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Lipid droplets: platforms with multiple functions in cancer hallmarks

André L. S. Cruz, Ester de A. Barreto, Narayana P. B. Fazolini and 2 more

Cell Death & Disease · 2020 · Review · CC BY

Abstract

Lipid droplets (also known as lipid bodies) are lipid-rich, cytoplasmic organelles that play important roles in cell signaling, lipid metabolism, membrane trafficking, and the production of inflammatory mediators. Lipid droplet biogenesis is a regulated process, and accumulation of these organelles within leukocytes, epithelial cells, hepatocytes, and other nonadipocyte cells is a frequently observed phenotype in several physiologic or pathogenic situations and is thoroughly described during inflammatory conditions. Moreover, in recent years, several studies have described an increase in intracellular lipid accumulation in different neoplastic processes, although it is not clear whether lipid droplet accumulation is directly involved in the establishment of these different types of malignancies. This review discusses current evidence related to the biogenesis, composition and functions of lipid droplets related to the hallmarks of cancer: inflammation, cell metabolism, increased proliferation, escape from cell death, and hypoxia. Moreover, the potential of lipid droplets as markers of disease and targets for novel anti-inflammatory and antineoplastic therapies will be discussed.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

Facts

1Lipid droplets are dynamic and multifunctional organelles involved in energy metabolism, signaling, and inflammatory mediator production.Lipid droplets accumulate in a variety of cancer cells.Lipid droplets modulate the cross-talk between tumors and other cell types in tumor microenvironment.Lipid droplet accumulation and catabolism are tightly coupled to energetic metabolism, cell signaling, and are critical to cancer cell proliferation, resistance to death, and aggressiveness.

2Lipid droplets are dynamic and multifunctional organelles involved in energy metabolism, signaling, and inflammatory mediator production.

3Lipid droplets accumulate in a variety of cancer cells.

4Lipid droplets modulate the cross-talk between tumors and other cell types in tumor microenvironment.

5Lipid droplet accumulation and catabolism are tightly coupled to energetic metabolism, cell signaling, and are critical to cancer cell proliferation, resistance to death, and aggressiveness.

Open questions

6Does LD play a causal role or is a consequence of tumorigenesis?How important is LD accumulation during the distinct phases of tumor development?Can lipid droplet be a cytoplasmic hub for protumorigenic cellular signaling?Are there roles for inhibitors of lipid droplet biogenesis as target for cancer therapy?

7Does LD play a causal role or is a consequence of tumorigenesis?

8How important is LD accumulation during the distinct phases of tumor development?

9Can lipid droplet be a cytoplasmic hub for protumorigenic cellular signaling?

10Are there roles for inhibitors of lipid droplet biogenesis as target for cancer therapy?

Introduction

11Lipid droplets (LDs) are cytoplasmic lipid-enriched organelles delimited by a monolayer of phospholipid, which covers a hydrophobic core composed of neutral lipids, mainly triacylglycerol (TAG) and cholesteryl esters (CEs), with a diverse content of proteins that may vary according to the cell and stimulatory conditions. In addition, LDs are coated by structural proteins of the PAT family that include perilipin-1, perilipin-2, and perilipin-3–. LDs are organelles that originate and are intimately related to the endoplasmic reticulum (ER), formed by the transfer of lipids and proteins from the ER to newly formed LDs. Although LD biogenesis involves specific and well-regulated mechanisms, the cellular and molecular mechanisms involved are still not completely understood.

12The first reports of LDs in human tumors date from the 1960s,; nevertheless, for many years, the study of LDs in cancer was restricted to descriptions in different tumors. A major breakthrough in LD research in cancer, came from the demonstration that LDs are major sites for prostaglandin E2 (PGE2) synthesis in colon cancer cells and have roles in tumor cell proliferation. Over the last decade, there was a considerable expansion of the mechanisms that regulate the formation and functions of LDs in cancer. LDs have been identified in all the processes involved in cancer development, including initiation, promotion, and progression. Hanahan and Weinberg outlined hallmarks that characterized the capabilities acquired during tumor development. Among these are sustaining proliferation, resisting death, evading growth suppressors, promoting replicative immortality, activating invasion and metastasis, as well as promoting angiogenesis, genome instability, inflammation, energy metabolism deregulation, and evasion of immune destruction. Here, we review the current knowledge of LD functions according to categories comprising the hallmarks of cancer, and two additional topics comprise LD roles in biomarkers and cancer stem cells (Fig. 1).

Lipid droplets and metabolism in cancer

13Lipid droplet accumulation in transformed cancer cells involves complex and mediated mechanisms, including increased lipid uptake, de novo lipid synthesis and remodeling, as well as regulations in lipolysis (Fig. 2). Lipogenesis is paramount among the anabolic processes in cancer, where fatty acid (FA) synthesis is critical for generating building blocks for more complex lipids. Signaling pathways that trigger tumor lipogenesis culminate in the accumulation of newly formed LDs,–. Indeed, accumulating evidence support a relationship between tumor development and both lipolytic or lipogenic enzymes, implying that lipid mobilization from LDs may be an appropriate target for cancer therapy. The main factors in this phenomenon are sterol regulatory element-binding proteins (SREBPs), a key regulator of lipid homeostasis, and mammalian target of rapamycin (mTOR), a crucial sensor that connects cellular growth to the availability of extracellular nutrients. SREBP1 upregulation triggers tumor growth and LD accumulation together with lipogenesis enzyme overexpression,,,,,,,. Moreover, both mTOR catalytic complexes, namely, mTORC1 and mTORC2, were implicated in LD biogenesis in cancer by SREBP1-dependent, and SREBP1-independent mechanisms.

14Obesity and its associated metabolic dysregulation are established risk factors for many cancers. Obesity-drive ectopic LD accumulation in non-adipose tissues have been associated with insulin-resistance, cardiovascular disease, and cancer. Different mechanisms may contribute to obesity-induced increased LDs in epithelial cells and other in non-adipose tissues. In addition to excess of free FAs and other lipids, adipose-derived leptin through mTOR activation may contribute to the obesity-related enhanced susceptibility to colon carcinoma by altering the intracellular lipid metabolism and inflammatory environment.

