恶性黑色素瘤调节肺组织微环境并促进肿瘤肺转移的实验研究

doi:10.6040/j.issn.1671-7554.0.2015.914

摘要/Abstract

摘要： 目的探讨转移前期原发黑色素瘤对肺组织微环境的作用及其对转移的影响。方法将黑色素瘤细胞B16种植于雌性Balb/c小鼠背部,建立荷瘤小鼠动物模型;通过小鼠尾静脉注射B16细胞建立转移模型;塞来昔布灌胃处理小鼠建立抗炎治疗模型。采用肺组织干湿比和HE染色分析肺组织炎症反应,应用ELISA试剂盒检测血清及细胞培养上清液中的细胞因子水平。结果在转移前期,与对照组小鼠相比,实验组荷瘤小鼠肺组织明显水肿,肺干湿比明显升高,两组相比差异有统计学意义(P<0.001);同时发现B16细胞易于出现在肺组织炎症细胞聚集的部位。ELISA检测结果显示,与对照组相比,实验组荷瘤小鼠血清VEGF、M-CSF和TNF-α含量明显升高,两组相比差异有统计学意义(P<0.001)。B16培养上清可以显著诱导肺组织炎症反应,与对照组相比,实验组小鼠肺组织转移瘤显著增多(P<0.001);给予抗炎药物塞来昔布处理后,与对照组相比,实验组小鼠肺组织炎症反应明显下降,肺转移瘤数目明显减少(P=0.005)。结论在肿瘤转移前期,原发恶性黑色素瘤能够调节肺组织微环境,诱导肺组织炎症反应并促进肺转移;塞来昔布可缓解肺组织炎症反应并抑制肺转移。

关键词: 肺, 黑色素瘤, 肿瘤转移, 炎症, 微环境, 细胞因子

Abstract: Objective To explore the effect of primary melanoma on lung microenvironment and metastasis. Methods Melanoma cells(B16)were implanted into the back of Balb/c mice to build tumor-bearing mice model. Metastatic model was established by injecting B16 into the caudal vein of mice intravenously, and anti-inflammatory treatment of celecoxib was applied by gavage. Pulmonary inflammation response was analyzed by wet/dry ratios and HE staining, the circulating levels of proinflammatory cytokines in sera were evaluated by ELISA. Results In the premetastatic phase, there was a significant increase in edema and lung wet/dry ratio in experimental group compared to the control group(P<0.001). HE staining showed that a large number of inflammatory cells aggregated in the lungs of experimental group. Tumor cells tended to metastasize to where the inflammatory cells invaded. ELISA showed that compared with the control group, there was a significant increase in the levels of VEGF, M-CSF and TNF-α in the experimental group. B16 conditioned media induced inflammation cells infiltrate in lung tissues, and the number of metastatic foci in lungs lesions was higher in the experimental group than that in the control group(P<0.001). There was a significant decrease in edema, lung wet/dry ratio, and inflammation cells infiltration in the experimental group compared to the 山东大学学报 (医学版)54卷11期 -袁冰,等.恶性黑色素瘤调节肺组织微环境并促进肿瘤肺转移的实验研究 \=-control group(P=0.005). Conclusion In the premetastatic phase, the melanoma induces pulmonary inflammation response, changes the lung environment and then facilitates lung metastasis. Applying of celecoxib can inhibit lung inflammation and prevent lung metastasis.

Key words: Microenvironment, Inflammation, Cytokines, Lung, Neoplasm metastasis, Melanoma

中图分类号:

R73-37

袁冰,李冉冉,韩明勇. 恶性黑色素瘤调节肺组织微环境并促进肿瘤肺转移的实验研究[J]. 山东大学学报（医学版）, 2016, 54(11): 13-18.

YUAN Bing, LI Ranran, HAN Mingyong. Primary tumor regulates the pulmonary microenvironment in melanoma carcinoma model and facilitates lung metastasis[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2016, 54(11): 13-18.

