Lipid droplet formation is a defining histological feature in clear-cell renal cell carcinoma (ccRCC) but the underlying mechanisms and importance of this biological behaviour have remained enigmatic. De novo fatty acid (FA) synthesis, uptake and suppression of FA oxidation have all been shown to contribute to lipid storage, which is a necessary tumour adaptation rather than a bystander effect. Clinical studies and mechanistic investigations into the roles of different enzymes in FA metabolism pathways have revealed new metabolic vulnerabilities that hold promise for clinical effect. Several metabolic alterations are associated with worse clinical outcomes in patients with ccRCC, as lipogenic genes drive tumorigenesis. Enzymes involved in the intrinsic FA metabolism pathway include FA synthase, acetyl-CoA carboxylase, ATP citrate lyase, stearoyl-CoA desaturase 1, cluster of differentiation 36, carnitine palmitoyltransferase 1A and the perilipin family, and each might be potential therapeutic targets in ccRCC owing to the link between lipid deposition and ccRCC risk. Adipokines and lipid species are potential biomarkers for diagnosis and treatment monitoring in patients with ccRCC. FA metabolism could potentially be targeted for therapeutic intervention in ccRCC as small-molecule inhibitors targeting the pathway have shown promising results in preclinical models.
This is a preview of subscription content, access via your institution
Subscribe to Nature+
Get immediate online access to Nature and 55 other Nature journal
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Linehan, W. M. et al. The metabolic basis of kidney cancer. Cancer Discov. 9, 1006–1021 (2019).
Cairns, P. Renal cell carcinoma. Cancer Biomark. 9, 461–473 (2010).
Tugnoli, V., Trinchero, A. & Tosi, M. R. Evaluation of the lipid composition of human healthy and neoplastic renal tissues. Ital. J. Biochem. 53, 169–182 (2004).
Kaelin, W. G. Jr The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma. Clin. Cancer Res. 13, 680s–684s (2007).
Kaelin, W. G. Jr & Ratcliffe, P. J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402 (2008).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Schito, L. & Semenza, G. L. Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer 2, 758–770 (2016).
Gameiro, P. A. et al. In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab. 17, 372–385 (2013).
Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2012).
Du, W. et al. HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nat. Commun. 8, 1769 (2017).
Qiu, B. et al. HIF2α-dependent lipid storage promotes endoplasmic reticulum homeostasis in clear-cell renal cell carcinoma. Cancer Discov. 5, 652–667 (2015).
Tan, S. K. et al. Obesity-dependent adipokine chemerin suppresses fatty acid oxidation to confer ferroptosis resistance. Cancer Discov. https://doi.org/10.1158/2159-8290.Cd-20-1453 (2021).
Du, Y. et al. Lysophosphatidylcholine acyltransferase 1 upregulation and concomitant phospholipid alterations in clear cell renal cell carcinoma. J. Exp. Clin. Cancer Res. 36, 66 (2017).
Sok, M., Šentjurc, M., Schara, M., Stare, J. & Rott, T. Cell membrane fluidity and prognosis of lung cancer. Ann. Thorac. Surg. 73, 1567–1571 (2002).
Campanella, R. Membrane lipids modifications in human gliomas of different degree of malignancy. J. Neurosurg. Sci. 36, 11–25 (1992).
Xie, H. et al. Glycogen metabolism is dispensable for tumour progression in clear cell renal cell carcinoma. Nat. Metab. 3, 327–336 (2021).
Xu, H. et al. Fatty acid metabolism reprogramming in advanced prostate cancer. Metabolites https://doi.org/10.3390/metabo11110765 (2021).
Monaco, M. E. Fatty acid metabolism in breast cancer subtypes. Oncotarget 8, 29487–29500 (2017).
Svensson, R. U. & Shaw, R. J. Lipid synthesis is a metabolic liability of non-small cell lung cancer. Cold Spring Harb. Symp. Quant. Biol. 81, 93–103 (2016).
Pizer, E. S. et al. Increased fatty acid synthase as a therapeutic target in androgen-independent prostate cancer progression. Prostate 47, 102–110 (2001).
Davis, A. L. & Kridel, S. J. Trimming the fat in non-small cell lung cancer: a new small molecule inhibitor of acetyl-CoA carboxylase to target fatty acid synthesis. Transl. Cancer Res. 5(S7), S1449–S1452 (2016).
Falchook, G. 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. EClinicalMedicine 34, 100797 (2021).
Menendez, J. A. & Lupu, R. Fatty acid synthase regulates estrogen receptor-α signaling in breast cancer cells. Oncogenesis 6, e299 (2017).
Tan, S. K. & Welford, S. M. Lipid in renal carcinoma: queen bee to target. Trends Cancer https://doi.org/10.1016/j.trecan.2020.02.017 (2020).