15TAG is one of the major neutral lipids in LDs. TAG is formed by a glycerol joined to three FAs and shares many steps with glycerophospholipid synthesis until the generation of DAG that is esterified by acyl-CoA diacylglycerol acyltransferase (DGAT) to TAG. The role of TAG metabolism remains poorly understood in cancer. Ackerman et al. showed that TAG acts as a buffer for lipid remodeling, especially under O2 and nutrient limitation. LD TAGs were enriched with unsaturated FAs, particularly oleate; however, during O2 and serum deprivation, oleate was released from LDs into phospholipid pools, which prevents cellular stress by avoiding the use of fully saturated, potentially toxic lipids. They also showed that inhibition of both DGAT isoforms increased cancer cell death in vivo, impairing tumor growth. In addition, DGAT1 was overexpressed in prostate cancer cells, and its inhibition decreased LD density, microtubule-organizing center numbers and microtubule stability, which affects cell migration and growth.

16TAG is sequentially hydrolyzed by three different lipases: adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), and monoacylglycerol lipase (MAGL). Consecutively, they hydrolyze TAG, DAG, and MAG into a glycerol backbone and free FAs. ATGL function could be regulated by CGI-58/ABHD5, a coactivator, and G0S2 (G0/G1 switch gene2), an inhibitor. The following data indicate that the role of lipases in cancer seems to be dependent on the cell type or protein studied. Loss of ATGL is a common feature in many human tumors and induces spontaneous lung cancer in animal models. In addition, ATGL deletion can induce a more aggressive phenotype in lung cancer cells through lipid accumulation. Moreover, CGI-58/ABHD5 deletion was correlated with cancer development and progression and epithelial–mesenchymal transition,. In contrast, ATGL inhibition by G0S2 decreased proliferation in tumor cell lines, suggesting that ATGL activity is common in some cancer types. MAGL regulates the network of free FAs in tumors, such as colorectal cancer, neuroblastoma, hepatocarcinoma, and nasopharyngeal carcinoma, by enabling tumor cells to mobilize and utilize FAs from stored TAGs–. These released FAs, including lysophosphatidic acid, PGE2, and endocannabinoids, were involved in signal cascades that induce carcinogenesis, tumor progression, and metastasis,. Interestingly, lipolysis also plays an important role in cancer-associated cachexia, a multifactorial metabolic syndrome associated with loss of muscle and adipose mass. Increased ATGL and, to a less extent, HSL activities were observed in white adipose tissue from cancer-associated cachexia patients, whereas ATGL-deficient mice with tumors maintained adipose tissue and gastrocnemious muscle mass. Therefore, further studies are needed to elucidate the role of TAG lipases in cancer.

17Another LD component is cholesteryl ester (CE), the storage form of cholesterol synthesized by acyl coenzyme A: cholesterol acyltransferase (ACAT). Free cholesterol maintains membrane fluidity and can be either de novo synthesized via the mevalonate pathway or taken up from exogenous lipoproteins. Aberrant CE accumulation in LDs is an important target of tumor metabolism remodeling. Increased CE is a metabolic signature in renal cell carcinoma, glioblastoma, breast, prostate and pancreatic cancer,,–. In addition, CE accumulation was positively correlated with advanced clinical staging, metastasis, and poor survival,–. Inhibition of ACAT significantly suppressed cancer proliferation, migration, invasion, and tumor growth in vitro and in vivo,,. CE accumulation is driven by PTEN loss and PI3k/Akt/mTOR upregulation and modulates signaling pathways, such as SREBP by blocking the SREBP-negative feedback loop caused by excess free cholesterol, maintaining tumor growth,,, and also Wnt/β-catenin by regulating FA availability for Wnt3a acylation. These studies suggest that cholesterol esterification may be a major target in cancer therapy.

18LDs are directed to autophagy pathways as an alternative route for lipid storage mobilization,. Lipid droplet inclusion in autophagossomes and subsequent degradation in lysosomes (known as macrolipophagy) regulates cellular lipid content, as inhibition of lipophagy decreases TAG breakdown. Upon engulfment, LD content are broken by lysosomal acid lipases (LAL), mostly known for its deficiency in Wolman disease and CE storage disease,. Another mechanism for LD hydrolysis in lysosomes is through chaperone-mediated autophagy (CMA), a lysosomal proteolysis carried by heat shock protein 70 (HSP70) and lysosome-associated membrane protein 2A (LAMP-2A). Degradation of perilipin-2 and perilipin-3 by CMA act as a prerequisite to stimulate both ATGL lipolysis and macrolypophagy. Several CMA-targeted proteins are relevant to cancer biology, though the relationship between CMA-dependent lipolysis and cancer is currently unknown. For more in-depth information, we recommend recently published reviews where lipophagy regulatory mechanisms and functions in other physiopathological conditions are comprehensively discussed,.

19Though poorly studied, lipophagy appears to play a dual role in cancer. LDs degradation by lipophagy increases viability of hepatocarcimoma cells during starvation, and protects androgen-sensitive prostate cancer cells during androgen-deprivation in vitro. Also, pharmacological inhibition of lipolysis in colorectal cancer cell line induced both LDs accumulation and cell death, while altering the profile of cancer stem cells toward a more invasive mesenchymal phenotype. On the other hand, lipophagy can display an antitumoral role in some cancer models. Overexpression of autophagy regulatory protein ATG14 increased LD lipophagy while sensitized HeLa cells to apoptosis.

