Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response.
Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response.
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间充质干细胞通过下调全身性抗肿瘤免疫反应来促进肺癌细胞的转移。
DOI：
10.1155/2017/6294717
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发表时间：
2017
影响因子：
4.3
通讯作者：
Volarevic V
中科院分区：
文献类型：
--
作者：
Gazdic M;Simovic Markovic B;Jovicic N;Misirkic-Marjanovic M;Djonov V;Jakovljevic V;Arsenijevic N;Lukic ML;Volarevic V
由于大多数系统给药的间充质干细胞（MSCs）被困在肺内，我们使用静脉注射Lewis肺癌1 （LLC1）细胞诱导的肺癌转移模型来研究MSCs介导的转移调节的分子机制。MSCs显著增强了llc1处理小鼠的肺癌转移，降低了促炎细胞因子（TNF-α、IL-17）的浓度，并增加了免疫抑制剂IL-10、一氧化氮和犬尿氨酸的水平。MSCs可显著降低荷瘤动物肺中巨噬细胞、产生TNF-α-的树突状细胞（dc）、TNF-α-和产生il -17的CD4+ T细胞的浸润，但增加产生il -10的CD4+ T淋巴细胞的浸润。LLC1 + msc处理小鼠的肺浸润、细胞毒性FasL、表达perforin、TNF-α-和产生il -17的CD8+ T淋巴细胞以及表达nkg2d的自然杀伤（NK）细胞的总数显著减少。mscs培养基抑制NK细胞的细胞毒性。诱导型一氧化氮合酶（iNOS）和吲哚胺2,3-双加氧酶（IDO）抑制剂消除了这一现象，提示iNOS和IDO在msc介导的NK细胞抗肿瘤细胞毒性抑制中起重要作用。这项研究提供了MSCs通过抑制抗肿瘤免疫反应促进肺癌转移的证据，这引起了人们对MSCs为基础的治疗在恶性疾病遗传易感性患者中的安全性的关注。
Since majority of systemically administered mesenchymal stem cells (MSCs) become entrapped within the lungs, we used metastatic model of lung cancer, induced by intravenous injection of Lewis lung cancer 1 (LLC1) cells, to investigate the molecular mechanisms involved in MSC-mediated modulation of metastasis. MSCs significantly augmented lung cancer metastasis, attenuate concentrations of proinflammatory cytokines (TNF-α, IL-17), and increase levels of immunosuppressive IL-10, nitric oxide, and kynurenine in sera of LLC1-treated mice. MSCs profoundly reduced infiltration of macrophages, TNF-α-producing dendritic cells (DCs), TNF-α-, and IL-17-producing CD4+ T cells but increased IL-10-producing CD4+ T lymphocytes in the lungs of tumor-bearing animals. The total number of lung-infiltrated, cytotoxic FasL, perforin-expressing, TNF-α-, and IL-17-producing CD8+ T lymphocytes, and NKG2D-expressing natural killer (NK) cells was significantly reduced in LLC1 + MSC-treated mice. Cytotoxicity of NK cells was suppressed by MSC-conditioned medium. This phenomenon was abrogated by the inhibitors of inducible nitric oxide synthase (iNOS) and indoleamine 2,3-dioxygenase (IDO), suggesting the importance of iNOS and IDO for MSC-mediated suppression of antitumor cytotoxicity of NK cells. This study provides the evidence that MSCs promote lung cancer metastasis by suppressing antitumor immune response raising concerns regarding safety of MSC-based therapy in patients who have genetic susceptibility for malignant diseases.
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影响因子：
12.4
作者：
通讯作者：
--
影响因子：
4.8
作者：
Gazdic, Marina;Volarevic, Vladislav;Stojkovic, Miodrag
通讯作者：
Stojkovic, Miodrag
影响因子：
1.9
作者：
Mao, Yousheng;Yang, Ding;Krasna, Mark J.
通讯作者：
Krasna, Mark J.
影响因子：
4.4
作者：
Nauta, Alma J.;Kruisselbrink, Alwine B.;Fibbe, Willem E.
通讯作者：
Fibbe, Willem E.
影响因子：
2.9
作者：
Tsai, Meng-Shu;Chang, Cheng-Chi;Wu, Ying-Tai
通讯作者：
Wu, Ying-Tai