参考文献

[1] Huang YJ, Song N, Ding YP, et al. Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis[J]. Cancer Res, 2009, 69(19): 7529-7537.
[2] Killock D. Cell signalling: melanoma melanosomes shape the stromal niche[J]. Nat Rev Clin Oncol, 2016, 13(10): 590-591.
[3] Carlini MJ, De Lorenzo MS, Puricelli L. Cross-talk between tumor cells and the microenvironment at the metastatic niche[J]. Curr Pharm Biotechnol, 2011, 12(11): 1900-1908.
[4] Gerber PA, Hippe A, Buhren BA, et al. Chemokines in tumor-associated angiogenesis[J]. Biol Chem, 2009, 390(12): 1213-1223.
[5] Gupta GP, Massague J. Cancer metastasis: building a framework[J]. Cell, 2006, 127(4): 679-695.
[6] Huang Y, Song N, Ding Y, et al. Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis[J]. Cancer Res, 2009, 69(19): 7529-7537.
[7] Serafini P, Borrello I, Bronte V. Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression[J]. Semin Cancer Biol, 2006, 16(1): 53-65.
[8] Gassmann P, Haier J, Schlüter K, et al. CXCR4 regulates the early extravasation of metastatic tumor cells in vivo[J]. Neoplasia, 2009, 11(7): 651-661.
[9] Hiratsuka S, Watanabe A, Aburatani H, et al. Tumor mediated up-regulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis[J]. Nat Cell Biol, 2006, 8(12): 1369-1375.
[10] Krüger A. Premetastatic niche formation in the liver: emerging mechanisms and mouse models[J]. J Mol Med(Berl), 2015, 93(11): 1193-1201.
[11] Sharma SK, Chintala NK, Vadrevu SK, et al. Pulmonary alveolar macrophages contribute to the premetastatic niche by suppressing antitumor T cell responses in the lungs[J]. J Immunol, 2015, 194(11): 5529-5538.
[12] Wu CF, Andzinski L, Kasnitz N, et al. The lack of type I interferon induces neutrophil-mediated pre-metastatic niche formation in the mouse lung[J]. Int J Cancer, 2015, 137(4): 837-847.
[13] Yan HH, Jiang J, Pang Y, et al. CCL9 induced by TGF-β signaling in myeloid cells enhances tumor cell survival in the premetastatic organ[J]. Cancer Res, 2015, 75(24): 5283-5298.
[14] Souza LE, Almeida DC, Yaochite JN, et al. Intravenous administration of bone marrow-derived multipotent mesenchymal stromal cells enhances the recruitment of CD11b+ myeloid cells to the lungs and facilitates B16-F10 melanoma colonization[J]. Exp Cell Res, 2015, 345(2): 141-149.
[15] Kaplan RN, Rafii S, Lyden D. Preparing the “soil”: the premetastatic niche[J]. Cancer Res, 2006, 66(23): 11089-11093.
[16] Mantovani A, Allavena P, Sica A, et al. Cancer-related inflammation[J]. Nature, 2008, 454(7203): 436-444.
[17] Kulbe H, Chakravarty P, Leinster DA, et al. A dynamic inflammatory cytokine network in the human ovarian cancer microenvironment[J]. Cancer Res, 2012, 72(1): 66-75.
[18] DeNardo DG, Coussens LM. Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression[J]. Breast Cancer Res, 2007, 9(4): 212.
[19] Dawson MR, Duda DG, Fukumura D, et al. VEGFR1 activity independent metastasis formation[J]. Nature, 2009, 461(7262): E4-E5.
[20] Solinas G, Marchesi F, Garlanda C, et al. Inflammation-mediated promotion of invasion and metastasis[J]. Cancer Metastasis Rev, 2010, 29(2): 243-248.

