With the advent of effective tools to study lipids, including mass spectrometry-based lipidomics, lipids are emerging as central players in cancer biology. Lipids function as essential building ...blocks for membranes, serve as fuel to drive energy-demanding processes and play a key role as signaling molecules and as regulators of numerous cellular functions. Not unexpectedly, cancer cells, as well as other cell types in the tumor microenvironment, exploit various ways to acquire lipids and extensively rewire their metabolism as part of a plastic and context-dependent metabolic reprogramming that is driven by both oncogenic and environmental cues. The resulting changes in the fate and composition of lipids help cancer cells to thrive in a changing microenvironment by supporting key oncogenic functions and cancer hallmarks, including cellular energetics, promoting feedforward oncogenic signaling, resisting oxidative and other stresses, regulating intercellular communication and immune responses. Supported by the close connection between altered lipid metabolism and the pathogenic process, specific lipid profiles are emerging as unique disease biomarkers, with diagnostic, prognostic and predictive potential. Multiple preclinical studies illustrate the translational promise of exploiting lipid metabolism in cancer, and critically, have shown context dependent actionable vulnerabilities that can be rationally targeted, particularly in combinatorial approaches. Moreover, lipids themselves can be used as membrane disrupting agents or as key components of nanocarriers of various therapeutics. With a number of preclinical compounds and strategies that are approaching clinical trials, we are at the doorstep of exploiting a hitherto underappreciated hallmark of cancer and promising target in the oncologist's strategy to combat cancer.
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One of the most important metabolic hallmarks of cancer cells is enhanced lipogenesis. Depending on the tumor type, tumor cells synthesize up to 95% of saturated and mono-unsaturated fatty acids (FA) ...de novo in spite of sufficient dietary lipid supply. This lipogenic conversion starts early when cells become cancerous and further expands as the tumor cells become more malignant. It is suggested that activation of FA synthesis is required for carcinogenesis and for tumor cell survival. These observations suggest that the enzymes involved in FA synthesis would be rational therapeutic targets for cancer treatment. However, several recent reports have shown that the anti-tumor effects, following inhibition of endogenous FA synthesis in cancer cell lines may be obviated by adding exogenous FAs. Additionally, high intake of dietary fat is reported to be a potential risk factor for development and poor prognosis for certain cancers. Recently it was reported that breast and liposarcoma tumors are equipped for both de novo fatty acid synthesis pathway as well as LPL-mediated extracellular lipolysis. These observations indicate that lipolytically acquired FAs may provide an additional source of FAs for cancer. This review focuses on our current understanding of lipogenic and lipolytic pathways in cancer cell progression.
Although it is established that fatty acid (FA) synthesis supports anabolic growth in cancer, the role of exogenous FA uptake remains elusive. Here we show that, during acquisition of resistance to ...HER2 inhibition, metabolic rewiring of breast cancer cells favors reliance on exogenous FA uptake over de novo FA synthesis. Through cDNA microarray analysis, we identify the FA transporter CD36 as a critical gene upregulated in cells with acquired resistance to the HER2 inhibitor lapatinib. Accordingly, resistant cells exhibit increased exogenous FA uptake and metabolic plasticity. Genetic or pharmacological inhibition of CD36 suppresses the growth of lapatinib-resistant but not lapatinib-sensitive cells in vitro and in vivo. Deletion of Cd36 in mammary tissues of MMTV-neu mice significantly attenuates tumorigenesis. In breast cancer patients, CD36 expression increases following anti-HER2 therapy, which correlates with a poor prognosis. Our results define CD36-mediated metabolic rewiring as an essential survival mechanism in HER2-positive breast cancer.
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•Lapatinib-resistant breast cancer cells upregulate CD36 expression for survival•Targeting CD36 re-sensitizes lapatinib-resistant cells to HER2-inhibition•Deletion of Cd36 significantly attenuates MMTV-neu-driven mammary tumor growth•CD36 is induced by HER2-targeted therapy and predicts poor clinical prognosis
The functional significance of lipid metabolism in cancer cells is not fully understood. Feng et al. show that the fatty acid transporter CD36 is essential for survival of breast cancer cells during anti-HER2 therapy, highlighting the role of lipid metabolism in acquired resistance to targeted therapy.
