脂肪酸代谢在恶性肿瘤发生机制及分子影像中的应用

刘畅; 张一帆

doi:10.12122/j.issn.1674-4500.2020.01.04

脂肪酸代谢在恶性肿瘤发生机制及分子影像中的应用

doi: 10.12122/j.issn.1674-4500.2020.01.04

刘畅,
张一帆^,

上海交通大学医学院附属瑞金医院核医学科，上海 200025

基金项目: 国家自然科学基金（81671720，81971644）

详细信息

作者简介:
刘畅：刘畅，博士研究生，E-mail：c494547843@126.com

通讯作者:
张一帆，博士，主任医师，E-mail：zhang_yifan@126.com

计量
- 文章访问数: 1013
- HTML全文浏览量: 402
- PDF下载量: 24
- 被引次数: 0
出版历程
- 收稿日期: 2020-02-10
- 刊出日期: 2020-01-01

Appliaction of fatty acid metabolism in occurrence and molecular imaging of malignant tumors

Chang LIU,
Yifan ZHANG^,

Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China

摘要

摘要: 恶性肿瘤的增殖需要多种能量物质包括糖、脂肪和蛋白质。代谢重编程为恶性肿瘤提供能量，促进肿瘤的发生发展。沃伯格效应被认为是肿瘤代谢的主要方式，在这个过程中葡萄糖利用增加，为肿瘤代谢提供能量；利用此特性¹⁸F-FDG显像因能准确反应肿瘤生物学特征、位置、进展和对治疗的反应，PET等分子影像已广泛应用于肿瘤诊断和治疗并发挥不可替代作用。此外，肿瘤还需要脂肪酸代谢产物调控蛋白质翻译后修饰，提供脂质信号分子及膜磷脂以抵抗化疗药物的作用等。利用肿瘤细胞脂肪酸合成增加这一特性，放射性核素标记短链脂肪酸可用于肿瘤显像。本文对肿瘤脂肪酸代谢及其分子影像学相关研究做一综述。
- 脂肪酸 /
- 肿瘤 /
- 代谢 /
- 放射性核素 /
- 分子影像
Abstract: Malignant proliferation of tumor cells require multiple energy substances, including glucose, fatty acid and protein. Metabolic reprogramming is an important biomarker of cancer which improves the occurrence and development of malignant tumors. The Warburg effect is a key metabolic hallmark of cancer, which significantly increased glucose consumption and provided energy for tumor metabolism. Using this characteristic, ¹⁸F-FDG imaging can accurately reflect tumor biological characteristics, location, progress and response to treatment. Molecular imaging such as PET has been widely used in cancer diagnosis and prognosis after treatment. In addition, fatty acid metabolites also regulate the post-translational modifications of protein and provides lipid signal molecule as well as membrane phospholipid to resist the effect of chemotherapeutic drugs. Thus, taking advantage of fatty acid synthesis in tumors, radiolabeled short-chain fatty acid can used for the diagnosis of cancer. This review focuses on the research of fatty acid metabolism and molecular imaging in cancer.
- fatty acid /
- cancer /
- metabolism /
- radionuclide /
- molecular imaging

HTML全文

参考文献(55)

