Phytogalactolipid dLGG Inhibits Mouse Melanoma Brain Metastasis through Regulating Oxylipin Activity and Re-Programming Macrophage Polarity in the Tumor Microenvironment.
Phytogalactolipid dLGG Inhibits Mouse Melanoma Brain Metastasis through Regulating Oxylipin Activity and Re-Programming Macrophage Polarity in the Tumor Microenvironment.
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DOI：
10.3390/cancers13164120
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发表时间：
2021-08-16
期刊：
影响因子：
5.2
通讯作者：
Shyur LF
中科院分区：
文献类型：
--
作者：
Yang CC;Chang MT;Chang CK;Shyur LF
转移性脑黑色素瘤是一种常见的转移性恶性肿瘤，死亡率高。目前的临床治疗方案使用抗血管生成药物贝伐单抗（Avastin）和/或Lipo-DOX（一种能够穿透血脑屏障的药物）;然而，这两种药物通常会导致不良副作用和有限的治疗结果。本研究提供证据支持植物甘油糖脂，1，2-二-O-α-亚麻酰基-3-O-β-吡喃半乳糖基-sn-甘油（dLGG）通过重编程肿瘤微环境以及与黑色素瘤细胞和巨噬细胞相互作用来抑制小鼠黑色素瘤脑转移（MBM）的功能。介绍了氧脂素9，10-EpOME +12，13-EpOME在防止黑色素瘤细胞侵袭和肿瘤微环境中小胶质细胞/巨噬细胞分布和极化中的新功能。本文提出的dLGG的新的抗黑色素瘤功能和潜在的分子机制可以被认为是对抗MBM的新的治疗策略。目前用于黑色素瘤脑转移（MBM）的常规癌症疗法仍然无效。在这项研究中，我们证明了植物甘油糖脂，1，2-二-O-α-亚麻酰基-3-O-β-吡喃半乳糖基-sn-甘油（dLGG）单独使用或与脂质体阿霉素（Lip-DOX）或安维汀联合使用在同基因B16 BM 4COX −2/Luc脑寻求黑色素瘤小鼠模型中对MBM的生物有效性。相对于未处理的肿瘤对照，用dLGG-10、dLGG-25、dLGG-10 + Avastin-5、Lipo-DOX-2、dLGG-10 + Lipo-DOX-2或Lipo-DOX-2 + Avastin-5处理分别抑制小鼠中17.9%、59.1%、55.7%、16.2%、44.5%和72.4%的MBM。在dLGG处理的小鼠中，肿瘤对照小鼠脑肿瘤微环境中的转移性PD-L1+黑色素瘤细胞、M2样巨噬细胞和CD 31+内皮细胞浸润以及15-LOX/CYP 450 4A酶的高表达水平显著减弱;相反，M1样常驻小胶质细胞和细胞毒性T细胞增加。脂质组学研究显示，dLGG促进B16 BM 4细胞向培养基中分泌氧脂素9，10-/12，13-EpOME。此外，用dLGG或9，10-EpOMEs +12，13-EpOMEs预处理的B16 BM 4细胞的条件培养基在体外驱动M2样巨噬细胞向M1样巨噬细胞转化。离体3D-培养测定进一步证明dLGG、9，10-EpOME或9，10-EpOME +12，13-EpOME预处理减弱侵入脑组织的B16 BM 4细胞，并防止小胶质细胞/巨噬细胞浸润到黑素瘤栓和脑器官/组织的界面中。总之，本报告提供了一种新的治疗策略和机制的见解植物半乳糖脂dLGG打击MBM。
Metastatic brain melanoma is a common metastatic cancer with a high mortality rate. Current clinical regimens use the anti-angiogenesis drug bevacizumab (Avastin) and/or Lipo-DOX, a drug capable penetrating the blood–brain barrier; however, both commonly result in adverse side effects and limited treatment results. This study provides evidence to support the function of a phyto-glyceroglycolipid, 1,2-di-O-α-linolenoyl-3-O-β-galactopyranosyl-sn-glycerol (dLGG) in inhibiting melanoma brain metastasis (MBM) in mice through reprogramming the tumor microenvironment and interacting with melanoma cells and macrophages. The novel function of oxylipin 9,10-EpOMEs + 12,13-EpOMEs in preventing melanoma cell invasion and microglia/macrophage distribution and polarization in the tumor microenvironment is presented. The novel anti-melanoma function and underlying molecular mechanism