Koundouros, N. & Poulogiannis, G. Reprogramming of fatty acid metabolism in cancer. Br. J. Cancer 122, 4–22 (2020).
Bauer, D. E., Hatzivassiliou, G., Zhao, F., Andreadis, C. & Thompson, C. B. ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24, 6314–6322 (2005).
Schug, Z. T. et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27, 57–71 (2015).
Ookhtens, M., Kannan, R., Lyon, I. & Baker, N. Liver and adipose tissue contributions to newly formed fatty acids in an ascites tumor. Am. J. Physiol. 247, R146–R153 (1984).
Pinthus, J. H., Whelan, K. F., Gallino, D., Lu, J. P. & Rothschild, N. Metabolic features of clear-cell renal cell carcinoma: mechanisms and clinical implications. Can. Urol. Assoc. J. 5, 274–282 (2011).
Medes, G., Thomas, A. & Weinhouse, S. Metabolism of neoplastic tissue. IV. A study of lipid synthesis in neoplastic tissue slices in vitro. Cancer Res. 13, 27–29 (1953).
Butler, L. M. et al. Lipids and cancer: emerging roles in pathogenesis, diagnosis and therapeutic intervention. Adv. Drug Deliv. Rev. 159, 245–293 (2020).
Khan, S. et al. Kidney proximal tubule lipoapoptosis is regulated by fatty acid transporter-2 (FATP2). J. Am. Soc. Nephrol. 29, 81–91 (2018).
Uhlén, M. et al. Proteomics. Tissue-based map of the human proteome. Science 347, 1260419 (2015).
DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci. Adv. 2, e1600200 (2016).
Riscal, R. et al. Cholesterol auxotrophy as a targetable vulnerability in clear cell renal cell carcinoma. Cancer Discov. 11, 3106–3125 (2021).
Yuan, Y. et al. Expression and prognostic significance of fatty acid synthase in clear cell renal cell carcinoma. Pathol. Res. Pract. 216, 153227 (2020).
Fujita, Y., Matsuoka, H. & Hirooka, K. Regulation of fatty acid metabolism in bacteria. Mol. Microbiol. 66, 829–839 (2007).
Peck, B. et al. Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments. Cancer Metab. 4, 6 (2016).
von Roemeling, C. A. et al. Stearoyl-CoA desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma. Clin. Cancer Res. 19, 2368–2380 (2013).
Jain, I. H. et al. Genetic screen for cell fitness in high or low oxygen highlights mitochondrial and lipid metabolism. Cell 181, 716–727 (2020).
Zaidi, N., Swinnen, J. V. & Smans, K. ATP-citrate lyase: a key player in cancer metabolism. Cancer Res. 72, 3709 (2012).
Watson, J. A., Fang, M. & Lowenstein, J. M. Tricarballylate and hydroxycitrate: substrate and inhibitor of ATP: citrate oxaloacetate lyase. Arch. Biochem. Biophys. 135, 209–217 (1969).
Sun, T., Hayakawa, K., Bateman, K. S. & Fraser, M. E. Identification of the citrate-binding site of human ATP-citrate lyase using X-ray crystallography. J. Biol. Chem. 285, 27418–27428 (2010).
Noh, K. H. et al. Ubiquitination of PPAR-gamma by pVHL inhibits ACLY expression and lipid metabolism, is implicated in tumor progression. Metabolism 110, 154302 (2020).
Guo, H. et al. The PI3K/AKT pathway and renal cell carcinoma. J. Genet. Genomics 42, 343–353 (2015).
Migita, T. et al. ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res. 68, 8547–8554 (2008).
Wang, S. et al. Novel molecular subtypes and related score based on histone acetylation modification in renal clear cell carcinoma. Front. Cell Dev. Biol. 9, 668810 (2021).
Carrer, A. et al. Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. Cancer Discov. 9, 416–435 (2019).
Teng, L. et al. Overexpression of ATP citrate lyase in renal cell carcinoma tissues and its effect on the human renal carcinoma cells in vitro. Oncol. Lett. 15, 6967–6974 (2018).
Zhao, Z. et al. The mRNA expression signature and prognostic analysis of multiple fatty acid metabolic enzymes in clear cell renal cell carcinoma. J. Cancer 10, 6599–6607 (2019).
Qi, X., Li, Q., Che, X., Wang, Q. & Wu, G. The uniqueness of clear cell renal cell carcinoma: summary of the process and abnormality of glucose metabolism and lipid metabolism in ccRCC. Front. Oncol. https://doi.org/10.3389/fonc.2021.727778 (2021).
Wang, X., Luo, S., Gan, X., He, C. & Huang, R. Safety and efficacy of ETC-1002 in hypercholesterolaemic patients: a meta-analysis of randomised controlled trials. Kardiol. Pol. 77, 207–216 (2019).
