Zhou Xian-Mei, Wang Dan, He Hai-Lang, Tang Jie, Wu Jing, Xu Ling, Li Jian-Xin
Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, PR China.
State Key Laboratory of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, PR China.
J Cancer. 2017 Jul 1;8(10):1786-1794. doi: 10.7150/jca.17859. eCollection 2017.
Lymphangiogenesis plays an important role in cancer metastasis. Bone marrow-derived mesenchymal stem cells (BMMSCs) migrate to the site of tumorigenesis and in turn promote the metastasis. However, whether BMMSCs involve in the lymphangiogenesis of lung cancer is unclear. Jinfukang has clinically been used for the treatment of non small cell lung cancer (NSCLC) in China. In this study, to investigate the involvement of BMMSCs in lymphangiogenesis in lung cancer, and evaluate the inhibitory effect of Jinfukang on the lymphangiogenesis, chimeric mice were prepared by transplanting bone marrow from green fluorescent protein (GFP) transgenic mice (C57BL/6-EGFP) into irradiated C57BL/6 mice. Then, the chimeric mice were injected subcutaneously with freshly prepared Lewis lung carcinoma cell suspension to make lung tumor model, and the model mice were further orally administrated with Jinfukang once per day for 3 weeks. Four weeks after the bone marrow transplantation, GFP-positive cells primarily existed in bone marrow of acceptor mice, and three more weeks after, Lewis lung carcinoma cells formed a tumor mass in chimeric mice. Observation of GFP-positive cells revealed that BMMSCs transferred into the lung tumor. Immunofluorescent analyses of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), a lymphatic endothelium marker, demonstrated a part of lymphatic endothelial cells in lung cancer were derived from BMMSCs, and those lymphatic endothelial cells contributed to the lung tumor lymphangiogenesis. Furthermore, Jinfukang treatment resulted in a significant reduction of the average weight of the tumor mass in chimeric mice, and displayed a significant lower number of LYVE-1 positive cells. The present results suggest that BMMSCs transfer to tumor, differentiate into lymphatic endothelial cells, and involve in the lymphangiogenesis in lung cancer of mice. Jinfukang inhibits the lung tumor mass via suppression of the BMMSCs transformation and lung tumor lymphangiogenesis. Our findings might provide the potential for the cancer therapies.
淋巴管生成在癌症转移中发挥着重要作用。骨髓间充质干细胞（BMMSCs）迁移至肿瘤发生部位，进而促进转移。然而，BMMSCs是否参与肺癌的淋巴管生成尚不清楚。在中国，金复康已临床用于治疗非小细胞肺癌（NSCLC）。在本研究中，为了探究BMMSCs在肺癌淋巴管生成中的作用，并评估金复康对淋巴管生成的抑制作用，将绿色荧光蛋白（GFP）转基因小鼠（C57BL/6-EGFP）的骨髓移植到经照射的C57BL/6小鼠体内，制备嵌合小鼠。然后，给嵌合小鼠皮下注射新鲜制备的Lewis肺癌细胞悬液以建立肺癌模型，模型小鼠进一步每天口服一次金复康，持续3周。骨髓移植4周后，GFP阳性细胞主要存在于受体小鼠的骨髓中，再过3周后，Lewis肺癌细胞在嵌合小鼠体内形成肿瘤块。对GFP阳性细胞的观察显示BMMSCs转移至肺肿瘤。对淋巴管内皮透明质酸受体-1（LYVE-1，一种淋巴管内皮标志物）进行免疫荧光分析表明，肺癌中的部分淋巴管内皮细胞来源于BMMSCs，且这些淋巴管内皮细胞促进了肺肿瘤的淋巴管生成。此外，金复康治疗使嵌合小鼠肿瘤块的平均重量显著降低，且LYVE-1阳性细胞数量显著减少。目前的结果表明，BMMSCs转移至肿瘤，分化为淋巴管内皮细胞，并参与小鼠肺癌的淋巴管生成。金复康通过抑制BMMSCs转化和肺肿瘤淋巴管生成来抑制肺肿瘤块。我们的发现可能为癌症治疗提供潜力。