Lipid droplets in inflammation and avoiding immune destruction

20In inflammation and cancer, LDs are linked to the regulation of immune and inflammatory responses by acting as specialized hubs of signaling with major roles in eicosanoid and other lipid mediator formation. Eicosanoids are signaling molecules derived from the enzymatic oxygenation of arachidonic acid (AA), which control key cellular processes, including cell activation, metabolism, proliferation, and death. It is well established that LDs are sites of esterified AA as well as of several enzymes involved in eicosanoid synthesis including cPLA2, cyclooxygenases and prostaglandin synthases,–. By means of eicosacell, a technique to localize newly formed eicosanoids at their sites of synthesis, it was established that LDs are major intracellular locales for the activation-elicited formation of PGE2 in cancer cells. Moreover, leukocytes, endothelial and epithelial cells involved in pathological conditions, such as in cancer, hypoxia, and during infections were shown to contain increased numbers of eicosanoid-synthesizing LDs leading to amplified eicosanoid production,–.

21The amplification of eicosanoid formation through the compartmentalization of eicosanoid-synthetic machinery at LDs in tumor cells may have implications to promote tumor growth by paracrinally regulating cancer cells, as well as by orchestrating the complex interactions to establish the tumor microenvironment (Fig. 3). Indeed, LD and LD-derived PGE2 were shown to promote tumor epithelial cell proliferation,,. Also, several reports indicate that PGE2 has a protumoral role by stimulating tumor cell proliferation and suppressing host immune surveillance of tumor–.

22The tumor microenvironment (TME) is a term that refers to a heterogeneous cell population of cancer cells and host resident and recruited cells, secreted factors and extracellular matrix that constitute the tumor mass. Furthermore, the TME plays a critical role in the prognosis of tumor development and therapeutic responses. Recent studies indicate that LDs modulate the cross-talk between tumors and phenotypic modulation of immune cells, mainly myeloid cells, such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and dendritic cells (DCs)– (Fig. 3). Indeed, as mentioned above, LDs are involved in increased eicosanoid synthesis in tumor cell LDs and inflammatory cells,,, suggesting roles of LDs as an eicosanoid production site in modulating TME cells. In addition to eicosanoids synthesis, LDs are emerging as sites for regulation of different signaling pathways with potential functions in TME regulation.

23TAMs are the major tumor-infiltrating leukocytes and promote malignant progression by stimulating angiogenesis and tissue remodeling and preventing immune destruction. The role of LDs in these cells are still not fully established, since the literature demonstrates both protumorigenic and antitumorigenic functions. FA-binding protein E (E-FABP), a lipid-binding chaperone, is highly expressed in TAMs presenting anticancer activities. In this scenario, IFN-β signaling is regulated through E-FABP-mediated LD biogenesis, recruiting natural killer cells to the tumor stroma. In contrast, cancer cells stimulate TAM differentiation toward a protumorigenic phenotype by a caspase-1-dependent, nonconventional cleavage of PPARγ. Cleaved PPARγ then translocates to mitochondria and reduces FA oxidation, increasing LDs and promoting protumor TAM differentiation. Also, Wu et al. showed that unsaturated FA, oleate, polarizes bone marrow-derived myeloid cells into an immunosuppressive TAM. This phenotype is dependent on mTOR signaling, LD formation, and utilization by mitochondrial respiration. Moreover, LDs from TAMs were shown as an effective target to avoid TAM polarization and tumor growth. Further work to elucidate the functions of the LDs in TAM differentiation and the origin of its lipids are necessary.

24MDSCs are a diverse group of immune cells from the myeloid lineage with strong immunoregulatory properties, which are shown to depend on both oxidative stress and lipid metabolism–. Tumor-infiltrating MDSCs increase FA uptake and oxidation, mitochondrial mass, and oxygen consumption rate. The inhibition of FA oxidation blocks the immunosuppressive functions of MDSCs, enhancing the efficacy of cancer immune therapy. These findings encouraged other studies focused on the role of lipids in the induction of the regulatory phenotype of MDSCs,. Wu et al. demonstrated that unsaturated FAs, but not saturated FAs, are capable of inducing a modulatory phenotype in these cells paralleled by increased LD formation. The inhibition of LD formation by DGAT blockade abrogated the MDSC phenotype, while the inhibition of de novo FA synthesis had no effect, suggesting a critical role for exogenous FA and LD biogenesis. In addition, Al-Khami et al. reached similar conclusions when evaluating a tumor-bearing mouse model. They observed that the tumor-released cytokines G-CSF and GM-CSF triggered lipid influx and LD biogenesis, oxidative metabolism and T-cell suppression. They verified that exogenous lipoproteins and unsaturated FAs, but not saturated FAs, enhanced the generation of immunosuppressive MDSCs. These results showed that the LD biogenesis necessary to regulate phenotype MDSCs in cancer was triggered by exogenous lipids. Although the source of lipids in the TME was not evaluated, the specific induction by unsaturated FAs may provide clues about the mechanisms similar to that of the DC regulation described below.

25DCs are central in the anticancer response due to cross-presentation of tumor-associated antigens via MHC-I complexes to CD8+ cytotoxic T cells. Although the presence of DCs is associated with a better prognosis, studies in tumor-bearing mice showed impaired cross-presentation by DCs in the TME–. There are conflicting data on the role of LDs, which are associated with both promotion and inhibition of cross-presentation in tumor-infiltrating DCs,–. These differences may be caused by LD quality, not quantity, and related to DC antigen presentation dysfunction. Veglia et al. showed that LDs from tumor-infiltrating DCs are enriched with oxidized triacylglycerol species. In addition, oxidized LDs sequestrated HSP70, which directed pMHCI localization to lysosomes rather than to the plasma membrane. Though the authors did not confirm the TME lipid source, it would reasonable to suggest the involvement of cancer lipogenesis. Thereafter, Jiang et al. confirmed that FASN overexpression of tumor cells was responsible for elevated levels of LDs and subsequent inhibition of DCs in an ovarian cancer mouse model. FASN silencing in cancer cells decreases LDs in DCs, consequently increasing infiltrative T cells and delaying tumor growth, which suggests that tumor cell lipogenesis could be involved in anticancer immunity.