Chuah, L. O., Yeap, S. K., Ho, W. Y., Beh, B. K. & Alitheen, N. B. In vitro and in vivo toxicity of garcinia or hydroxycitric acid: a review. Evid. Based Complement. Altern. Med. 2012, 197920 (2012).
Berkhout, T. A., Havekes, L. M., Pearce, N. J. & Groot, P. H. The effect of (−)-hydroxycitrate on the activity of the low-density-lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase levels in the human hepatoma cell line Hep G2. Biochem. J. 272, 181–186 (1990).
Burke, A. C. et al. Bempedoic acid lowers low-density lipoprotein cholesterol and attenuates atherosclerosis in low-density lipoprotein receptor-deficient (LDLR+/− and LDLR−/−) Yucatan Miniature Pigs. Arterioscler. Thromb. Vasc. Biol. 38, 1178–1190 (2018).
Wang, C., Rajput, S., Watabe, K., Liao, D. F. & Cao, D. Acetyl-CoA carboxylase-a as a novel target for cancer therapy. Front. Biosci. 2, 515–526 (2010).
Bianchi, A. et al. Identification of an isozymic form of acetyl-CoA carboxylase. J. Biol. Chem. 265, 1502–1509 (1990).
Creighton, C. J. et al. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).
Luo, J. et al. Acetyl-CoA carboxylase rewires cancer metabolism to allow cancer cells to survive inhibition of the Warburg effect by cetuximab. Cancer Lett. 384, 39–49 (2017).
Qu, Y. Y. et al. Inactivation of the AMPK-GATA3-ECHS1 pathway induces fatty acid synthesis that promotes clear cell renal cell carcinoma growth. Cancer Res. 80, 319–333 (2020).
He, D., Sun, X., Yang, H., Li, X. & Yang, D. TOFA induces cell cycle arrest and apoptosis in ACHN and 786-O cells through inhibiting PI3K/Akt/mTOR pathway. J. Cancer 9, 2734–2742 (2018).
Lee, M. et al. Phosphorylation of acetyl-CoA carboxylase by AMPK reduces renal fibrosis and is essential for the anti-fibrotic effect of metformin. J. Am. Soc. Nephrol. 29, 2326–2336 (2018).
Song, A., Zhang, C. & Meng, X. Mechanism and application of metformin in kidney diseases: an update. Biomed. Pharmacother. 138, 111454 (2021).
Liu, J. et al. Metformin inhibits renal cell carcinoma in vitro and in vivo xenograft. Urol. Oncol. 31, 264–270 (2013).
Fang, Z., Xu, X., Zhou, Z., Xu, Z. & Liu, Z. Effect of metformin on apoptosis, cell cycle arrest migration and invasion of A498 cells. Mol. Med. Rep. 9, 2251–2256 (2014).
Liu, Y., Li, J., Song, M., Qi, G. & Meng, L. High-concentration metformin reduces oxidative stress injury and inhibits the growth and migration of clear cell renal cell carcinoma. Comput. Math. Methods Med. 2022, 1466991 (2022).
El-Mir, M. Y. et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 275, 223–228 (2000).
Psutka, S. P. et al. The association between metformin use and oncologic outcomes among surgically treated diabetic patients with localized renal cell carcinoma. Urol. Oncol. 33, e15–e23 (2015).
Li, Y., Hu, L., Xia, Q., Yuan, Y. & Mi, Y. The impact of metformin use on survival in kidney cancer patients with diabetes: a meta-analysis. Int. Urol. Nephrol. 49, 975–981 (2017).
Takahiro, T., Shinichi, K. & Toshimitsu, S. Expression of fatty acid synthase as a prognostic indicator in soft tissue sarcomas. Clin. Cancer Res. 9, 2204–2212 (2003).
Notarnicola, M. et al. Serum levels of fatty acid synthase in colorectal cancer patients are associated with tumor stage. J. Gastrointest. Cancer 43, 508–511 (2012).
Menendez, J. A. & Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 7, 763–777 (2007).
Maier, T., Jenni, S. & Ban, N. Architecture of mammalian fatty acid synthase at 4.5 A resolution. Science 311, 1258–1262 (2006).
Asturias, F. J. et al. Structure and molecular organization of mammalian fatty acid synthase. Nat. Struct. Mol. Biol. 12, 225–232 (2005).
Menendez, J. A. et al. Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc. Natl Acad. Sci. USA 101, 10715–10720 (2004).
Horiguchi, A. et al. Fatty acid synthase over expression is an indicator of tumor aggressiveness and poor prognosis in renal cell carcinoma. J. Urol. 180, 1137–1140 (2008).
Hakimi, A. A. et al. An epidemiologic and genomic investigation into the obesity paradox in renal cell carcinoma. J. Natl Cancer Inst. 105, 1862–1870 (2013).