Many types of cancer cells require a supply of fatty acids (FA) for growth and survival, and interrupting de novo FA synthesis in model systems causes potent anticancer effects. We hypothesized that, ...in addition to synthesis, cancer cells may obtain preformed, diet-derived FA by uptake from the bloodstream. This would require hydrolytic release of FA from triglyceride in circulating lipoprotein particles by the secreted enzyme lipoprotein lipase (LPL), and the expression of CD36, the channel for cellular FA uptake. We find that selected breast cancer and sarcoma cells express and secrete active LPL, and all express CD36. We further show that LPL, in the presence of triglyceride-rich lipoproteins, accelerates the growth of these cells. Providing LPL to prostate cancer cells, which express low levels of the enzyme, did not augment growth, but did prevent the cytotoxic effect of FA synthesis inhibition. Moreover, LPL knockdown inhibited HeLa cell growth. In contrast to the cell lines, immunohistochemical analysis confirmed the presence of LPL and CD36 in the majority of breast, liposarcoma, and prostate tumor tissues examined (n = 181). These findings suggest that, in addition to de novo lipogenesis, cancer cells can use LPL and CD36 to acquire FA from the circulation by lipolysis, and this can fuel their growth. Interfering with dietary fat intake, lipolysis, and/or FA uptake will be necessary to target the requirement of cancer cells for FA.
Obesity is an increasingly urgent global problem, yet, little is known about its causes and less is known how obesity can be effectively treated. We showed previously that the aryl hydrocarbon ...receptor (AHR) plays a role in the regulation of body mass in mice fed Western diet. The AHR is a ligand-activated nuclear receptor that regulates genes involved in a number of biological pathways, including xenobiotic metabolism and T cell polarization. This study was an investigation into whether inhibition of the AHR prevents Western diet-based obesity. Male C57Bl/6J mice were fed control and Western diets with and without the AHR antagonist α-naphthoflavone or CH-223191, and a mouse hepatocyte cell line was used to delineate relevant cellular pathways. Studies are presented showing that the AHR antagonists α-naphthoflavone and CH-223191 significantly reduce obesity and adiposity and ameliorates liver steatosis in male C57Bl/6J mice fed a Western diet. Mice deficient in the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) were also resistant to obesity. Using an AHR-directed, luciferase-expressing mouse hepatocyte cell line, we show that the transforming growth factor β1 (TGFβ1) signaling pathway via PI3K and NF-κB and the toll-like receptor 2/4 (TLR2/4) signaling pathway stimulated by oxidized low-density lipoproteins via NF-κB, each induce luciferase expression; however, TLR2/4 signaling was significantly reduced by inhibition of IDO1. At physiological levels, kynurenine but not kynurenic acid (both tryptophan metabolites and known AHR agonists) activated AHR-directed luciferase expression. We propose a hepatocyte-based model, in which kynurenine production is increased by enhanced IDO1 activity stimulated by TGFβ1 and TLR2/4 signaling, via PI3K and NF-κB, to perpetuate a cycle of AHR activation to cause obesity; and inhibition of the AHR, in turn, blocks the cycle's output to prevent obesity. The AHR with its broad ligand binding specificity is a promising candidate for a potentially simple therapeutic approach for the prevention and treatment of obesity and associated complications.
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•The AHR acts as a hub in Western diet-based obesity.•Inhibition of AHR signaling by antagonists prevents obesity and liver steatosis.•ox-LDL stimulates AHR activity via a TLR2/4, NF-kB, IDO1, kynurenine axis.•TGFβ stimulates AHR activity in Hepa-1c1c7 cells via PI3K and NF-kB.•The AHR offers a simple and promising approach for treating obesity.
We previously described the expression of CD36 and LPL by breast cancer (BC) cells and tissues and the growth-promoting effect of VLDL observed only in the presence of LPL. We now report a model in ...which LPL is bound to a heparan sulfate proteoglycan motif on the BC cell surface and acts in concert with the VLDL receptor to internalize VLDLs via receptor-mediated endocytosis. We also demonstrate that gene-expression programs for lipid synthesis versus uptake respond robustly to triglyceride-rich lipoprotein availability. The literature emphasizes de novo FA synthesis and exogenous free FA uptake using CD36 as paramount mechanisms for lipid acquisition by cancer cells. We find that the uptake of intact lipoproteins is also an important mechanism for lipid acquisition and that the relative reliance on lipid synthesis versus uptake varies among BC cell lines and in response to VLDL availability. This metabolic plasticity has important implications for the development of therapies aimed at the lipid dependence of many types of cancer, in that the inhibition of FA synthesis may elicit compensatory upregulation of lipid uptake. Moreover, the mechanism that we have elucidated provides a direct connection between dietary fat and tumor biology..
Despite adjuvant endocrine therapy for patients with estrogen receptor alpha (ER)-positive breast cancer, dormant residual disease can persist for years and eventually cause tumor recurrence. We ...sought to deduce mechanisms underlying the persistence of dormant cancer cells to identify therapeutic strategies.
Mimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed preclinical models of dormancy in ER
breast cancer induced by estrogen withdrawal in mice. We analyzed tumor xenografts and cultured cancer cells for molecular and cellular responses to estrogen withdrawal and drug treatments. Publicly available clinical breast tumor gene expression datasets were analyzed for responses to neoadjuvant endocrine therapy.
Dormant breast cancer cells exhibited upregulated 5' adenosine monophosphate-activated protein kinase (AMPK) levels and activity, and upregulated fatty acid oxidation. While the antidiabetes AMPK-activating drug metformin slowed the estrogen-driven growth of cells and tumors, metformin promoted the persistence of estrogen-deprived cells and tumors through increased mitochondrial respiration driven by fatty acid oxidation. Pharmacologic or genetic inhibition of AMPK or fatty acid oxidation promoted clearance of dormant residual disease, while dietary fat increased tumor cell survival.
AMPK has context-dependent effects in cancer, cautioning against the widespread use of an AMPK activator across disease settings. The development of therapeutics targeting fat metabolism is warranted in ER
breast cancer.
BACKGROUND:Our previous case series suggested that a 1-week, low-calorie and low-fat diet was associated with decreased intraoperative blood loss in patients undergoing liver surgery.
OBJECTIVE:The ...current study evaluates the effect of this diet in a randomized controlled trial.
METHODS:We randomly assigned 60 patients with a body mass index ≥25 kg/m to no special diet or an 800-kcal, 20 g fat, and 70 g protein diet for 1 week before liver resection. Surgeons were blinded to diet assignment. Hepatic glycogen stores were evaluated using periodic acid Schiff (PAS) stains.
RESULTS:Ninety four percent of the patients complied with the diet. The diet group consumed fewer daily total calories (807 vs 1968 kcal, P < 0.001) and fat (21 vs 86 g, P < 0.001) than the no diet group. Intraoperative blood loss was less in the diet groupmean blood loss 452 vs 863 mL (P = 0.021). There was a trend towards decreased transfusion in the diet group (138 vs 322 mL, P = 0.06). The surgeon judged the liver to be easier to manipulate in the diet group1.86 versus 2.90, P = 0.004. Complication rate (20% vs 17%), length of stay (median 5 vs 4 days) and mortality did not differ between groups. There was no difference in hepatic steatosis between groups. There was less glycogen in hepatocytes in the diet group (PAS stain score 1.61 vs 2.46, P < 0.0001).
CONCLUSIONS:A short-course, low-fat, and low-calorie diet significantly decreases bleeding and makes the liver easier to manipulate in hepatic surgery.
It is well recognized that many cancers are addicted to a constant supply of fatty acids (FAs) and exhibit brisk de novo FA synthesis. Upregulation of a key lipogenic enzyme, fatty acid synthase ...(FASN), is a near-universal feature of human cancers and their precursor lesions, and has been associated with chemoresistance, tumor metastasis, and diminished patient survival. FASN inhibition has been shown to be effective in killing cancer cells, but progress in the field has been hindered by off-target effects and poor pharmaceutical properties of candidate compounds. Our initial hit (compound
) was identified from a high-throughput screening effort by the Sanford-Burnham Center for Chemical Genomics using purified FASN thioesterase (FASN-TE) domain. Despite being a potent inhibitor of purified FASN-TE, compound
proved highly unstable in mouse plasma and only weakly cytotoxic to breast cancer (BC) cells in vitro. An iterative process of synthesis, cytotoxicity testing, and plasma stability assessment was used to identify a new lead (compound
). This lead is more cytotoxic against multiple BC cell lines than tetrahydro-4-methylene-2
-octyl-5-oxo-3
-furancarboxylic acid (the literature standard for inhibiting FASN), is stable in mouse plasma, and shows negligible cytotoxic effects against nontumorigenic mammary epithelial cells. Compound
also has drug-like physical properties based on Lipinski's rules and is, therefore, a valuable new lead for targeting fatty acid synthesis to exploit the requirement of tumor cells for fatty acids. SIGNIFICANCE STATEMENT: An iterative process of synthesis and biological testing was used to identify a novel thioesterase domain FASN inhibitor that has drug-like properties, is more cytotoxic to breast cancer cells than the widely used tetrahydro-4-methylene-2
-octyl-5-oxo-3
-furancarboxylic acid, and has negligible effects on the growth and proliferation of noncancerous mammary epithelial cells. Our studies have confirmed the value of using potent and selective FASN inhibitors in the treatment of BC cells and have shown that the availability of exogenous lipoproteins may impact both cancer cell FA metabolism and survival.
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