26In conclusion, these data demonstrate that LDs are associated with the immunometabolic modulation phenotype of myeloid cells, which largely culminate in cancer immune evasion. However, more research is necessary to understand the exact mechanisms of how LDs are involved in phenotype modulation. In the DC studies, the combination of a lipid-enriched microenvironment and oxidative stress was necessary to trigger modulation. High levels of circulating lipids and oxidative stress are widely described in many tumors and are associated with a poor prognosis–. The identification of the lipid source used in LD biogenesis may also be an important aspect in the signaling in which these organelles are involved, since these lipids may come from both external sources, such as tumor cells and adipose tissue, and from intracellular sources, such as de novo synthesis or autophagy. Surprisingly, cell free LDs were described in a 3D bioengineered brain tumor glioblastoma tissue platform, where it was suggested may participate in drug response, however, the role and mechanism remain unclear. In addition, it is necessary to determine how LDs are involved in the exclusion of T cells from the TME, since this may be an intriguing target in immune cancer therapy.

Lipid droplets in cell proliferation

27Accumulating evidence have shown that an increase in LD numbers occurs in cells undergoing proliferation, which is a common feature in many neoplastic processes, suggesting LD may contribute to cell proliferation. Although no definitive studies establish a causal link between the increase in LD numbers and cancer development, recent studies are starting to shed light in this process. Indeed, emerging data associates increased LD biosynthesis and cell cycle progression. It was recently described that cell cycle progression regulates the number and cellular localization of LDs in nontransformed cells, with an increase in LDs numbers and dispersed subcellular localization upon entering S phase. Moreover, detailed analysis of the distribution of lipid droplets during mitosis showed their polarization before cell division. In addition, it was observed that the yeast lipase Tgl4 (human ATGL analog) is a target for phosphorylation by the major cell cycle regulator Cdc28 (human CDK1 analog), which is necessary for Tgl4 activity and cell cycle progression. In mammals, a lipid-mediated PTEN-dependent late G1 checkpoint was recently described. In this work, lipid deprivation in culture media was able to induce G1 arrest in several cancer cells, except in clear-cell renal carcinoma cells, where it is suggested that an increase in LDs contributes to bypass this checkpoint. Collectively, these results suggest that cell cycle progression and lipid homeostasis are coordinated by a shared mechanism acting at the G1/S transition, thus suggesting that lipid droplet maintenance, biogenesis, or consumption is involved in cell cycle progression through S phase.

28Activation of specific signaling pathways in colon cancer cells is linked with LD formation and cell growth modulation. FOXO3 plays a pivotal role in inhibiting colon cancer cell proliferation, mainly through upregulation of the cell cycle inhibitor p27kip1. However, FOXO3 activity is dependent on LD density, and an increase in LD numbers induced the loss of FOXO3 and p27kip1 expression. Increased LD density promoted proliferation of colon cancer cells in a FOXO3 loss-dependent manner. In addition, the mouse model for FOXO3 deficiency resulted in a decrease in Sirtuin6, a negative regulator of lipid metabolism, revealing the existence of a regulatory network between LD biogenesis and FOXO3 activity Interestingly, in vitro cellular transformation using H-RasV12 oncoprotein was associated with LD accumulation, and an increase in perilipin-2 protein levels, although perilipin-2 overexpression alone was not enough to induce cell transformation in murine fibroblasts.

29Of note, a variety of signaling-associated proteins have been found within LDs, suggesting a key role for this organelle as a cytoplasmic hub favoring quick proliferative signaling. Proteins with well-established roles in oncogenic transformation, tumorigenesis, and metastasis, including PI3K, ERK1, ERK2, p38, PKC, and caveolin, were shown to localize to LDs in a variety of cell types,,. Nevertheless, until now, no study has unraveled the actual role of lipid droplet-resident kinases in cell proliferation. Hence, LDs could be a potential downstream target against uncontrolled triggering of the membrane receptor signaling cascade. Despite all suggestive data linking LDs and cell cycle progression, further studies are necessary to characterize whether LDs play a direct role in cell proliferation.

Lipid droplets in apoptosis and cell death

30It has been reported that apoptosis induction leads to an early onset and subsequent accumulation of LDs–. Indeed, LD formation during apoptosis may delay the accumulation of toxic FAs,. Apoptosis-induced activation of p53 and inhibition of mTOR and MYC in tumor cells leads to lipid accumulation due to inhibition of FA β-oxidation and redirection of FAs to de novo lipogenesis. In addition, the increase in LD content has been used as an in vivo marker of post treatment tumor cell death through 1H nuclear magnetic resonance spectroscopy, a noninvasive diagnostic technique to detect the earliest signs of cell death following cancer treatment,.

31Increased LDs in cancer cells may play an indirect role in maintaining cell survival during cancer therapy. An increase in LD numbers was previously observed in drug-resistant cancer cells, and thus, these organelles were postulated to sequester hydrophobic therapeutic agents, reducing drug effectiveness,. The development of drug-resistant cells derived from myeloid leukemia also revealed a positive correlation between increased LD content and resistance to an aminopeptidase inhibitor, along with activation of the ERK/Akt/mTOR survival pathway. These data prompt the idea of hampering LD biogenesis to improve cancer therapy efficiency. Interestingly, reduction of LD formation by inhibition of cPLA2α enhanced the effectiveness of the anticancer agent curcumin in glioblastoma cells. Hence, impairing LD drug sequestration could be interesting in a variety of other multidrug resistance scenarios to improve cell death upon antineoplastic drug administration.