Albiges, L. et al. Body mass index and metastatic renal cell carcinoma: clinical and biological correlations. J. Clin. Oncol. 34, 3655–3663 (2016).
Chang, L. et al. Inhibition of FASN suppresses the malignant biological behavior of non-small cell lung cancer cells via deregulating glucose metabolism and AKT/ERK pathway. Lipids Health Dis. 18, 118 (2019).
Schroeder, B. et al. Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells. Cell Death Dis. 12, 977 (2021).
Swinnen, J. V. et al. Fatty acid synthase drives the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains. Biochem. Biophys. Res. Commun. 302, 898–903 (2003).
Kuchiba, A. et al. Body mass index and risk of colorectal cancer according to fatty acid synthase expression in the nurses’ health study. J. Natl Cancer Inst. 104, 415–420 (2012).
Horiguchi, A. et al. Pharmacological inhibitor of fatty acid synthase suppresses growth and invasiveness of renal cancer cells. J. Urol. 180, 729–736 (2008).
Pizer, E. S. et al. Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenografts. Cancer Res. 60, 213–218 (2000).
Sadowski, M. C. et al. The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer. Oncotarget 5, 9362–9381 (2014).
van der Mijn, J. C., Panka, D. J., Geissler, A. K., Verheul, H. M. & Mier, J. W. Novel drugs that target the metabolic reprogramming in renal cell cancer. Cancer Metab. 4, 14 (2016).
Shimokawa, T., Kumar, M. V. & Lane, M. D. Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides. Proc. Natl Acad. Sci. USA 99, 66–71 (2002).
Vargas, T. et al. ColoLipidGene: signature of lipid metabolism-related genes to predict prognosis in stage-II colon cancer patients. Oncotarget 6, 7348–7363 (2015).
Takahashi, H. et al. Macrophage migration inhibitory factor and stearoyl-CoA desaturase 1: potential prognostic markers for soft tissue sarcomas based on bioinformatics analyses. PLoS One 8, e78250 (2013).
Holder, A. M. et al. High stearoyl-CoA desaturase 1 expression is associated with shorter survival in breast cancer patients. Breast Cancer Res. Treat. 137, 319–327 (2013).
Huang, J. et al. SCD1 is associated with tumor promotion, late stage and poor survival in lung adenocarcinoma. Oncotarget 7, 39970–39979 (2016).
Jeffords, E. et al. Y-box binding protein 1 acts as a negative regulator of stearoyl CoA desaturase 1 in clear cell renal cell carcinoma. Oncol. Lett. 20, 165 (2020).
Wang, J. et al. High expression of stearoyl-CoA desaturase 1 predicts poor prognosis in patients with clear-cell renal cell carcinoma. PLoS One 11, e0166231 (2016).
Castro, B. B. A., Foresto-Neto, O., Saraiva-Camara, N. O. & Sanders-Pinheiro, H. Renal lipotoxicity: insights from experimental models. Clin. Exp. Pharmacol. Physiol. 48, 1579–1588 (2021).
Zhang, Y. et al. Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2103240118 (2021).
Iwai, T. et al. Stearoyl-CoA desaturase-1 protects cells against lipotoxicity-mediated apoptosis in proximal tubular cells. Int. J. Mol. Sci. https://doi.org/10.3390/ijms17111868 (2016).
Li, J. et al. Lipid desaturation is a metabolic marker and therapeutic target of ovarian cancer stem cells. Cell Stem Cell 20, 303–314 e305 (2017).
Malta, T. M. et al. Machine learning identifies stemness features associated with oncogenic dedifferentiation. Cell 173, 338–354.e315 (2018).
Tracz-Gaszewska, Z. & Dobrzyn, P. Stearoyl-CoA desaturase 1 as a therapeutic target for the treatment of cancer. Cancers https://doi.org/10.3390/cancers11070948 (2019).
Yang, P. et al. Formation and antiproliferative effect of prostaglandin E3 from eicosapentaenoic acid in human lung cancer cells. J. Lipid Res. 45, 1030–1039 (2004).
Sapieha, P. et al. 5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of ω-3 polyunsaturated fatty acids. Sci. Transl. Med. 3, 69ra12 (2011).
Iwamoto, H. et al. Cancer lipid metabolism confers antiangiogenic drug resistance. Cell Metab. 28, 104–117.e105 (2018).
Zhang, Y., Wang, H., Zhang, J., Lv, J. & Huang, Y. Positive feedback loop and synergistic effects between hypoxia-inducible factor-2α and stearoyl-CoA desaturase-1 promote tumorigenesis in clear cell renal cell carcinoma. Cancer Sci. 104, 416–422 (2013).
von Roemeling, C. A. et al. Accelerated bottom-up drug design platform enables the discovery of novel stearoyl-CoA desaturase 1 inhibitors for cancer therapy. Oncotarget 9, 3–20 (2017).