of dLGG proposed herein can be considered as a novel therapeutic strategy to combat MBM. Current conventional cancer therapies for melanoma brain metastasis (MBM) remain ineffective. In this study, we demonstrated the bioefficacy of a phyto-glyceroglycolipid, 1,2-di-O-α-linolenoyl-3-O-β-galactopyranosyl-sn-glycerol (dLGG) alone, or in combination with liposomal doxorubicin (Lip-DOX) or Avastin against MBM in a syngeneic B16BM4COX−2/Luc brain-seeking melanoma mouse model. Treatment with dLGG–10, dLGG–25, dLGG–10 + Avastin–5, Lipo-DOX–2, dLGG–10 + Lipo-DOX–2 or Lipo-DOX–2 + Avastin–5 suppressed, respectively, 17.9%, 59.1%, 55.7%, 16.2%, 44.5% and 72.4% of MBM in mice relative to the untreated tumor control. Metastatic PD-L1+ melanoma cells, infiltration of M2-like macrophages and CD31+ endothelial cells, and high expression levels of 15-LOX/CYP450 4A enzymes in the brain tumor microenvironment of the tumor control mice were significantly attenuated in dLGG-treated mice; conversely, M1-like resident microglia and cytotoxic T cells were increased. A lipidomics study showed that dLGG promoted B16BM4 cells to secrete oxylipins 9,10-/12,13-EpOMEs into the culture medium. Furthermore, the conditioned medium of B16BM4 cells pretreated with dLGG or 9,10-EpOMEs + 12,13-EpOMEs drove M2-like macrophages to polarize into M1-like macrophages in vitro. An ex vivo 3D-culture assay further demonstrated that dLGG, 9,10-EpOME or 9,10-EpOME + 12,13-EpOME pretreatment attenuated B16BM4 cells invading brain tissue, and prevented microglia/macrophages infiltrating into the interface of melanoma plug and brain organ/tissue. In summary, this report provides a novel therapeutic strategy and mechanistic insights into phytogalactolipid dLGG for combating MBM.
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DOI：
10.1016/bs.apha.2015.05.002
发表时间：
2015
期刊：
Advances in pharmacology (San Diego, Calif.)
影响因子：
--
作者：
Johnson AL;Edson KZ;Totah RA;Rettie AE
通讯作者：
Rettie AE
影响因子：
8
作者：
Chen XW;Yu TJ;Zhang J;Li Y;Chen HL;Yang GF;Yu W;Liu YZ;Liu XX;Duan CF;Tang HL;Qiu M;Wang CL;Zheng H;Yue J;Guo AM;Yang J
通讯作者：
Yang J
影响因子：
5.7
作者：
Apaya, Maria Karmella;Lin, Chih-Yu;Shyur, Lie-Fen
通讯作者：
Shyur, Lie-Fen
影响因子：
16.6
作者：
Linde N;Casanova-Acebes M;Sosa MS;Mortha A;Rahman A;Farias E;Harper K;Tardio E;Reyes Torres I;Jones J;Condeelis J;Merad M;Aguirre-Ghiso JA
通讯作者：
Aguirre-Ghiso JA
影响因子：
1.6
作者：
Bai L;Wang F;Li ZZ;Ren C;Zhang DS;Zhao Q;Lu YX;Wang DS;Ju HQ;Qiu MZ;Wang ZQ;Wang FH;Xu RH
通讯作者：
Xu RH