32Increased neutral lipids may enable further survival of cancer cells through other mechanisms. A recent study described a protective role of LDs in colorectal cancer cells against chemotherapy-induced cell death. LD biogenesis mediated by lysophosphatidylcholine acyltransferase 2 (LPCAT2) in these cells impaired ER stress pathways, resulting in diminished calreticulin (CRT) membrane exposure and, consequently, a reduction in immunogenic cell death after treatment. Cell-surface CRT exposure is a key feature in anticancer immune responses, and interestingly, CRT appeared to be sequestrated in LDs in these chemoresistant colorectal cells. Other studies also revealed altered lipid metabolism in other resistant cancer cell lines, such as breast,, and ovarian cancer; thus, LD formation may be involved in drug resistance. An interesting example was recently described in hypoxic conditions, where increased expression of acylglycerol-3-phosphate acyltransferase 2 (AGPAT2) was directly involved in LD accumulation and cell survival upon etoposide treatment in different cancer cell lines.

Lipid droplets in hypoxia and angiogenesis

33Hypoxia is defined as a reduction of oxygen (O2) concentration, a condition encountered in a variety of pathological conditions. Hypoxia responses are transcriptionally regulated by the hypoxia-inducible factor (HIF) family, which includes heterodimeric transcription factors consisting of an oxygen-regulated α-subunit (HIF-1α or HIF-2α) and a constitutively expressed β-subunit (HIF-β/ARNT)–. Hanahan and Weinberg suggest that the hypoxia response system not only causes an induction of the “angiogenic switch” in cancer, but is also one of the factors that acts in the reprogramming of cancer cell metabolism,. In fact, evidence points out important changes in lipid metabolism in these instances. Increased FA synthesis is thought to be stimulated in low O2 conditions; for example, FA synthase is upregulated during hypoxia through the HIF-1α/Akt/SREBP-1 signaling pathway, whereas HIF-1α activation increases glycolysis and free FA uptake by upregulating PPARγ expression. This supports the idea that hypoxia responses can significantly alter cell lipid metabolism in several pathologies, including cancer, and that LDs would accumulate in hypoxic cells. Indeed, an inverse correlation between the oxygen concentration and LD levels was first observed in endothelial cells derived from bovine aortic or pulmonary vascular beds, emerging as a specific rather than a standardized response for any variety of cellular stresses. Accordingly, perilipin-2 expression was increased in cancer cell lines under hypoxic conditions, as well as in the liver of mice treated with CoCl2, an inducer of hypoxia-like responses. LD staining was also found in highly hypoxic cells located at the periphery of necrotic areas of intracerebral glioma. In this scenario, HIF transcription factors seem to portray specific roles in LD regulation. Interestingly, HIF-2α—but not HIF-1α—promotes PLIN2 gene overexpression in clear-cell renal cell carcinoma, and perilipin-2 accumulation in these cells was associated with increased cancer cell viability. Likewise, expression of both HIF-1α and HIF-2α was found to be important for establishing an invasive and metastatic phenotype in triple-negative breast cancer cells, but single inhibition of HIF-2α expression alone resulted in altered metabolism and reduced formation of LDs in these cells. In addition, in a mouse glioblastoma xenograft model, hypoxia induced LD accumulation in an HIF-1α-dependent manner due to increased FA uptake but not de novo lipid synthesis. FABP3, FABP7, and perilipin-2 were essential for the formation of LDs under hypoxic conditions in this work, and disruption of FABP3, FABP7, or perilipin-2 expression in this model reduced ATP production and increased ROS levels, which were accompanied by a decrease in cell growth and survival both in vitro and in vivo. This evidence highlights the importance of lipid modulation during hypoxia as an important mechanism that directly regulates cell survival and aggressiveness.

Lipid droplets in cancer aggressiveness, invasion, and metastasis

34Epithelial–mesenchymal transition (EMT) is the first of several steps toward a carcinoma metastasis event. In this process, carcinoma cells lose epithelial traits, such as apical–basal polarity and epithelial cell junctions, and display mesenchymal cell morphology and increased cell migration potential. It was recently shown that the lipid profile differs between epithelial and mesenchymal breast cancer cells, revealing that monounsaturated lipids and de novo FA synthesis are markedly characteristic of epithelial cells, whereas reduced lipogenesis, increased polyunsaturated FA levels, and the expression of genes involved in TAG synthesis and LD formation were mainly traits of mesenchymal breast cancer cells. In parallel, loss of CGI-58/ABHD5 promotes invasion and proliferation in prostate cancer through an ATGL-independent mechanism and correlated with increased aerobic glycolysis and loss of E-cadherin expression and Snail accumulation, markers of the EMT process. However, the importance of LD accumulation in cell invasion and metastasis is still debatable, particularly why and when lipid mobilization from LDs would be necessary to trigger a more aggressive phenotype in cancer cells. Wright and collaborators discuss the necessity of an LD increase in primary cancer cells prior to a metastasis event. In these observations, in vitro accumulation of prometastatic protein CDCP-1 (CUB-domain containing protein 1) decreased the lipid content in triple-negative breast cancer cells and was correlated with augmented invasion in 3D culture. Interestingly, primary tumors in vivo displayed increased LDs, along with decreased CDCP-1 activity, when compared with their corresponding metastatic nodules.

35Some studies also indicate that fat mobilization between stromal and cancer cells is required for metastasis and cancer aggressiveness. Metastasis of ovarian cancer to the omentum was shown to be mediated by local adipocytes that released cytokines and provided FAs to cancer cells, which displayed increased LD formation and β-oxidation, a mechanism dependent on FABP4. Adipocyte-induced FA translocator CD36 expression confers a more aggressive phenotype in ovarian cancer cells. In addition, CD36 inhibition was sufficient to reduce LD accumulation in cocultured cancer cells and limit tumor growth and invasion both in vitro and in vivo. Indeed, CD36+ cells were previously highlighted as initiators of metastasis in mouse oral squamous cell carcinomas, and CD36 expression correlated drastically with poor prognosis in lung squamous cell cancer, bladder cancer, or luminal A breast cancer. Moreover, ATGL accumulation and increased activity were observed predominately in aggressive breast cancer cell lines, and its expression increased in cells with direct contact with adipocytes in primary human breast cancer samples. These findings add a new layer of complexity to the implications of the TME in cancer aggressiveness.

