Exosomes từ môi trường khối u điều chỉnh đa dạng quá trình chuyển hóa của tế bào ung thư
Tóm tắt
Các nguyên bào sợi liên quan đến ung thư (CAFs) là thành phần tế bào chính trong môi trường vi mô của khối u ở hầu hết các loại ung thư đặc. Sự thay đổi chuyển hóa tế bào là một dấu hiệu đặc trưng của ung thư, và phần lớn tài liệu đã công bố tập trung vào các quá trình tự chủ của tế bào u cho những thích nghi này. Chúng tôi chứng minh rằng các exosome được tiết ra từ CAFs có nguồn gốc từ bệnh nhân có thể tái lập trình mạnh mẽ bộ máy chuyển hóa sau khi bị hấp thụ bởi các tế bào ung thư. Chúng tôi phát hiện ra rằng exosomes do CAFs tạo ra (CDEs) ức chế phosphorylation oxi hóa của ty thể, qua đó làm tăng quá trình glycolysis và carboxyl hóa giảm phụ thuộc vào glutamine trong các tế bào ung thư. Thông qua các thí nghiệm đánh dấu đồng vị 13C, chúng tôi làm rõ rằng các exosomes cung cấp amino acid cho các tế bào ung thư thiếu dinh dưỡng theo một cơ chế tương tự như sự kỵ khí lớn, mặc dù không phụ thuộc vào tín hiệu oncogenic-Kras như đã được mô tả trước đó. Sử dụng phân tích chuyển hóa trong exosome, chúng tôi cung cấp bằng chứng thuyết phục rằng CDEs chứa các chuyển hóa nguyên vẹn, bao gồm amino acid, lipid và các chất trung gian trong chu trình TCA, mà các tế bào ung thư sử dụng tích cực cho chuyển hóa carbon trung tâm và thúc đẩy sự phát triển của khối u trong điều kiện thiếu dinh dưỡng hoặc căng thẳng dinh dưỡng.
Từ khóa
#ung thư #exosomes #quá trình chuyển hóa #CAFs #vi môi trường khối uTài liệu tham khảo
Allinen, 2004, Molecular characterization of the tumor microenvironment in breast cancer, Cancer Cell, 6, 17, 10.1016/j.ccr.2004.06.010
Brauer, 2013, Impact of Tumor Microenvironment and Epithelial Phenotypes on Metabolism in Breast Cancer, Clinical Cancer Research, 19, 571, 10.1158/1078-0432.CCR-12-2123
Casella, 1981, Cytochalasin D inhibits actin polymerization and induces depolymerization of actin filaments formed during platelet shape change, Nature, 293, 302, 10.1038/293302a0
Christianson, 2013, Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity, Proceedings of the National Academy of Sciences, 110, 17380, 10.1073/pnas.1304266110
Chung, 2006, Stromal-Epithelial Interaction in Prostate Cancer Progression, Clinical Genitourinary Cancer, 5, 162, 10.3816/CGC.2006.n.034
Commisso, 2013, Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells, Nature, 497, 633, 10.1038/nature12138
Costa-Silva, 2015, Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver, Nature Cell Biology, 17, 816, 10.1038/ncb3169
Dang, 2010, Glutaminolysis: Supplying carbon or nitrogen or both for cancer cells?, Cell Cycle, 9, 3884, 10.4161/cc.9.19.13302
Daye, 2012, Metabolic reprogramming in cancer: Unraveling the role of glutamine in tumorigenesis, Seminars in Cell & Developmental Biology, 23, 362, 10.1016/j.semcdb.2012.02.002
De Schrijver, 2003, RNA interference-mediated silencing of the fatty acid synthase gene attenuates growth and induces morphological changes and apoptosis of LNCaP prostate cancer cells, Cancer Research, 63, 3799
DeBerardinis, 2010, Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer, Oncogene, 29, 313, 10.1038/onc.2009.358
Delinassios, 1987, Fibroblasts against cancer cells in vitro, Anticancer Research, 7, 1005
Ekström, 2012, Characterization of mRNA and microRNA in human mast cell-derived exosomes and their transfer to other mast cells and blood CD34 progenitor cells, Journal of Extracellular Vesicles, 1, 10.3402/jev.v1i0.18389
Feig, 2012, The Pancreas Cancer Microenvironment, Clinical Cancer Research, 18, 4266, 10.1158/1078-0432.CCR-11-3114
Fendt, 2013, Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells, Nature Communications, 4, 2236, 10.1038/ncomms3236
Feng, 2010, Cellular Internalization of Exosomes Occurs Through Phagocytosis, Traffic, 11, 675, 10.1111/j.1600-0854.2010.01041.x
Feron, 2009, Pyruvate into lactate and back: From the Warburg effect to symbiotic energy fuel exchange in cancer cells, Radiotherapy and Oncology, 92, 329, 10.1016/j.radonc.2009.06.025
Fiaschi, 2012, Oxidative Stress, Tumor Microenvironment, and Metabolic Reprogramming: A Diabolic Liaison, International Journal of Cell Biology, 2012, 1, 10.1155/2012/762825
Gaglio, 2009, Glutamine Deprivation Induces Abortive S-Phase Rescued by Deoxyribonucleotides in K-Ras Transformed Fibroblasts, PLoS ONE, 4, 10.1371/journal.pone.0004715
Gangoda, 2015, Extracellular vesicles including exosomes are mediators of signal transduction: are they protective or pathogenic?, Proteomics, 15, 260, 10.1002/pmic.201400234
Gatenby, 2006, Acid-Mediated Tumor Invasion: a Multidisciplinary Study, Cancer Research, 66, 5216, 10.1158/0008-5472.CAN-05-4193
Hazlehurst, 2003, Role of the tumor microenvironment in mediating de novo resistance to drugs and physiological mediators of cell death, Oncogene, 22, 7396, 10.1038/sj.onc.1206943
Hoshino, 2015, Tumour exosome integrins determine organotropic metastasis, Nature, 527, 329, 10.1038/nature15756