[1]	Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism[J]. Cell Metab, 2016, 23(1): 27-47. doi: 10.1016/j.cmet.2015.12.006
[2]	Phannasil P, Thuwajit C, Warnnissorn M, et al. Pyruvate carboxylase is up-regulated in breast cancer and essential to support growth and invasion of MDA-MB-231 cells[J]. PLoS One, 2015, 10(6): e0129848. doi: 10.1371/journal.pone.0129848
[3]	Urata K, Kajihara I, Miyauchi H, et al. The Warburg effect and tumour immune microenvironment in extramammary Paget's disease: overexpression of lactate dehydrogenase a correlates with immune resistance[J]. J Eur Acad Dermatol Venereol, 2019, 12: e16145-56.
[4]	Kitazawa M, Hatta T, Sasaki Y, et al. Promotion of the Warburg effect is associated with poor benefit from adjuvant chemotherapy in colorectal cancer[J]. Cancer Sci, 2020, 111(2): 658-66. doi: 10.1111/cas.14275
[5]	Annibaldi A, Widmann C. Glucose metabolism in cancer cells[J]. Curr Opin Clin Nutr Metab Care, 2010, 13(4): 466-70. doi: 10.1097/MCO.0b013e32833a5577
[6]	Senga S, Kobayashi N, Kawaguchi K, et al. Fatty acid-binding protein 5(FABP5) promotes lipolysis of lipid droplets, de novo fatty acid (FA) synthesis and activation of nuclear factor-kappa B (NF-κB) signaling in cancer cells[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2018, 1863(9): 1057-67. doi: 10.1016/j.bbalip.2018.06.010
[7]	Buckley D, Duke G, Heuer TS, et al. Fatty acid synthase - Modern tumor cell biology insights into a classical oncology target[J]. Pharmacol Ther, 2017, 177: 23-31. doi: 10.1016/j.pharmthera.2017.02.021
[8]	Uddin S, Siraj AK, Al-Rasheed M, et al. Fatty acid synthase and AKT pathway signaling in a subset of papillary thyroid cancers[J]. J Clin Endocrinol Metab, 2008, 93(10): 4088-97. doi: 10.1210/jc.2008-0503
[9]	Friedenreich CM. Physical activity and breast cancer: review of the epidemiologic evidence and biologic mechanisms[J]. Recent Results Cancer Res, 2011, 188: 125-39.
[10]	Pan H, Gray R, Braybrooke J, et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years[J]. N Engl J Med, 2017, 377(19): 1836-46. doi: 10.1056/NEJMoa1701830
[11]	Goswami S, Sharma-Walia N. Crosstalk between osteoprotegerin (OPG), fatty acid synthase (FASN) and, cycloxygenase-2(COX-2) in breast cancer: implications in carcinogenesis[J]. Oncotarget, 2016, 7(37): 58953-74.
[12]	Zhou L, Jiang SF, Fu Q, et al. FASN, ErbB2-mediated glycolysis is required for breast cancer cell migration[J]. Oncol Rep, 2016, 35(5): 2715-22. doi: 10.3892/or.2016.4627
[13]	Wilmanski T, Buhman K, Donkin SS, et al. 1α, 25-dihydroxyvitamin D inhibits de novo fatty acid synthesis and lipid accumulation in metastatic breast cancer cells through down-regulation of pyruvate carboxylase[J]. J Nutr Biochem, 2017, 40: 194-200. doi: 10.1016/j.jnutbio.2016.11.006
[14]	Rossi S, Graner E, Febbo P, et al. Fatty acid synthase molecular signatures expression defines distinct in prostate cancer[J]. Mol Cancer Res, 2003, 1(10): 707-15.
[15]	Wu X, Serrano MA, Zou Y, et al. Abstract 2124: non-homologues end joining mediates fatty acid synthase(FASN)-associated resistance to DNA-damaging chemotherapeutics[J]. Cancer Res, 2012, 72(11): 1305-16.
[16]	Xiao RJ, Su Y, Simmen RCM, et al. Dietary soy protein inhibits DNA damage and cell survival of colon epithelial cells through attenuated expression of fatty acid synthase[J]. Am J Physiol - Gastrointest Liver Physiol, 2008, 294(4): G868-76. doi: 10.1152/ajpgi.00515.2007
[17]	Kao YC, Lee SW, Lin LC, et al. Fatty acid synthase overexpression confers an independent prognosticator and associates with radiation resistance in nasopharyngeal carcinoma[J]. Tumour Biol, 2013, 34(2): 759-68. doi: 10.1007/s13277-012-0605-y