Lipid droplets and cancer stem cells

36Cancer stem cells (CSCs) comprise a small subpopulation of malignant cells that can propagate clones indefinitely as a self-renewal feature and also maintain the tumor by generating heterogeneous cancer cells that compose the bulk of the tumor mass,. Consequently, a single CSC holds an inherent potential for cancer initiation– and is directly involved in cancer therapy resistance and efficiency. The identification and isolation of CSCs from different cancer types are still matters of discussion,–, and currently, the idea that stemness is a flexible, reversible trait of some cancer cells is being upheld.

37Current data show that CSCs have higher LD contents than differentiated tumor cells–. In a colorectal cancer model, cells with a high LD content showed CSC tumorigenic features in vitro and in vivo. In addition, there was a positive correlation between a high LD content, CD133 expression, and Wnt/β-catenin upregulation. In the ovarian cancer cell population, the activity of stearoyl-CoA desaturase 1 (SCD1), an enzyme involved in monounsaturated FA synthesis, was strongly associated with LD levels and cancer stemness. The ovarian CSC population had higher levels of LDs and unsaturated FAs. SCD1 blockade decreased LDs and impaired cancer stemness by inactivating the NF-кB pathway. In addition, some reported that CSCs accumulate LDs to use as lipid reserves for energy supply,. Singh et al. showed that blocking lipolysis by targeting vesicle-mediated COPI complex, which transports lipases to the LD surface, starves CSCs to death. In addition, a CSC glioblastoma population showed a strong dependence on oxidative metabolism, FA uptake and high LD content, which is preferentially metabolized under glucose-deprived conditions,,. In summary, the role of LDs in CSCs was associated with both energy demands and activation of cancer stemness pathways, such as Wnt/β-catenin and NF-κB signaling–. These data demonstrate that LDs are important for CSC maintenance, but further studies are needed to clarify their role and possible application as CSC-targeted therapy.

Lipid droplets as a cancer biomarker

38From the first observations in the late 1960s,, the indication of the increased LD numbers in cancer has raised the possibility of using the detection of LDs as biomarkers for diagnosis and prognosis (Table 1). Most studies correlate PAT proteins expression, mostly perilipin-2, with clinical–pathological features, since RNA from tumor samples or paraffin-embedded tissues is a readily available resource in biomarker studies. Overexpression of PAT proteins has been correlated with the differentiation between malignant and benign tissues–, clinical staging,, invasion–, and survival in several tumors,–.

39Recent advances in lipidomic detection, particularly in hyperspectral-stimulating Raman scattering microscopy, allowed the evaluation of the individual LD composition in a single cell. This raised the possibility that LD lipid composition could have prognostic value in cancer. Indeed, an aberrant accumulation of CEs in LDs was demonstrated in high-grade and metastatic prostate cancers but not in benign lesions or normal tissues,,. Previous data that evaluated the total lipid composition of tumors also showed that CE accumulation was able to differentiate normal from tumor tissue in prostate cancer, leukemia cells, and clear renal cell carcinoma,,.

40The potential of LDs as a biomarker also came directly from clinical practice in endoscopy for cancer diagnosis. Some works have evaluated whether microvascular patterns on magnifying endoscopy could be used to diagnose benign and malignant lesions, since tumor vessels are structurally and functionally abnormal,. The presence of a white opaque substance (WOS) that prevented the identification of the microvasculature pattern has been reported to discriminate benign and malignant lesions. Later, it was shown that the WOS was strongly associated with the presence of LDs, as evidenced by perilipin-2 immunohistochemical and/or Oil red O staining, in gastric, esophageal, and colorectal tumors–.

Concluding remarks

41Although in the past, the presence of LDs was solely implicated in storage and lipid trafficking, it is currently recognized that these organelles may partake in several cellular functions through a variety of mechanisms. Still, to a great extent, these mechanisms have not yet been fully elucidated. Throughout this review, we discussed features that involve LDs in cancer establishment, pointing out recent evidence that associates these organelles with some of the currently accepted hallmarks of cancer. This draws attention to a potential role of LDs during cancer development, wherein the intricate regulation of LDs could be targeted for drug development or their increased biogenesis inspected as a potential biomarker for diseases. Nevertheless, there are still open questions of fundamental importance to determine a causal relationship between these organelles and tumorigenesis. First, how important is LD biogenesis or lipid metabolism during the distinct phases of tumor development? Second, why is LD accumulation or PAT protein expression in cancer an event that seems to be cell and tissue specific? As discussed above, LDs may have a role during either the initial tumor promotion, by converging mitogenic signaling pathways, partaking in cancer cell metabolism, and providing proinflammatory signaling molecules for TME establishment, or during more advanced cancerous stages, protecting cancer cells from hypoxia and or boosting cells for an aggressive, metastatic phenotype. These points are currently under intense investigation, and therefore, LDs might be suitable candidates for future anticancer therapies.