相关文章 15

[1]	徐宁宇王磊郝恩魁苏国海. STEMI患者急诊PCI前口服阿托伐他汀对炎症介质及左心室功能的影响[J]. 山东大学学报(医学版), 2209, 47(6): 69-72.
[2]	郝跃伟刘雪平赵婷婷郑敏王一兵. 环氧化酶2基因多态性与动脉粥样硬化缺血性脑卒中的相关性[J]. 山东大学学报(医学版), 2209, 47(6): 95-98.
[3]	梁晨,姚丽娟,吕龙飞,唐泽,秦达,崔有斌,余孝淇. 三维重建联合CT引导下穿刺定位在微创治疗肺磨玻璃结节中的应用[J]. 山东大学学报 (医学版), 2026, 64(5): 74-82.
[4]	陆晨琳,许露,杨俊发,潘华琴,倪清涛. 基于动态列线图及机器学习的慢性阻塞性肺疾病急性加重期伴发肺性脑病风险预测模型构建及验证[J]. 山东大学学报 (医学版), 2026, 64(3): 108-115.
[5]	黄佩文, 王旭东. 治疗非小细胞肺癌新药:靶向c-Met蛋白的抗体药物偶联物Telisotuzumab Vedotin[J]. 山东大学学报 (医学版), 2026, 64(3): 124-130.
[6]	于昊志,史桂东,徐国鹏,姜云鹏,冯世庆,刘新宇,祁磊. 抗氧化碳点纳米酶调控神经再生微环境的研究进展[J]. 山东大学学报 (医学版), 2026, 64(2): 44-49.
[7]	殷悦,莫振飞,吴培昕,刘金霞,魏元辉,任佳博,李春笋. GPX1基因在肺癌中的表达特征及其对肺腺癌细胞增殖、迁移、侵袭、凋亡的影响[J]. 山东大学学报 (医学版), 2026, 64(1): 65-73.
[8]	赵灿斌,邵将,管东辉,秦英,丁强,郭良,王伟伟,陈威,闫小龙,曾平. 木犀草素在炎症微环境下调控Wnt/β-catenin信号通路促进骨髓间充质干细胞成软骨分化的机制[J]. 山东大学学报 (医学版), 2025, 63(7): 11-22.
[9]	韩觉明,王晖,吴倩,郑慧玲,朱琳. B4GALNT4促进肺腺癌细胞增殖、迁移和侵袭能力[J]. 山东大学学报 (医学版), 2025, 63(7): 23-31.
[10]	葛雪,赵红艳. 疱疹病毒感染对重症肺炎患者临床预后及呼吸道微生态的影响[J]. 山东大学学报 (医学版), 2025, 63(6): 27-37.
[11]	曹洛菲,王珊珊,王金荣,姜荷云,苗瑜,马光增. 哮喘发作期FeNO升高儿童肺功能舒张试验的特点分析[J]. 山东大学学报 (医学版), 2025, 63(6): 38-44.
[12]	王磊,常霄,王梓萌,李娇娇,崔书君,杨飞,朱月香. 瘤内及瘤周DCE-MRI影像组学对宫颈癌患者无进展生存期的预测价值[J]. 山东大学学报 (医学版), 2025, 63(6): 45-54.
[13]	贾若曦,吕丽,刘涵云,吴寅平,李凤彩,赵泽华,王凯,范玉琛. 血细胞计数相关标志物对慢加急性乙型肝炎肝衰竭患者28天预后的诊断价值[J]. 山东大学学报 (医学版), 2025, 63(6): 89-99.
[14]	赵志敏,王春,李白翎. del Nido停搏液在心脏外科的应用:过去、现在与未来[J]. 山东大学学报 (医学版), 2025, 63(5): 54-59.
[15]	赵汉卿,周新睿,李子建,唐兴. 循环肿瘤细胞联合血清学检测在非小细胞肺癌中的应用[J]. 山东大学学报 (医学版), 2025, 63(5): 79-85.

多维度评价

Viewed

Full text

Abstract

Cited

Shared

Discussed