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肿瘤相关巨噬细胞MGLL缺失促进免疫抑制和结直肠癌细胞腹腔种植转移
MGLL deficiency in tumor-associated macrophages promotes immunosuppression and colorectal peritoneal metastases in mice
- 陆军军医大学学报 2023年45卷第6期 页码：530-538
- 作者机构：
400038 重庆，陆军军医大学(第三军医大学)基础医学院生物化学与分子生物学教研室
- 作者简介：
[缪洪明，E-mail：hongmingmiao@sina.com MIAO Hongming, E-mail: hongmingmiao@sina.com
- 基金信息：国家自然科学基金面上项目(82173134)
DOI：10.16016/j.2097-0927.202209246
中图分类号： R392.3;R73-37;R735.35收稿：2022-09-26，
修回：2022-10-13，
纸质出版：2023-03-30
- 稿件说明：
移动端阅览
袁静, 缪洪明. 肿瘤相关巨噬细胞MGLL缺失促进免疫抑制和结直肠癌细胞腹腔种植转移[J]. 陆军军医大学学报, 2023,45(6):530-538.
Jing YUAN, Hongming MIAO. MGLL deficiency in tumor-associated macrophages promotes immunosuppression and colorectal peritoneal metastases in mice[J]. Journal of Army Medical University, 2023, 45(6): 530-538.
袁静, 缪洪明. 肿瘤相关巨噬细胞MGLL缺失促进免疫抑制和结直肠癌细胞腹腔种植转移[J]. 陆军军医大学学报, 2023,45(6):530-538. DOI： 10.16016/j.2097-0927.202209246.
Jing YUAN, Hongming MIAO. MGLL deficiency in tumor-associated macrophages promotes immunosuppression and colorectal peritoneal metastases in mice[J]. Journal of Army Medical University, 2023, 45(6): 530-538. DOI： 10.16016/j.2097-0927.202209246.
摘要
目的
2
探究单酰甘油脂肪酶(monoacylglycerol lipase，MGLL)在肿瘤相关巨噬细胞(tumor-associated macrophages，TAMs)中调节结直肠癌腹腔种植转移(colorectal cancer peritoneal metastases，CRC-PM)的效应和机制。
方法
2
首先构建了巨噬细胞MGLL特异性敲除(conditional knockout，cKO)小鼠，并进一步构建CRC-PM模型，最后结合细胞生物学和高通量测序等方法探究肿瘤相关巨噬细胞MGLL在小鼠结直肠癌细胞腹腔种植转移中的效应和机制。
结果
2
相较于对照组小鼠，特异性敲除巨噬细胞MGLL小鼠的生存期显著缩短(
P
<
0.05)，腹腔肿瘤重量显著增加(
P
<
0.05)，同时肿瘤微环境(tumor microenvironment
TME)中T细胞占比显著减少(
P
<
0.01)而M2型巨噬细胞占比显著增加(
P
<
0.05)，并且RNA-seq结果显示MGLL特异性敲除巨噬细胞的TRLs、PD-1/PDL-1以及HIF-1等信号通路发生显著改变。
结论
2
在结直肠癌腹腔种植转移中，肿瘤相关巨噬细胞MGLL缺失促使TAMs向M2型极化，进而抑制基于T细胞的抗肿瘤免疫，最终促进结直肠癌的腹腔种植转移。其机制可能与TRLs、PD-1/PDL-1以及HIF-1等信号通路的改变相关。
Abstract
Objective
2
To investigate the effects and mechanisms of monoacylglycerol lipase (MGLL) in tumor-associated macrophages (TAMs) for the progression of colorectal cancer peritoneal metastases (CRC-PM).
Methods
2
After macrophage MGLL conditional knockout (cKO) mice was constructed
a CRC-PM model was established in these cKO mice. The effects and mechanism of MGLL deficiency on TAMs were studies with cell biological and RNA-Seq assays.
Results
2
Compared with the control mice
macrophage MGLL deficiency significantly shortened the survival time of CRC-PC mice (
P
<
0.05)
increased the weight of peritoneal tumor masses (
P
<
0.05)
diminished the percentage of T cells in the tumor microenvironment (
P
<
0.01)
while elevated the percentage of M2 macrophages in cKO mice (
P
<
0.05). And the results of RNA-seq showed that TRLs
PD-1/PDL-1
and HIF-1 signal pathways were significantly changed in MGLL deficiency macrophages.
Conclusion
2
In the process of CRC-PC
MGLL deficiency leads to macrophage activation towards an M2-type phenotype and further destroys T cell-based anti-tumor immunity capacity
and ultimately promotes the progression of CRC-PC. The mechanisms may be due to the changes in TRLs
PD-1/PDL-1
and HIF-1 signal pathways.
关键词
Keywords
references
SIEGEL R L, MILLER K D, FUCHS H E, et al . Cancer statistics, 2022[J ] . CA Cancer J Clin, 2022, 72(1): 7-33. DOI: 10.3322/caac.21708.
KOPPE M J, BOERMAN O C, OYEN W J, et al .Peritoneal carcinomatosis of colorectal origin: incidence and current treatment strategies[J ] . Ann Surg, 2006, 243(2): 212-222. DOI: 10.1097/01.sla.0000197702.46394.16.
BREUER E, HEBEISEN M, SCHNEIDER M A, et al . Site of recurrence and survival after surgery for colorectal peritoneal metastasis[J ] . J Natl Cancer Inst, 2021, 113(8): 1027-1035. DOI: 10.1093/jnci/djab001.