[18]	Li JB, Huang QC, Long XY, et al. CD147 reprograms fatty acid metabolism in hepatocellular carcinoma cells through Akt/mTOR/SREBP1c and P38/PPARα pathways[J]. J Hepatol, 2015, 63(6): 1378-89. doi: 10.1016/j.jhep.2015.07.039
[19]	Guo DL, Bell EH, Mischel P, et al. Targeting SREBP-1-driven lipid metabolism to treat cancer[J]. Curr Pharm Des, 2014, 20(15): 2619-26. doi: 10.2174/13816128113199990486
[20]	Tang X, Guo N, Xu LX, et al. CD147/EMMPRIN: an effective therapeutic target for hepatocellular carcinoma[J]. J Drug Target, 2013, 21(3): 224-31. doi: 10.3109/1061186X.2012.702769
[21]	Hapala I, Marza E, Ferreira T. Is fat so bad? Modulation of endoplasmic Reticulum stress by lipid droplet formation[J]. Biol Cell, 2011, 103(6): 271-85. doi: 10.1042/BC20100144
[22]	Ramapriyan R, Caetano MS, Barsoumian HB, et al. Altered cancer metabolism in mechanisms of immunotherapy resistance[J]. Pharmacol Ther, 2019, 195: 162-71. doi: 10.1016/j.pharmthera.2018.11.004
[23]	Cappel D, Deja S, Fu XR, et al. Pyruvate carboxylase is required for hepatic gluconeogenesis and TCA cycle function[J]. Diabetes, 2018, 67(Supplement 1): 1882-9. doi: 10.2337/db18-1882-P
[24]	Zhao S, Torres A, Henry RA, et al. ATP-citrate lyase controls a glucose-to-acetate metabolic switch[J]. Cell Rep, 2016, 17(4): 1037-52. doi: 10.1016/j.celrep.2016.09.069
[25]	Svensson RU, Parker SJ, Eichner LJ, et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models[J]. Nat Med, 2016, 22(10): 1108-19. doi: 10.1038/nm.4181
[26]	Menendez JA, Lupu R. Fatty acid synthase (FASN) as a therapeutic target in breast cancer[J]. Expert Opin Ther Targets, 2017, 21(11): 1001-16. doi: 10.1080/14728222.2017.1381087
[27]	Yoshii Y, Furukawa T, Saga T, et al. Acetate/acetyl-CoA metabolism associated with cancer fatty acid synthesis: overview and application[J]. Cancer Lett, 2015, 356(2 Pt A): 211-6.
[28]	Yang Y, Morin PJ, Han WF, et al. Regulation of fatty acid synthase expression in breast cancer by sterol regulatory element binding protein-1c[J]. Exp Cell Res, 2003, 282(2): 132-7. doi: 10.1016/S0014-4827(02)00023-X
[29]	Shimomura I, Shimano H, Horton JD, et al. Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells[J]. J Clin Invest, 1997, 99(5): 838-45. doi: 10.1172/JCI119247
[30]	Lu CX, Jiang QF, Hu MJ, et al. Preliminary biological evaluation of ¹⁸F-AlF-NOTA-MAL-Cys-Annexin V as a novel apoptosis imaging agent[J]. Oncotarget, 2017, 8(31): 51086-95.
[31]	Finessi M, Bisi G, Deandreis D. Hyperglycemia and 18F-FDG PET/CT, issues and problem solving: a literature review[J]. Acta Diabetol, 2020, 57(3): 253-62. doi: 10.1007/s00592-019-01385-8
[32]	Imai M, Kosaka Y, Tachi M, et al. Does delayed image of myocardial fatty acid metabolism SPECT predict prognosis[J]. J Nucl Med, 2019, 60: 313-4.
[33]	Kero T, Rosengren S, Lubberink M, et al. PET in cardiac amyloidosis - altered resting biventricular MBF measured with 11C-acetate is a strong indicator of disease severity[J]. Eur J Nucl Med Mol I, 2012, 39: s179-87.
[34]	Derlin T, Weiberg D, Sohns JM. Multitracer molecular imaging of Paget disease targeting bone remodeling, fatty acid metabolism, and PSMA expression on PET/CT[J]. Clin Nucl Med, 2016, 41(12): 991-2. doi: 10.1097/RLU.0000000000001413
[35]	Schug ZT, Peck B, Jones DT, et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress[J]. Cancer Cell, 2015, 27(1): 57-71. doi: 10.1016/j.ccell.2014.12.002
[36]	Malkowski B, Pankowska V, Malkowski B, et al. Predictive value of 11C-Acetate PET-CT in metastatic renal cell carcinoma[J]. Eur J Nucl Med Mol, 2017, 34(15): e16088-96.
[37]	Regulal NK, Lubberink M, Jorulf H, et al. Dynamic imaging of prostate cancer with 11C-acetate PET/CT[J]. J Nucl Med, 2017, 58(s1): 662-73.
