摘要:肾脏肿瘤作为泌尿系统常见恶性肿瘤之一,发病率和死亡率仍在逐年攀升。尽管靶向药物的出现极大改善 了晚期肾癌患者的预后,但耐药性的发生仍给患者带来巨大的治疗压力。肾透明细胞癌是肾癌中最常见的病理类 型,被广泛报道是一种由代谢重编程参与的代谢性疾病。这种代谢异常不仅支持蛋白质、脂质和核酸等大分子的 合成,而且促进肿瘤进展。脂质代谢的改变,尤其是参与合成生物膜成分、提供肿瘤进展能源、调控肿瘤发生信 号转导的脂肪酸代谢,在肿瘤发生、发展中至关重要。本文对脂质代谢途径中的关键分子进行系统归纳,旨在为 肾透明细胞癌寻找潜在的治疗靶点,进一步阐明干扰脂肪酸代谢途径在肾脏肿瘤治疗中的潜在临床应用前景。
图 1 脂质代谢途径机制图
[1] BRAY F, FERLAY J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J]. CA Cancer J Clin, 2018, 68(6): 394-424
[2] GREEF B, EISEN T. Medical treatment of renal cancer: new horizons [J]. Br J Cancer, 2016, 115(5): 505-516
[3] MOTZER RJ, BANCHEREAU R, HAMIDI H, et al. Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade [J]. Cancer Cell, 2020, 38(6):803-817.e4
[4] CHOI KM, KIM JJ, YOO J, et al. The interferon- inducible protein viperin controls cancer metabolic reprogramming to enhance cancer progression [J]. J Clin Invest, 2022, 132(24): e157302
[5] TAN SK, HOUGEN HY, MERCHAN JR, et al. Fatty acid metabolism reprogramming in ccRCC: mechanisms and potential targets [J]. Nat Rev Urol, 2023, 20(1): 48-60
[6] TAN SK,WELFORD SM. Lipid in Renal Carcinoma: Queen Bee to Target [J]. Trends Cancer, 2020, 6(6): 448- 450
[7] VAN DER MIJN JC, FU L, KHANI F, et al. Combined Metabolomics and Genome- Wide Transcriptomics Analyses Show M ultiple H IF1alpha- Induced Changes in Lipid Metabolism in Early Stage Clear Cell Renal Cell Carcinoma [J]. Transl Oncol, 2020, 13(2): 177-185
[8] ACHARYA R, SHETTY SS, KUMARI NS. Fatty acid transport proteins (FATPs) in cancer [J]. Chem Phys Lipids, 2023, 250: 105269
[9] BLACK PN, AHOWESSO C, MONTEFUSCO D, et al. Fatty Acid Transport Proteins: Targeting FATP2 as a Gatekeeper Involved in the Transport of Exogenous Fatty Acids [J]. Medchemcomm, 2016, 7(4): 612-622
[10] KIM YS, JUNG J, JEONG H, et al. High Membranous Expression of Fatty Acid Transport Protein 4 Is Associated with Tumorigenesis and Tumor Progression in Clear Cell Renal Cell Carcinoma [J]. Dis Markers, 2019, 2019:5702026
[11] WU G, ZHANG Z, TANG Q, et al. Study of FABP's interactome and detecting new molecular targets in clear cell renal cell carcinoma [J]. J Cell Physiol, 2020, 235(4): 3776-3789
[12] MAAN M, PETERS JM, DUTTA M, et al. Lipid metabolism and lipophagy in cancer [J]. Biochem Biophys Res Commun, 2018, 504(3): 582-589
[13] ALBIGES L, HAKIMI AA, XIE W, et al. Body Mass Index and Metastatic Renal Cell Carcinoma: Clinical and Biological Correlations [J]. J Clin Oncol, 2016, 34(30): 3655-3663
[14 XU W, HU X, ANWAIER A, et al. Fatty Acid Synthase Correlates With Prognosis- Related Abdominal Adipose Distribution and Metabolic Disorders of Clear Cell Renal Cell Carcinoma [J]. Front Mol Biosci, 2020, 7: 610229
[15] TENG L, CHEN Y, CAO Y, et al. Overexpression of ATP citrate lyase in renal cell carcinoma tissues and its effect on the human renal carcinoma cells in vitro [J]. Oncol Lett, 2018, 15(5): 6967-6974