Hu, 2015, Fibroblast-Derived Exosomes Contribute to Chemoresistance through Priming Cancer Stem Cells in Colorectal Cancer, PLOS ONE, 10, 10.1371/journal.pone.0125625
Ishikawa, 2008, ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis, Science, 320, 661, 10.1126/science.1156906
Johnson, 2003, Effect of glutamine on glutathione, IGF-I, and TGF-β1, Journal of Surgical Research, 111, 222, 10.1016/S0022-4804(03)00083-0
Johnstone, 1987, Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes), The Journal of Biological Chemistry, 262, 9412, 10.1016/S0021-9258(18)48095-7
Kamphorst, 2014, Quantitative analysis of acetyl-CoA production in hypoxic cancer cells reveals substantial contribution from acetate, Cancer & Metabolism, 2, 23, 10.1186/2049-3002-2-23
Karnoub, 2007, Mesenchymal stem cells within tumour stroma promote breast cancer metastasis, Nature, 449, 557, 10.1038/nature06188
Kharroubi, 1992, Isotopomer spectral analysis of triglyceride fatty acid synthesis in 3T3-L1 cells, The American Journal of Physiology, 263
King, 2006, Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer, Oncogene, 25, 4675, 10.1038/sj.onc.1209594
Koukourakis, 2005, Pyruvate Dehydrogenase and Pyruvate Dehydrogenase Kinase Expression in Non Small Cell Lung Cancer and Tumor-Associated Stroma, Neoplasia, 7, 1, 10.1593/neo.04373
Li, 2014, starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein–RNA interaction networks from large-scale CLIP-Seq data, Nucleic Acids Research, 42, D92, 10.1093/nar/gkt1248
Liao, 2009, Cancer Associated Fibroblasts Promote Tumor Growth and Metastasis by Modulating the Tumor Immune Microenvironment in a 4T1 Murine Breast Cancer Model, PLoS ONE, 4, 10.1371/journal.pone.0007965
Metallo, 2012, Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia, Nature, 481, 380, 10.1038/nature10602
Modica-Napolitano, 2004, Mitochondrial dysfunction in cancer, Mitochondrion, 4, 755, 10.1016/j.mito.2004.07.027
Mullen, 2012, Reductive carboxylation supports growth in tumour cells with defective mitochondria, Nature, 481, 385, 10.1038/nature10642
Orimo, 2005, Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion, Cell, 121, 335, 10.1016/j.cell.2005.02.034
Pizer, 1996, Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells, Cancer Research, 56, 2745
Rajagopalan, 2011, Role of Glutamine in Cancer: Therapeutic and Imaging Implications, Journal of Nuclear Medicine, 52, 1005, 10.2967/jnumed.110.084244
Rattigan, 2012, Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment, Experimental Cell Research, 318, 326, 10.1016/j.yexcr.2011.11.014
Saifer, 1969, Amino acid composition of monomeric and polymeric human serum albumin, Analytical Biochemistry, 27, 1, 10.1016/0003-2697(69)90214-0
Salimian Rizi, 2015, Nitric oxide mediates metabolic coupling of omentum-derived adipose stroma to ovarian and endometrial cancer cells, Cancer Research, 75, 456, 10.1158/0008-5472.CAN-14-1337
Santidrian, 2013, Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression, Journal of Clinical Investigation, 123, 1068, 10.1172/JCI64264
Selak, 2005, Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase, Cancer Cell, 7, 77, 10.1016/j.ccr.2004.11.022
Shanware, 2011, Glutamine: pleiotropic roles in tumor growth and stress resistance, Journal of Molecular Medicine, 89, 229, 10.1007/s00109-011-0731-9
Simons, 2009, Exosomes – vesicular carriers for intercellular communication, Current Opinion in Cell Biology, 21, 575, 10.1016/j.ceb.2009.03.007
Warburg, 1927, The metabolism of tumors in the body, The Journal of General Physiology, 8, 519, 10.1085/jgp.8.6.519
Weinberg, 2010, Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity, Proceedings of the National Academy of Sciences, 107, 8788, 10.1073/pnas.1003428107
Whiteside, 2008, The tumor microenvironment and its role in promoting tumor growth, Oncogene, 27, 5904, 10.1038/onc.2008.271
Wise, 2008, Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction, Proceedings of the National Academy of Sciences, 105, 18782, 10.1073/pnas.0810199105
Wise, 2010, Glutamine addiction: a new therapeutic target in cancer, Trends in Biochemical Sciences, 35, 427, 10.1016/j.tibs.2010.05.003
Wise, 2011, Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of -ketoglutarate to citrate to support cell growth and viability, Proceedings of the National Academy of Sciences, 108, 19611, 10.1073/pnas.1117773108
Xiao, 2014, Exosomes: Decreased Sensitivity of Lung Cancer A549 Cells to Cisplatin, PLoS ONE, 9, 10.1371/journal.pone.0089534
Yang, 2014, Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer, Molecular Systems Biology, 10, 728, 10.1002/msb.20134892
Ying, 2012, Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism, Cell, 149, 656, 10.1016/j.cell.2012.01.058
Yoshimoto, 2001, Characterization of acetate metabolism in tumor cells in relation to cell proliferation: Acetate metabolism in tumor cells, Nuclear Medicine and Biology, 28, 117, 10.1016/S0969-8051(00)00195-5
Zaidi, 2012, ATP-Citrate Lyase: A Key Player in Cancer Metabolism, Cancer Research, 72, 3709, 10.1158/0008-5472.CAN-11-4112