[38]	Zieba R. 11C-Acetate advantage over 18F-FDG in PET imaging of prostate cancer[J]. J Nucl Med, 2016, 57(s2): 2817-26.
[39]	Regula N, Häggman M, Johansson S, et al. Malignant lipogenesis defined by 11C-acetate PET/CT predicts prostate cancer-specific survival in patients with biochemical relapse after prostatectomy[J]. Eur J Nucl Med Mol Imaging, 2016, 43(12): 2131-8. doi: 10.1007/s00259-016-3449-7
[40]	Kang SC, Park HH, Kim JY, et al. Comparison of one-day and two-day protocol of 11C-Acetate and 18F-FDG scan in hepatoma[J]. J Nucl Med, 2010, 51(s1): 903-14.
[41]	Balogh J, Victor D 3rd, Asham EH, et al. Hepatocellular carcinoma: a review[J]. J Hepatocell Carcinoma, 2016, 3(1): 41-53.
[42]	Deford-Watts LM, Mintz A, Kridel SJ. The potential of ¹¹C-acetate PET for monitoring the Fatty acid synthesis pathway in Tumors[J]. Curr Pharm Biotechnol, 2013, 14(3): 300-12. doi: 10.2174/1389201011314030006
[43]	Zhao J, Zhang ZW, Nie DH, et al. PET imaging of hepatocellular carcinomas: ¹⁸F-fluoropropionic acid as a complementary radiotracer for ¹⁸F-fluorodeoxyglucose[J]. Mol Imaging, 2019, 18(7): 1032-41.
[44]	Wang HL, Tang GH, Hu KZ, et al. Comparison of three short fatty acid probes and 18F-FDG for differentiation tumor from inflammation in mice[J]. J Nuclear Med, 2014, 55(6): 190-201.
[45]	Witney TH, Pisaneschi F, Alam IS, et al. Preclinical evaluation of 3-18F-fluoro-2, 2-dimethylpropionic acid as an imaging agent for tumor detection[J]. J Nucl Med, 2014, 55(9): 1506-12. doi: 10.2967/jnumed.114.140343
[46]	Chakravarty B, Gu ZW, Chirala SS, et al. Human fatty acid synthase: structure and substrate selectivity of the thioesterase domain[J]. Proc Natl Acad Sci USA, 2004, 101(44): 15567-72. doi: 10.1073/pnas.0406901101
[47]	Guo CB, Cui NH, Yu GY, et al. Effects of cerulenin on the endogenous fatty acid synthetic activity in squamous cell carcinoma of the oral cavity[J]. J Oral Maxillofac Surg, 2003, 61(8): 909-12. doi: 10.1016/S0278-2391(03)00237-4
[48]	Menendez JA, Vellon L, Mehmi I, et al. Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells[J]. Proc Natl Acad Sci USA, 2004, 101(29): 10715-20. doi: 10.1073/pnas.0403390101
[49]	Price AC, Choi KH, Heath RJ, et al. Inhibition of beta-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism[J]. J Biol Chem, 2001, 276(9): 6551-9. doi: 10.1074/jbc.M007101200
[50]	Pizer ES, Jackisch C, Wood FD, et al. Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells[J]. Cancer Res, 1996, 56(12): 2745-7.
[51]	Murata S, Yanagisawa K, Fukunaga K, et al. Fatty acid synthase inhibitor cerulenin suppresses liver metastasis of colon cancer in mice[J]. Cancer Sci, 2010, 101(8): 1861-5. doi: 10.1111/j.1349-7006.2010.01596.x
[52]	Alli PM, Pinn ML, Jaffee EM, et al. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice[J]. Oncogene, 2005, 24(1): 39-46. doi: 10.1038/sj.onc.1208174
[53]	Guseva NV, Rokhlin OW, Glover RA, et al. TOFA (5-tetradecyl-oxy-2-furoic acid) reduces fatty acid synthesis, inhibits expression of AR, neuropilin-1 and Mcl-1 and kills prostate cancer cells independent of p53 status[J]. Cancer Biol Ther, 2011, 12(1): 80-5. doi: 10.4161/cbt.12.1.15721
[54]	Currie E, Schulze A, Zechner R, et al. Cellular fatty acid metabolism and cancer[J]. Cell Metab, 2013, 18(2): 153-61. doi: 10.1016/j.cmet.2013.05.017
[55]	Huang LH, Chung HY, Su HM. Docosahexaenoic acid reduces sterol regulatory element binding protein-1 and fatty acid synthase expression and inhibits cell proliferation by inhibiting pAkt signaling in a human breast cancer MCF-7 cell line[J]. BMC Cancer, 2017, 17(1): 890-8. doi: 10.1186/s12885-017-3936-7