated. Given its antioxidative activities, we speculated that melatonin may reduce pyroptosis, and thereby modulate both angiogenesis and lymphangiogenesis. We revealed that a co-culture of A549 cells and THP-1 macrophages strongly enhanced expressions of the NLRP3 inflammasome axis members, and augmented angiogenesis and lymphangiogenesis. Next, we overexpressed NLRP3 in the A549 cells, and demonstrated that excess NLRP3 expression substantially upregulated VEGF and CXCL cytokine expressions, and enhanced lymphatic endothelial cells (LECs) tube formation. In contrast, NLRP3 inhibition produced the opposite effect. In addition, relative to controls, melatonin administration strongly inhibited the NLRP3 inflammasome axis, as well as angiogenesis and lymphangiogenesis in the co-culture system. Subsequent animal experiments using a Lewis Lung Carcinoma (LLC) subcutaneous tumor model in mice corroborate these findings. Melatonin treatment and NLRP3 knockdown significantly inhibit tumor growth and downregulate NLRP3 and IL-1β expression in tumor tissues. Furthermore, melatonin downregulates the expression of angiogenic and lymphangiogenic markers in tumor tissues. Taken together, the evidence suggested that a THP-1 macrophage and A549 cell co-culture stimulates angiogenesis and lymphangiogenesis via the NLRP3 axis. Melatonin protected against the TAMs- and NLRP3 axis-associated promotion of the aforementioned events and . Hence, melatonin is a promising candidate for managing for tumor-related angiogenesis and lymphangiogenesis in lung adenocarcinoma.
肿瘤相关巨噬细胞（TAMs）存在于肿瘤微环境（TME）中，严格调节肿瘤血管生成和淋巴管生成。然而，这些事件的相关信号网络和候选药物靶点仍有待阐明。鉴于其抗氧化活性，我们推测褪黑素可能会减少细胞焦亡，从而调节血管生成和淋巴管生成。我们发现，A549 细胞和 THP-1 巨噬细胞的共培养强烈增强了 NLRP3 炎性小体轴成员的表达，并增强了血管生成和淋巴管生成。接下来，我们在 A549 细胞中转染 NLRP3，结果表明过量的 NLRP3 表达显著上调了 VEGF 和 CXCL 细胞因子的表达，并增强了淋巴管内皮细胞（LEC）管形成。相比之下，NLRP3 抑制产生了相反的效果。此外，与对照组相比，褪黑素处理强烈抑制了共培养系统中 NLRP3 炎性小体轴以及血管生成和淋巴管生成。随后在小鼠Lewis 肺癌（LLC）皮下肿瘤模型中的动物实验证实了这些发现。褪黑素治疗和 NLRP3 敲低显著抑制肿瘤生长，并下调肿瘤组织中 NLRP3 和 IL-1β 的表达。此外，褪黑素下调了肿瘤组织中血管生成和淋巴管生成标志物的表达。综上所述，这些证据表明 THP-1 巨噬细胞和 A549 细胞共培养通过 NLRP3 轴刺激血管生成和淋巴管生成。褪黑素通过保护 TAMs 和 NLRP3 轴相关促进上述事件来对抗肿瘤相关性血管生成和淋巴管生成。因此，褪黑素是管理肺腺癌相关血管生成和淋巴管生成的有前途的候选药物。