Imamura, K. et al. Discovery of novel and potent stearoyl coenzyme A desaturase 1 (SCD1) inhibitors as anticancer agents. Bioorg. Med. Chem. 25, 3768–3779 (2017).
Oballa, R. M. et al. Development of a liver-targeted stearoyl-CoA desaturase (SCD) inhibitor (MK-8245) to establish a therapeutic window for the treatment of diabetes and dyslipidemia. J. Med. Chem. 54, 5082–5096 (2011).
Bhattacharya, D. et al. Aramchol downregulates stearoyl CoA-desaturase 1 in hepatic stellate cells to attenuate cellular fibrogenesis. JHEP Rep. 3, 100237–100237 (2021).
Wang, J. & Li, Y. CD36 tango in cancer: signaling pathways and functions. Theranostics 9, 4893–4908 (2019).
Abumrad, N. A., el-Maghrabi, M. R., Amri, E. Z., Lopez, E. & Grimaldi, P. A. Cloning of a rat adipocyte membrane protein implicated in binding or transport of long-chain fatty acids that is induced during preadipocyte differentiation. Homology with human CD36. J. Biol. Chem. 268, 17665–17668 (1993).
Pepino, M. Y., Kuda, O., Samovski, D. & Abumrad, N. A. Structure-function of CD36 and importance of fatty acid signal transduction in fat metabolism. Annu. Rev. Nutr. 34, 281–303 (2014).
Coburn, C. T. et al. Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J. Biol. Chem. 275, 32523–32529 (2000).
Zaoui, M. et al. Breast-associated adipocytes secretome induce fatty acid uptake and invasiveness in breast cancer cells via CD36 independently of body mass index, menopausal status and mammary density. Cancers https://doi.org/10.3390/cancers11122012 (2019).
Watt, M. J. et al. Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aau5758 (2019).
Jiang, M. et al. Fatty acid-induced CD36 expression via O-GlcNAcylation drives gastric cancer metastasis. Theranostics 9, 5359–5373 (2019).
Hale, J. S. et al. Cancer stem cell-specific scavenger receptor CD36 drives glioblastoma progression. Stem Cell 32, 1746–1758 (2014).
Kim, Y. S. et al. High membranous expression of fatty acid transport protein 4 is associated with tumorigenesis and tumor progression in clear cell renal cell carcinoma. Dis. Markers 2019, 5702026 (2019).
Xu, W. H. et al. Elevated CD36 expression correlates with increased visceral adipose tissue and predicts poor prognosis in ccRCC patients. J. Cancer 10, 4522–4531 (2019).
Mwaikambo, B. R., Yang, C., Chemtob, S. & Hardy, P. Hypoxia up-regulates CD36 expression and function via hypoxia-inducible factor-1- and phosphatidylinositol 3-kinase-dependent mechanisms. J. Biol. Chem. 284, 26695–26707 (2009).
Yang, P. et al. Dietary oleic acid-induced CD36 promotes cervical cancer cell growth and metastasis via up-regulation Src/ERK pathway. Cancer Lett. 438, 76–85 (2018).
Pan, J. et al. CD36 mediates palmitate acid-induced metastasis of gastric cancer via AKT/GSK-3beta/beta-catenin pathway. J. Exp. Clin. Cancer Res. 38, 52 (2019).
Li, J. et al. TCPA: a resource for cancer functional proteomics data. Nat. Methods 10, 1046–1047 (2013).
Bocharov, A. V. et al. Synthetic amphipathic helical peptides targeting CD36 attenuate lipopolysaccharide-induced inflammation and acute lung injury. J. Immunol. 197, 611–619 (2016).
Wang, S. et al. Development of a prosaposin-derived therapeutic cyclic peptide that targets ovarian cancer via the tumor microenvironment. Sci. Transl. Med. 8, 329ra334 (2016).
Coronella, J. et al. Selective activity against proliferating tumor endothelial cells by CVX-22, a thrombospondin-1 mimetic CovX-Body. Anticancer. Res. 29, 2243–2252 (2009).
Pascual, G. et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541, 41–45 (2017).
Pascual, G. et al. Dietary palmitic acid promotes a prometastatic memory via Schwann cells. Nature 599, 485–490 (2021).
Lee, K., Kerner, J. & Hoppel, C. L. Mitochondrial carnitine palmitoyltransferase 1a (CPT1a) is part of an outer membrane fatty acid transfer complex. J. Biol. Chem. 286, 25655–25662 (2011).
McGarry, J. D., Mannaerts, G. P. & Foster, D. W. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J. Clin. Investig. 60, 265–270 (1977).
Rasmussen, B. B. et al. Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle. J. Clin. Invest. 110, 1687–1693 (2002).
