Department of Integration of Chinese and Western Medicine, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital & Institute, Beijing 100142, P.R. China.
Departments of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing 100142, P.R. China.
Phytomedicine. 2022 Nov;106:154409. doi: 10.1016/j.phymed.2022.154409. Epub 2022 Aug 28.
Modified Bu-Fei decoction (MBFD), a formula of traditional Chinese medicine, is used for treating lung cancer in clinic. The actions and mechanisms of MBFD on modulating lung microenvironment is not clear.
Lung microenvironment is rich in vascular endothelial cells (ECs). This study is aimed to examine the actions of MBFD on tumor biology, and to uncover the underlying mechanisms by focusing on pulmonary ECs.
The Lewis lung carcinoma (LLC) xenograft model and the metastatic cancer model were used to determine the efficacy of MBFD on inhibiting tumor growth and metastasis. Flow cytometry and trans-well analysis were used to determine the role of ECs in anti-metastatic actions of MBFD. The in silico analysis and function assays were used to identify the mechanisms of MBFD in retarding lung metastasis. Plasma from lung cancer patients were used to verify the effects of MBFD on angiogenin-like protein 4 (ANGPTL4) in clinical conditions.
MBFD significantly suppressed spontaneous lung metastasis of LLC tumors, but not tumor growth, at clinically relevant concentrations. The anti-metastatic effects of MBFD were verified in metastatic cancer models created by intravenous injection of LLC or 4T1 cells. MBFD inhibited lung infiltration of circulating tumor cells, without reducing tumor cell proliferations in lung. In vitro, MBFD dose-dependently inhibited trans-endothelial migrations of tumor cells. RNA-seq assay and verification experiments confirmed that MBFD potently depressed endothelial ANGPTL4 which is able to broke endothelial barrier and protect tumor cells from anoikis. Database analysis revealed that high ANGPTL4 levels is negatively correlated with overall survival of cancer patients. Importantly, MBFD therapy reduced plasma levels of ANGPTL4 in lung cancer patients. Finally, MBFD was revealed to inhibit ANGPTL4 expressions in a hypoxia inducible factor-1α (HIF-1α)-dependent manner, based on results from specific signaling inhibitors and network pharmacology analysis.
MBFD, at clinically relevant concentrations, inhibits cancer lung metastasis via suppressing endothelial ANGPTL4. These results revealed novel effects and mechanisms of MBFD in treating cancer, and have a significant clinical implication of MBFD therapy in combating metastasis.
中药方剂补肺汤（MBFD）临床上用于治疗肺癌。其调节肺部微环境的作用和机制尚不清楚。
肺部微环境富含血管内皮细胞（ECs）。本研究旨在探讨 MBFD 对肿瘤生物学的作用，并通过聚焦于肺 ECs 来揭示其潜在机制。
使用 Lewis 肺癌（LLC）异种移植模型和转移性癌症模型来确定 MBFD 抑制肿瘤生长和转移的功效。使用流式细胞术和 Trans-well 分析来确定 ECs 在 MBFD 抗转移作用中的作用。使用计算机分析和功能测定来确定 MBFD 减缓肺转移的机制。使用来自肺癌患者的血浆来验证 MBFD 在临床条件下对血管生成素样蛋白 4（ANGPTL4）的影响。
MBFD 在临床相关浓度下显著抑制 LLC 肿瘤的自发性肺转移，但不抑制肿瘤生长。MBFD 的抗转移作用在通过静脉注射 LLC 或 4T1 细胞创建的转移性癌症模型中得到验证。MBFD 抑制循环肿瘤细胞向肺部浸润，而不会减少肺部肿瘤细胞的增殖。在体外，MBFD 剂量依赖性地抑制肿瘤细胞的跨内皮迁移。RNA-seq 分析和验证实验证实，MBFD 能强烈抑制内皮细胞的 ANGPTL4，后者能够破坏内皮屏障并保护肿瘤细胞免受凋亡。数据库分析显示，高 ANGPTL4 水平与癌症患者的总生存率呈负相关。重要的是，MBFD 治疗可降低肺癌患者血浆中的 ANGPTL4 水平。最后，通过特异性信号抑制剂和网络药理学分析，揭示 MBFD 通过抑制缺氧诱导因子-1α（HIF-1α）依赖性途径抑制 ANGPTL4 的表达。
MBFD 在临床相关浓度下通过抑制内皮细胞的 ANGPTL4 抑制癌症肺转移。这些结果揭示了 MBFD 在治疗癌症方面的新作用和机制，并且 MBFD 治疗在对抗转移方面具有重要的临床意义。