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7.
Wright D. H. Lipid content of malignant lymphomas. Journal of Clinical Pathology. 1968;21(5):643-649.
Not in our library10.1136/jcp.21.5.643
8.
Accioly MT, et al. Lipid bodies are reservoirs of cyclooxygenase-2 and sites of prostaglandin-E2 synthesis in colon cancer cells. Cancer Res. 2008;68:1732-1740.
Not in our library10.1158/0008-5472.can-07-1999
9.
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000.
Not in our library10.1016/s0092-8674(00)81683-9
10.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674.
Not in our library10.1016/j.cell.2011.02.013
11.
Röhrig Florian, Schulze Almut. The multifaceted roles of fatty acid synthesis in cancer. Nature Reviews Cancer. 2016;16(11):732-749.
Not in our library10.1038/nrc.2016.89
12.
Huang W.-C., Li X., Liu J., Lin J., Chung L. W. K. Activation of Androgen Receptor, Lipogenesis, and Oxidative Stress Converged by SREBP-1 Is Responsible for Regulating Growth and Progression of Prostate Cancer Cells. Molecular Cancer Research. 2011;10(1):133-142.
Not in our library10.1158/1541-7786.mcr-11-0206
13.
Yu M, et al. Expression of CIDE proteins in clear cell renal cell carcinoma and their prognostic significance. Mol. Cell Biochem. 2013;378:145-151.
Not in our library10.1007/s11010-013-1605-y
14.
Audet-Walsh Étienne, Vernier Mathieu, Yee Tracey, Laflamme Chloé, Li Susan, Chen Yonghong, Giguère Vincent. SREBF1 Activity Is Regulated by an AR/mTOR Nuclear Axis in Prostate Cancer. Molecular Cancer Research. 2018;16(9):1396-1405.
Not in our library10.1158/1541-7786.mcr-17-0410
15.
Chakraborty, P. K. et al. Role of cystathionine beta synthase in lipid metabolism in ovarian cancer. Oncotarget10.18632/oncotarget.5424 (2015).
Not in our library10.18632/oncotarget.5424
16.
Morrison SF, Nakamura K, Madden CJ. Central control of thermogenesis in mammals. Exp. Physiol. 2008;93:773-797.
Not in our library10.1113/expphysiol.2007.041848
17.
Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer · 2016
No notice
18.
Valli A, et al. Hypoxia induces a lipogenic cancer cell phenotype via HIF1α-dependent and -independent pathways. Oncotarget. 2015;6:1920-1941.
Not in our library10.18632/oncotarget.3058
19.
Gang, X. et al. P300 acetyltransferase regulates fatty acid synthase expression, lipid metabolism and prostate cancer growth. Oncotarget10.18632/oncotarget.7715 (2016).
Not in our library10.18632/oncotarget.7715
20.
Guri Y, et al. mTORC2 promotes tumorigenesis via lipid synthesis. Cancer Cell. 2017;32:807-823.e12.
Not in our library10.1016/j.ccell.2017.11.011
21.
Yue S, et al. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab. 2014;19:393-406.
Not in our library10.1016/j.cmet.2014.01.019
22.
O'Malley Jordan, Kumar Rahul, Kuzmin Andrey N., Pliss Artem, Yadav Neelu, Balachandar Srimmitha, Wang Jianmin, Attwood Kristopher, Prasad Paras N., Chandra Dhyan. Lipid quantification by Raman microspectroscopy as a potential biomarker in prostate cancer. Cancer Letters. 2017;397:52-60.
Not in our library10.1016/j.canlet.2017.03.025
23.
Shimano Hitoshi, Sato Ryuichiro. SREBP-regulated lipid metabolism: convergent physiology — divergent pathophysiology. Nature Reviews Endocrinology. 2017;13(12):710-730.
Not in our library10.1038/nrendo.2017.91
24.
Kim Joungmok, Guan Kun-Liang. mTOR as a central hub of nutrient signalling and cell growth. Nature Cell Biology. 2019;21(1):63-71.
Not in our library10.1038/s41556-018-0205-1
25.
Li Jibin, Huang Qichao, Long Xiaoyu, Zhang Jing, Huang Xiaojun, Aa Jiye, Yang Hushan, Chen Zhinan, Xing Jinliang. CD147 reprograms fatty acid metabolism in hepatocellular carcinoma cells through Akt/mTOR/SREBP1c and P38/PPARα pathways. Journal of Hepatology. 2015;63(6):1378-1389.
Not in our library10.1016/j.jhep.2015.07.039
26.
Lee Gina, Zheng Yuxiang, Cho Sungyun, Jang Cholsoon, England Christina, Dempsey Jamie M., Yu Yonghao, Liu Xiaolei, He Long, Cavaliere Paola M., Chavez Andre, Zhang Erik, Isik Meltem, Couvillon Anthony, Dephoure Noah E., Blackwell T. Keith, Yu Jane J., Rabinowitz Joshua D., Cantley Lewis C., Blenis John. Post-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling. Cell. 2017;171(7):1545-1558.e18.
Not in our library10.1016/j.cell.2017.10.037
27.
Fazolini NP, et al. Leptin activation of mTOR pathway in intestinal epithelial cell triggers lipid droplet formation, cytokine production and increased cell proliferation. Cell Cycle. 2015;14:2667-2676.
Not in our library10.1080/15384101.2015.1041684
28.
Triglycerides Promote Lipid Homeostasis during Hypoxic Stress by Balancing Fatty Acid Saturation · 2018
No notice
29.
Nardi, F. et al. DGAT1 inhibitor suppresses prostate tumor growth and migration by regulating intracellular lipids and non-centrosomal MTOC protein GM130. Sci. Rep. 10.1038/s41598-019-39537-z (2019).
Not in our library10.1038/s41598-019-39537-z
30.
Lu Xin, Yang Xingyuan, Liu Jun. Differential control of ATGL-mediated lipid droplet degradation by CGI-58 and G0S2. Cell Cycle. 2010;9(14):2791-2797.
Not in our library10.4161/cc.9.14.12181
31.
Al-Zoughbi W, et al. Loss of adipose triglyceride lipase is associated with human cancer and induces mouse pulmonary neoplasia. Oncotarget. 2016;7:33832-33840.
Not in our library10.18632/oncotarget.9418
32.
Gindlhuber J, et al. Deletion of adipose triglyceride lipase links triacylglycerol accumulation to a more-aggressive phenotype in A549 lung carcinoma cells. J. Proteome Res. 2018;17:1415-1425.