WU T, DAI Y. Tumor microenvironment and therapeutic response[J]. Cancer Lett, 2017, 387: 61-68. DOI: 10.1016/j.canlet.2016.01.043.
CIARDIELLO F, CIARDIELLO D, MARTINI G, et al . Clinical management of metastatic colorectal cancer in the era of precision medicine[J ] . CA Cancer J Clin, 2022, 72(4): 372-401. DOI: 10.3322/caac.21728.
XIANG W, SHI R C, KANG X, et al . Monoacylglycerol lipase regulates cannabinoid receptor 2-dependent macrophage activation and cancer progression[J ] . Nat Commun, 2018, 9(1): 2574. DOI: 10.1038/s41467-018-04999-8.
DI FRANCO S, BIANCA, SARDINA D S, et al . Adipose stem cell niche reprograms the colorectal cancer stem cell metastatic machinery[J ] . Nat Commun, 2021, 12(1): 5006. DOI: 10.1038/s41467-021-25333-9.
QIAN B Z, POLLARD J W. Macrophage diversity enhances tumor progression and metastasis[J]. Cell, 2010, 141(1): 39-51. DOI: 10.1016/j.cell.2010.03.014.
GUERRIERO J L. Macrophages: the road less traveled, changing anticancer therapy[J]. Trends Mol Med, 2018, 24(5): 472-489. DOI: 10.1016/j.molmed.2018.03.006.
BATISTA-GONZALEZ A, VIDAL R, CRIOLLO A, et al . New insights on the role of lipid metabolism in the metabolic reprogramming of macrophages[J ] . Front Immunol, 2019, 10: 2993. DOI: 10.3389/fimmu.2019.02993.
HAM M, LEE J W, CHOI A H, et al . Macrophage glucose-6-phosphate dehydrogenase stimulates proinflammatory responses with oxidative stress[J ] . Mol Cell Biol, 2013, 33(12): 2425-2435. DOI: 10.1128/MCB.01260-12.
ZHAO Q Y, KUANG D M, WU Y, et al . Activated CD69+ T cells foster immune privilege by regulating IDO expression in tumor-associated macrophages[J ] . J Immunol, 2012, 188(3): 1117-1124. DOI: 10.4049/jimmunol.1100164.
KANG S J, NAKANISHI Y, KIOI Y, et al . Semaphorin 6D reverse signaling controls macrophage lipid metabolism and anti-inflammatory polarization[J ] . Nat Immunol, 2018, 19(6): 561-570. DOI: 10.1038/s41590-018-0108-0.
SU P, WANG Q, BI E G, et al . Enhanced lipid accumulation and metabolism are required for the differentiation and activation of tumor-associated macrophages[J ] . Cancer Res, 2020, 80(7): 1438-1450. DOI: 10.1158/0008-5472.CAN-19-2994.
MARTINEZ F O, GORDON S, LOCATI M, et al . Transcriptional profiling of the human monocyte-to-macrophagedifferentiation and polarization: new molecules and patterns of gene expression[J ] . J Immunol, 2006, 177(10): 7303-7311. DOI: 10.4049/jimmunol.177.10.7303.
KÖRNER A, BERNARD A, FITZGERALD J C, et al . Sema7A is crucial for resolution of severe inflammation[J ] . Proc Natl Acad Sci USA, 2021, 118(9): e2017527118. DOI: 10.1073/pnas.2017527118.
GIL-ORDÓÑEZ A, MARTÍN-FONTECHA M, ORTEGA-GUTIÉRREZ S, et al . Monoacylglycerol lipase (MAGL) as a promising therapeutic target[J ] . Biochem Pharmacol, 2018, 157: 18-32. DOI: 10.1016/j.bcp.2018.07.036.
NOMURA D K, LOMBARDI D P, CHANG J W, et al . Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer[J ] . Chem Biol, 2011, 18(7): 846-856. DOI: 10.1016/j.chembiol.2011.05.009.
HU W R, LIAN Y F, PENG L X, et al . Monoacylglycerol lipase promotes metastases in nasopharyngeal carcinoma[J ] . Int J Clin Exp Pathol, 2014, 7(7): 3704-3713.
BABA Y, FUNAKOSHI T, MORI M, et al . Expression of monoacylglycerol lipase as a marker of tumour invasion and progression in malignant melanoma[J ] . J Eur Acad Dermatol Venereol, 2017, 31(12): 2038-2045. DOI: 10.1111/jdv.14455.
NOMURA D K, LONG J Z, NIESSEN S, et al . Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis[J ] . Cell, 2010, 140(1): 49-61. DOI: 10.1016/j.cell.2009.11.027.
ZHANG Y, DU W W, CHEN Z L, et al . Upregulation of PD-L1 by SPP 1 mediates macrophage polarization and facilitates immune escape in lung adenocarcinoma[J ] . Exp Cell Res, 2017, 359(2): 449-457. DOI: 10.1016/j.yexcr.2017.08.028..
WU J Y, HUANG T W, HSIEH Y T, et al . Cancer-derived succinate promotes macrophage polarization and cancer metastasis via succinate receptor[J ] . Mol Cell, 2020, 77(2): 213-227. e5. DOI: 10.1016/j.molcel.2019.10.023..
XU F, CUI W Q, WEI Y, et al . Astragaloside Ⅳ inhibits lung cancer progression and metastasis by modulating macrophage polarization through AMPK signaling[J ] . J Exp Clin Cancer Res, 2018, 37(1): 207. DOI: 10.1186/s13046-018-0878-0.
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