[16] WU X, HUANG T. Recent development in acetyl- CoA carboxylase inhibitors and their potential as novel drugs [J]. Future Med Chem, 2020, 12(6): 533-561
[17] CHEN L, DUAN Y, WEI H, et al. Acetyl- CoA carboxylase (ACC) as a therapeutic target for metabolic syndrome and recent developments in ACC1/2 inhibitors [J]. Expert Opin Investig Drugs, 2019, 28(10): 917-930
[18] TESFAY L, PAUL BT, KONSTORUM A, et al. Stearoyl- CoA Desaturase 1 Protects Ovarian Cancer Cells from Ferroptotic Cell Death [J]. Cancer Res, 2019, 79(20): 5355-5366
[19] WANG J, XU Y, ZHU L, et al. High Expression of Stearoyl- CoA Desaturase 1 Predicts Poor Prognosis in Patients with Clear- Cell Renal Cell Carcinoma [J]. PLoS One, 2016, 11(11): e0166231
[20] YANG H, ZHANG X, LIU F, et al. SREBP1- driven lipid desaturation supports clear cell renal cell carcinoma growth through regulation of NF- kappaB signaling [J]. Biochem Biophys Res Commun, 2018, 495(1): 1383-1388
[21] ZHANG X, WU J, WU C, et al. The LINC01138 interacts with PRMT5 to promote SREBP1- mediated lipid desaturation and cell growth in clear cell renal cell carcinoma [J]. Biochem Biophys Res Commun, 2018, 507(1-4): 337-342
[22] LONGO N, AMAT DI SAN FILIPPO C, PASQUALI M. Disorders of carnitine transport and the carnitine cycle [J]. Am J Med Genet C Semin Med Genet, 2006, 142C(2): 77-85
[23] MELONE MAB, VALENTINO A, MARGARUCCI S, et al. The carnitine system and cancer metabolic plasticity [J]. Cell Death Dis, 2018, 9(2): 228
[24] DU W, ZHANG L, BRETT- MORRIS A, et al. HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism [J]. Nat Commun, 2017, 8(1): 1769
[25] GALICIA-MORENO M, SILVA- GOMEZ JA, LucanoLanderos S, et al. Liver Cancer: Therapeutic Challenges and the Importance of Experimental Models [J]. Can J Gastroenterol Hepatol, 2021, 2021: 8837811
[26] SANCHEZ DJ, STEGER DJ, SKULI N, et al. PPARgamma is dispensable for clear cell renal cell carcinoma progression [J]. Mol Metab, 2018, 14: 139-149
[27] PASCUAL G, AVGUSTINOVA A, MEJETTA S, et al. Targeting metastasis- initiating cells through the fatty acid receptor CD36 [J]. Nature, 2017, 541(7635): 41-45
[28] GONG J, LIN Y, ZHANG H, et al. Reprogramming of lipid metabolism in cancer- associated fibroblasts potentiates migration of colorectal cancer cells [J]. Cell Death Dis, 2020, 11(4): 267
[29] LANDBERG N, VON PALFFY S, ASKMYR M, et al. CD36 defines primitive chronic myeloid leukemia cells less responsive to imatinib but vulnerable to antibody- based therapeutic targeting [J]. Haematologica, 2018, 103(3): 447-455
[30] FENG WW, WILKINS O, BANG S, et al. CD36-Mediated Metabolic Rewiring of Breast Cancer Cells Promotes Resistance to HER2- Targeted Therapies [J]. Cell Rep, 2019, 29(11): 3405-3420.e5
[31] HAN J, QU H, HAN M, et al. MSC- induced lncRNA AGAP2- AS1 promotes stemness and trastuzumab resistance through regulating CPT1 expression and fatty acid oxidation in breast cancer [J]. Oncogene, 2021, 40(4): 833-847