Xu, Y. et al. Identification of CPT1A as a prognostic biomarker and potential therapeutic target for kidney renal clear cell carcinoma and establishment of a risk signature of CPT1A-related genes. Int. J. Genomics 2020, 9493256 (2020).
Lopaschuk, G. D., Wall, S. R., Olley, P. M. & Davies, N. J. Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine. Circ. Res. 63, 1036–1043 (1988).
Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on cell death 2018. Cell death Differ. 25, 486–541 (2018).
Hornsveld, M. & Dansen, T. B. The hallmarks of cancer from a redox perspective. Antioxid. Redox Signal. 25, 300–325 (2016).
Gius, D. & Spitz, D. R. Redox signaling in cancer biology. Antioxid. Redox Signal. 8, 1249–1252 (2006).
Zou, Y. et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat. Commun. 10, 1617 (2019).
Miess, H. et al. The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma. Oncogene 37, 5435–5450 (2018).
Itabe, H., Yamaguchi, T., Nimura, S. & Sasabe, N. Perilipins: a diversity of intracellular lipid droplet proteins. Lipids Health Dis. 16, 83 (2017).
Brasaemle, D. L. et al. Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis. J. Biol. Chem. 275, 38486–38493 (2000).
Blanchette-Mackie, E. J. et al. Perilipin is located on the surface layer of intracellular lipid droplets in adipocytes. J. Lipid Res. 36, 1211–1226 (1995).
Wolins, N. E. et al. Adipocyte protein S3-12 coats nascent lipid droplets. J. Biol. Chem. 278, 37713–37721 (2003).
Brasaemle, D. L. et al. Adipose differentiation-related protein is an ubiquitously expressed lipid storage droplet-associated protein. J. Lipid Res. 38, 2249–2263 (1997).
Lu, X. et al. The murine perilipin gene: the lipid droplet-associated perilipins derive from tissue-specific, mRNA splice variants and define a gene family of ancient origin. Mamm. Genome 12, 741–749 (2001).
Zheng, P. et al. Plin5 alleviates myocardial ischaemia/reperfusion injury by reducing oxidative stress through inhibiting the lipolysis of lipid droplets. Sci. Rep. 7, 42574 (2017).
Cao, Q. et al. Overexpression of PLIN2 is a prognostic marker and attenuates tumor progression in clear cell renal cell carcinoma. Int. J. Oncol. 53, 137–147 (2018).
Wang, K. et al. PLIN3 is up-regulated and correlates with poor prognosis in clear cell renal cell carcinoma. Urol. Oncol. 36, 343.e349–343.e319 (2018).
Xu, G. et al. Post-translational regulation of adipose differentiation-related protein by the ubiquitin/proteasome pathway. J. Biol. Chem. 280, 42841–42847 (2005).
Bayat Mokhtari, R. et al. The role of Sulforaphane in cancer chemoprevention and health benefits: a mini-review. J. Cell Commun. Signal. 12, 91–101 (2018).
Tian, S. et al. Targeting PLIN2/PLIN5-PPARγ: sulforaphane disturbs the maturation of lipid droplets. Mol. Nutr. Food Res. 63, e1900183 (2019).
Xiao, Y., Bi, M., Guo, H. & Li, M. Multi-omics approaches for biomarker discovery in early ovarian cancer diagnosis. EBioMedicine 79, 104001 (2022).
Graham, J. et al. Cytoreductive nephrectomy in metastatic papillary renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). J. Clin. Oncol. 36, 581–581 (2018).
Ouchi, N., Parker, J. L., Lugus, J. J. & Walsh, K. Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol. 11, 85–97 (2011).
Arita, Y. et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem. Biophys. Res. Commun. 257, 79–83 (1999).
Hotta, K. et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler. Thromb. Vasc. Biol. 20, 1595–1599 (2000).
Matsuzawa, Y., Funahashi, T., Kihara, S. & Shimomura, I. Adiponectin and metabolic syndrome. Arterioscler. Thromb. Vasc. Biol. 24, 29–33 (2004).
Miyoshi, Y. et al. Association of serum adiponectin levels with breast cancer risk. Clin. Cancer Res. 9, 5699–5704 (2003).
Wei, E. K., Giovannucci, E., Fuchs, C. S., Willett, W. C. & Mantzoros, C. S. Low plasma adiponectin levels and risk of colorectal cancer in men: a prospective study. J. Natl Cancer Inst. 97, 1688–1694 (2005).
Goktas, S. et al. Prostate cancer and adiponectin. Urology 65, 1168–1172 (2005).
Bråkenhielm, E. et al. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc. Natl Acad. Sci. USA 101, 2476–2481 (2004).
Spyridopoulos, T. N. et al. Low adiponectin levels are associated with renal cell carcinoma: a case-control study. Int. J. Cancer 120, 1573–1578 (2007).