[32] ALOIA A, MULLHAUPT D, CHABBERT CD, et al. A Fatty Acid Oxidation- dependent Metabolic Shift Regulates the Adaptation of BRAF- mutated Melanoma to MAPK Inhibitors [J]. Clin Cancer Res, 2019, 25(22): 6852-6867
[33] ADORNO- CRUZ V, HOFFMANN AD, LIU X, et al. ITGA2 promotes expression of ACLY and CCND1 in enhancing breast cancer stemness and metastasis [J]. Genes Dis, 2021, 8(4): 493-508
[34] RYSMAN E, BRUSSELMANS K, SCHEYS K, et al. De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation [J]. Cancer Res, 2010, 70(20): 8117-8126
[35] RIOS GARCIA M, STEINBAUER B, SRIVASTAVA K, et al. Acetyl-CoA Carboxylase 1-Dependent Protein Acetylation Controls Breast Cancer Metastasis and Recurrence [J]. Cell Metab, 2017, 26(6): 842-855.e5
[36] FALCHOOK G, INFANTE J, ARKENAU HT, et al. First- in- human study of the safety, pharmacokinetics, and pharmacodynamics of first- in- class fatty acid synthase inhibitor TVB- 2640 alone and with a taxane in advanced tumors [J]. EClinical Medicine, 2021, 34: 100797
[37] FHU CW, ALI A. Fatty Acid Synthase: An Emerging Target in Cancer [J]. Molecules, 2020, 25(17): 3935
[38] SEGUIN F, CARVALHO MA, BASTOS DC, et al. The fatty acid synthase inhibitor orlistat reduces experimental metastases and angiogenesis in B16- F10 melanomas [J]. Br J Cancer, 2012, 107(6): 977-987
[39] PAPAEVANGELOU E, ALMEIDA GS, BOX C, et al. The effect of FASN inhibition on the growth and metabolism of a cisplatin- resistant ovarian carcinoma model [J]. Int J Cancer, 2018, 143(4): 992-1002
[40] VON ROEMELING CA, MARLOW LA, WEI JJ, et al. Stearoyl- CoA desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma [J]. Clin Cancer Res, 2013, 19(9): 2368-2380
[41] WANG H, ZHANG Y, LU Y, et al. The role of stearoylcoenzyme A desaturase 1 in clear cell renal cell carcinoma [J]. Tumour Biol, 2016, 37(1): 479-489
[42] LUCARELLI G, FERRO M, LOIZZO D, et al. Integration of Lipidomics and Transcriptomics Reveals Reprogramming of the Lipid Metabolism and Composition in Clear Cell Renal Cell Carcinoma [J]. Metabolites, 2020, 10(12): 509
[43] HEO MJ, KANG SH, KIM YS, et al. UBC12-mediated SREBP- 1 neddylation worsens metastatic tumor prognosis [J]. Int J Cancer, 2020, 147(9): 2550-2563
[44] SUN Q, YU X, PENG C, et al. Activation of SREBP-1c alters lipogenesis and promotes tumor growth and metastasis in gastric cancer [J]. Biomed Pharmacother, 2020, 128: 110274
[45] BELORIBI- DJEFAFLIA S, VASSEUR S, GUILLAUMOND F. Lipid metabolic reprogramming in cancer cells [J]. Oncogenesis, 2016, 5: e189
[46] GEBHARD RL, CLAYMAN RV, PRIGGE WF, et al. Abnormal cholesterol metabolism in renal clear cell carcinoma [J]. J Lipid Res, 1987, 28(10): 1177-1184
[47] ZHENG M, WANG W, LIU J, et al. Lipid Metabolism in Cancer Cells [J]. Adv Exp Med Biol, 2021, 1316: 49-69
[48] ZHANG X, ZHANG H, DAI J, et al. The influence of dynamic changes in lipid metabolism on survival outcomes in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors [J]. Jpn J Clin Oncol, 2020, 50(12): 1454-1463.