Liao, L. M. et al. Prediagnostic circulating adipokine concentrations and risk of renal cell carcinoma in male smokers. Carcinogenesis 34, 109–112 (2013).
Choi, S. H., Chun, S. Y., Kim, T. H. & Kwon, T. G. Identifying the emerging role of adipokine as a diagnostic and prognostic biomarker of renal cell carcinoma. Urol. Oncol. 34, 259.e215–259 (2016).
Pinthus, J. H. et al. Lower plasma adiponectin levels are associated with larger tumor size and metastasis in clear-cell carcinoma of the kidney. Eur. Urol. 54, 866–873 (2008).
Yap, N. Y., Yap, F. N., Perumal, K. & Rajandram, R. Circulating adiponectin as a biomarker in renal cell carcinoma: a systematic review and meta-analysis. Biomarkers 24, 607–614 (2019).
de Martino, M. et al. Serum adiponectin predicts cancer-specific survival of patients with renal cell carcinoma. Eur. Urol. Focus. 2, 197–203 (2016).
Ito, R. et al. The impact of obesity and adiponectin signaling in patients with renal cell carcinoma: a potential mechanism for the “obesity paradox”. PLoS One 12, e0171615 (2017).
Sun, G. et al. The adiponectin-AdipoR1 axis mediates tumor progression and tyrosine kinase inhibitor resistance in metastatic renal cell carcinoma. Neoplasia 21, 921–931 (2019).
Rajandram, R., Perumal, K. & Yap, N. Y. Prognostic biomarkers in renal cell carcinoma: is there a relationship with obesity. Transl. Androl. Urol. 8, S138–S146 (2019).
Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).
Farooqi, I. S. et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J. Clin. Invest. 110, 1093–1103 (2002).
Kumar, R. et al. Association of leptin with obesity and insulin resistance. Cureus 12, e12178 (2020).
Housa, D., Housova, J., Vernerova, Z. & Haluzik, M. Adipocytokines and cancer. Physiol. Res. 55, 233–244 (2006).
Sánchez-Jiménez, F., Pérez-Pérez, A., de la Cruz-Merino, L. & Sánchez-Margalet, V. Obesity and breast cancer: role of leptin. Front. Oncol. https://doi.org/10.3389/fonc.2019.00596 (2019).
Perumal, K. et al. Role of leptin as a biomarker for early detection of renal cell carcinoma? No evidence from a systematic review and meta-analysis. Med. Hypotheses 129, 109239 (2019).
Spyridopoulos, T. N. et al. Inverse association of leptin levels with renal cell carcinoma: results from a case-control study. Hormones 8, 39–46 (2009).
Zhu, H., Li, W., Mao, S. & Wang, L. Association between leptin level and renal cell carcinoma susceptibility and progression: a meta-analysis. J. Cancer Res. Ther. 14, 873–880 (2018).
Goralski, K. B. et al. Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism. J. Biol. Chem. 282, 28175–28188 (2007).
Wittamer, V. et al. Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J. Exp. Med. 198, 977–985 (2003).
Lehrke, M. et al. Chemerin is associated with markers of inflammation and components of the metabolic syndrome but does not predict coronary atherosclerosis. Eur. J. Endocrinol. 161, 339–344 (2009).
Yoo, W. et al. HIF-1α expression as a protective strategy of HepG2 cells against fatty acid-induced toxicity. J. Cell Biochem. 115, 1147–1158 (2014).
Stockwell, B. R. et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171, 273–285 (2017).
Lin, E. et al. Roles of the dynamic tumor immune microenvironment in the individualized treatment of advanced clear cell renal cell carcinoma. Front. Immunol. 12, 653358 (2021).
Manzi, M. et al. Coupled mass-spectrometry-based lipidomics machine learning approach for early detection of clear cell renal cell carcinoma. J. Proteome Res. 20, 841–857 (2021).
Mock, A. et al. Serum very long-chain fatty acid-containing lipids predict response to immune checkpoint inhibitors in urological cancers. Cancer Immunol. Immunother. 68, 2005–2014 (2019).
Parisi, L. R., Li, N. & Atilla-Gokcumen, G. E. Very long chain fatty acids are functionally involved in necroptosis. Cell Chem. Biol. 24, 1445–1454.e1448 (2017).
Tamura, K., Horikawa, M., Sato, S., Miyake, H. & Setou, M. Discovery of lipid biomarkers correlated with disease progression in clear cell renal cell carcinoma using desorption electrospray ionization imaging mass spectrometry. Oncotarget 10, 1688–1703 (2019).
Lucarelli, G. et al. Integration of lipidomics and transcriptomics reveals reprogramming of the lipid metabolism and composition in clear cell renal cell carcinoma. Metabolites https://doi.org/10.3390/metabo10120509 (2020).
Renehan, A. G., Tyson, M., Egger, M., Heller, R. F. & Zwahlen, M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371, 569–578 (2008).
Peck, B. & Schulze, A. Lipid metabolism at the nexus of diet and tumor microenvironment. Trends Cancer 5, 693–703 (2019).
Lien, E. C. & Vander Heiden, M. G. A framework for examining how diet impacts tumour metabolism. Nat. Rev. Cancer 19, 651–661 (2019).
Petrelli, F. et al. Association of obesity with survival outcomes in patients with cancer: a systematic review and meta-analysis. JAMA Netw. Open 4, e213520 (2021).
Pischon, T. et al. Body size and risk of renal cell carcinoma in the European Prospective Investigation into Cancer and nutrition (EPIC). Int. J. Cancer 118, 728–738 (2006).
Chow, W. H., Dong, L. M. & Devesa, S. S. Epidemiology and risk factors for kidney cancer. Nat. Rev. Urol. 7, 245–257 (2010).
Chow, W. H., Gridley, G., Fraumeni, J. F. Jr & Jarvholm, B. Obesity, hypertension, and the risk of kidney cancer in men. N. Engl. J. Med. 343, 1305–1311 (2000).
Keaney, J. F. Jr et al. Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study. Arterioscler. Thromb. Vasc. Biol. 23, 434–439 (2003).
Wang, Q. et al. Circulating obesity-driven biomarkers are associated with risk of clear cell renal cell carcinoma: a two-stage, case-control study. Carcinogenesis 40, 1191–1197 (2019).
Bertrand, L. A. et al. Obesity as defined by waist circumference but not body mass index is associated with higher renal mass complexity. Urol. Oncol. 35, 661.e661–661.e666 (2017).
Gan, C. L. & Heng, D. Y. C. New insights into the obesity paradox in renal cell carcinoma. Nat. Rev. Nephrol. 16, 253–254 (2020).
Seon, D. Y., Kwak, C., Kim, H. H., Ku, J. H. & Kim, H. S. Prognostic implication of body mass index on survival outcomes in surgically treated nonmetastatic renal cell carcinoma: a single-institutional retrospective analysis of a large cohort. Ann. Surg. Oncol. 27, 2459–2467 (2020).
Choi, Y. et al. Body mass index and survival in patients with renal cell carcinoma: a clinical-based cohort and meta-analysis. Int. J. Cancer 132, 625–634 (2013).
Lalani, A.-K. A. et al. Assessment of immune checkpoint inhibitors and genomic alterations by body mass index in advanced renal cell carcinoma. JAMA Oncol. 7, 773–775 (2021).
Sanchez, A. et al. Transcriptomic signatures related to the obesity paradox in patients with clear cell renal cell carcinoma: a cohort study. Lancet Oncol. 21, 283–293 (2020).
Zhang, C. et al. Association of dyslipidemia with renal cell carcinoma: a 1∶2 matched case-control study. PLoS One 8, e59796 (2013).
Wang, H. & Peng, D. Q. New insights into the mechanism of low high-density lipoprotein cholesterol in obesity. Lipids Health Dis. 10, 176 (2011).
Hao, B. et al. Preoperative serum high-density lipoprotein cholesterol as a predictor of poor survival in patients with clear cell renal cell cancer. Int. J. Biol. Markers 34, 168–175 (2019).
van der Mijn, J. C. et al. Combined metabolomics and genome-wide transcriptomics analyses show multiple HIF1α-induced changes in lipid metabolism in early stage clear cell renal cell carcinoma. Transl. Oncol. 13, 177–185 (2020).
Motzer, R. J. et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 24, 16–24 (2006).
Choueiri, T. K. et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1814–1823 (2015).
Jonasch, E. et al. Belzutifan for renal cell carcinoma in von Hippel–Lindau disease. N. Engl. J. Med. 385, 2036–2046 (2021).
Chen, W. et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 539, 112–117 (2016).
Reinfeld, B. I. et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature 593, 282–288 (2021).
Gordan, J. D., Bertout, J. A., Hu, C.-J., Diehl, J. A. & Simon, M. C. HIF-2α promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11, 335–347 (2007).
Raval, R. R. et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol. Cell Biol. 25, 5675–5686 (2005).
Gordan, J. D. et al. HIF-α effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 14, 435–446 (2008).
This work was supported in part by a grant from the National Institutes of Health R01CA254409 to S.M.W.
The authors declare no competing interests.
Peer review information
Nature Reviews Urology thanks Kimryn Rathmell, who co-reviewed with Dakim Gaines, Barrie Peck and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Tan, S.K., Hougen, H.Y., Merchan, J.R. et al. Fatty acid metabolism reprogramming in ccRCC: mechanisms and potential targets. Nat Rev Urol (2022). https://doi.org/10.1038/s41585-022-00654-6