孙恺,杨天民,夏庆华. 生物再生材料修复前尿道狭窄的单中心经验[J]. 泌尿外科杂志(电子版),2023,15(1):8-17. DOI:10.20020/j.CNKI.1674-7410.2023.01.03
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肾细胞癌 (renal cell carcinoma,RCC) 是常 见的泌尿系统恶性肿瘤,2018年预估全球新发肾肿 瘤数为 403 262 例,同年在全世界范围内预估有 175 098例患者因肾癌死亡[1] 。手术切除是早期肾癌 一线治疗方案,而晚期转移性肾癌患者,外科治疗 效果较差,尽管靶向治疗的出现给晚期患者带来了 治疗曙光,但是耐药性和药物不良反应的发生使中 位生存率不足 3 年[2] 。研究认为肾癌属于代谢性疾 病,在肾癌的发生发展过程中,存在很多基因的突变,包括 Von Hippel-Lindau (VHL) 等[3] 。这些基 因的突变直接改变了肾癌细胞的代谢过程,而参与 氧、能量以及营养物质代谢通路的改变在肾癌的发 生发展过程中具有重要意义[4] 。 肾透明细胞癌 (clear cell renal cell carcinoma, ccRCC) 是肾细胞癌最常见的病理类型,因其细胞 质含丰富的脂质和糖原病理染色呈“透明”状态 而得名。研究表明,脂肪酸 (fatty acids,FAs) 在 ccRCC 的膜结构、能量代谢及信号转导等方面发挥 作用,提示调节脂肪酸水平对于调控肿瘤发生发展 具有重要作用,这不仅包括从微环境中调节脂肪酸 的合成,修饰和摄取,也包括从其他脂质种类中释 放脂肪酸[5-6] 。大量研究证实,脂肪酸代谢在 ccRCC 的进程中具有重要意义,靶向脂肪酸代谢可能成为 逆转耐药并改善 ccRCC预后的潜在途径。 本文总结脂肪酸代谢的关键因子在 ccRCC 中的 研究进展,阐述其在 ccRCC 进展中的作用,以寻找 ccRCC 潜在的治疗靶点,进一步阐明干扰脂肪酸代 谢途径在肾脏肿瘤治疗中的潜在临床应用前景。
1 脂质的摄取
2 脂质的生物合成
3 脂质的代谢
4 靶向脂肪酸代谢途径在肿瘤治疗中的作用
5 总结及展望
5 总结及展望
脂肪酸被视为癌症发展过程中重要的生化成 分。它们是细胞膜及细胞器膜的重要组成成分,以 “脂质筏”的形式募集信号蛋白,促进信号转导的蛋 白-蛋白相互作用。脂肪酸的组成和丰度不仅能调节 膜的流动性,也可以改变蛋白质动力学特征。例如, 饱和磷脂 (Phospholipid,PL) 被证明可以调节信号 转导,参与癌细胞对氧化损伤的防御,及对化疗药 物摄取的抵抗[45] 。除了其结构作用外,脂肪酸还可以 协调信号转导级联反应,也可以分解为具有生物活 性的分子,调节多种致癌过程[46] 。
代谢重编程是癌症的标志,可以通过改变肿瘤 细胞代谢能力,进而在肿瘤进展中发挥重要作用。 尽管大多数关于癌症代谢失调的研究都集中在碳水 化合物上,但脂质代谢相关改变的重要性已经开始 被认识到。大量研究证实肿瘤细胞的脂肪代谢对生 物膜的合成、脂质的合成和降解、以及信号传导等 多方面产生影响[47] 。RCC 中异常的脂肪酸代谢在 1987 年被首次报道,该报道利用气相色谱方法发现 肾肿瘤组织中的胆固醇酯含量明显高于正常肾组织[6] 。 RCC 脂肪酸代谢重编程,主要表现在四个方面: ① 从头合成和外源摄取在细胞脂肪酸池中的作用; ②分子异质性和致癌信号转导途径调节脂肪酸代谢 的机制;③脂肪酸作为癌症进展和转移的重要介质 重塑肿瘤微环境;④靶向癌症中脂肪酸代谢的治疗 策略[48] 。
近年来包括蛋白组学、代谢组学、脂质组学在 内的多种组学技术使对 ccRCC 这一典型的代谢性疾 病的研究进入高速发展期。其中,ccRCC 中脂质代 谢相关机制的深入研究尤为引人注目。ccRCC 作为 具有经典的分子改变 (VHL失活),以脂质沉积为显 著特征的代谢性疾病,是研究肿瘤脂质代谢极好的 范例。进一步研究在致癌信号通路和脂肪酸代谢失 调之间复杂的相互作用,将为揭示新的代谢通路和 提高靶向治疗提供广阔的前景。
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