Not in our library10.1021/acs.jproteome.7b00782
33.
Ou Juanjuan, Miao Hongming, Ma Yinyan, Guo Feng, Deng Jia, Wei Xing, Zhou Jie, Xie Ganfeng, Shi Hang, Xue Bingzhong, Liang Houjie, Yu Liqing. Loss of Abhd5 Promotes Colorectal Tumor Development and Progression by Inducing Aerobic Glycolysis and Epithelial-Mesenchymal Transition. Cell Reports. 2014;9(5):1798-1811.
Not in our library10.1016/j.celrep.2014.11.016
34.
Ror2 signaling regulates Golgi structure and transport through IFT20 for tumor invasiveness · 2017
No notice
35.
Zagani, R., El-Assaad, W., Gamache, I. & Teodoro, J. G. Inhibition of adipose triglyceride lipase (ATGL) by the putative tumor suppressor G0S2 or a small molecule inhibitor attenuates the growth of cancer cells. Oncotarget10.18632/oncotarget.5061 (2015).
Not in our library10.18632/oncotarget.5061
36.
Nomura DK, et al. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell. 2010;140:49-61.
Not in our library10.1016/j.cell.2009.11.027
37.
Hu WR, et al. Monoacylglycerol lipase promotes metastases in nasopharyngeal carcinoma. Int. J. Clin. Exp. Pathol. 2014;7:3704-3713.
Not in our library
38.
Pagano Ester, Borrelli Francesca, Orlando Pierangelo, Romano Barbara, Monti Martina, Morbidelli Lucia, Aviello Gabriella, Imperatore Roberta, Capasso Raffaele, Piscitelli Fabiana, Buono Lorena, Di Marzo Vincenzo, Izzo Angelo A. Pharmacological inhibition of MAGL attenuates experimental colon carcinogenesis. Pharmacological Research. 2017;119:227-236.
Not in our library10.1016/j.phrs.2017.02.002
39.
Zhang, J. et al. Monoacylglycerol lipase: a novel potential therapeutic target and prognostic indicator for hepatocellular carcinoma. Sci. Rep. 10.1038/srep35784 (2016).
Not in our library10.1038/srep35784
40.
Ye Lin, Zhang Bo, Seviour Elena G, Tao Kai-xiong, Liu Xing-hua, Ling Yan, Chen Jian-ying, Wang Guo-bin. Monoacylglycerol lipase (MAGL) knockdown inhibits tumor cells growth in colorectal cancer. Cancer Letters. 2011;307(1):6-17.
Not in our library10.1016/j.canlet.2011.03.007
41.
Nomura Daniel K., Lombardi Donald P., Chang Jae Won, Niessen Sherry, Ward Anna M., Long Jonathan Z., Hoover Heather H., Cravatt Benjamin F. Monoacylglycerol Lipase Exerts Dual Control over Endocannabinoid and Fatty Acid Pathways to Support Prostate Cancer. Chemistry & Biology. 2011;18(7):846-856.
Not in our library10.1016/j.chembiol.2011.05.009
42.
Tisdale MJ. Mechanisms of cancer cachexia. Physiol. Rev. 2009;89:381-410.
Not in our library10.1152/physrev.00016.2008
43.
Das SK, et al. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science. 2011;333:233-238.
Not in our library10.1126/science.1198973
44.
Chang Ta-Yuan, Li Bo-Liang, Chang Catherine C. Y., Urano Yasuomi. Acyl-coenzyme A:cholesterol acyltransferases. American Journal of Physiology-Endocrinology and Metabolism. 2009;297(1):E1-E9.
Not in our library10.1152/ajpendo.90926.2008
45.
Chang Ta-Yuan, Chang Catherine C.Y., Ohgami Nobutaka, Yamauchi Yoshio. Cholesterol Sensing, Trafficking, and Esterification. Annual Review of Cell and Developmental Biology. 2006;22(1):129-157.
Not in our library10.1146/annurev.cellbio.22.010305.104656
46.
Geng F, et al. Inhibition of SOAT1 suppresses glioblastoma growth via blocking SREBP-1-mediated lipogenesis. Clin. Cancer Res. 2016;22:5337-5348.
Not in our library10.1158/1078-0432.ccr-15-2973
47.
Intratumor cholesteryl ester accumulation is associated with human breast cancer proliferation and aggressive potential: a molecular and clinicopathological study · 2015
No notice
48.
Integration of lipidomics and transcriptomics unravels aberrant lipid metabolism and defines cholesteryl oleate as potential biomarker of prostate cancer · 2016
No notice
49.
Lipidomic Signatures and Associated Transcriptomic Profiles of Clear Cell Renal Cell Carcinoma · 2016
No notice
50.
Lee Hyeon Jeong, Li Jie, Vickman Renee E., Li Junjie, Liu Rui, Durkes Abigail C., Elzey Bennett D., Yue Shuhua, Liu Xiaoqi, Ratliff Timothy L., Cheng Ji-Xin. Cholesterol Esterification Inhibition Suppresses Prostate Cancer Metastasis by Impairing the Wnt/β-catenin Pathway. Molecular Cancer Research. 2018;16(6):974-985.
Not in our library10.1158/1541-7786.mcr-17-0665
51.
Wang CW. Lipid droplets, lipophagy, and beyond. Biochim. Biophys. Acta. 2016;1861:793-805.
Not in our library10.1016/j.bbalip.2015.12.010
52.
Lipid Droplets in Cancer: Guardians of Fat in a Stressful World · 2018
No notice
53.
Singh R, et al. Autophagy regulates lipid metabolism. Nature. 2009;458:1131-1135.
Not in our library10.1038/nature07976
54.
Mayatepek E, Seedorf U, Wiebusch H, Lenhartz H, Assmann G. Fatal genetic defect causing Wolman disease. J. Inherit. Metab. Dis. 1999;22:93-94.
Not in our library10.1023/a:1005428122457
55.
Du H, et al. Lysosomal acid lipase-deficient mice: depletion of white and brown fat, severe hepatosplenomegaly, and shortened life span. J. Lipid Res. 2001;42:489-500.
Not in our library
56.
Chiang HL, Terlecky SR, Plant CP, Dice JF. A role for a 70-kilodaton heat shock protein in lysosomal degradation of intracellular proteins. Science. 1989;246:382-385.
Not in our library10.1126/science.2799391
57.
Cuervo AM, Dice JF. A receptor for the selective uptake and degradation of proteins by lysosomes. Science. 1996;273:501-503.
Not in our library10.1126/science.273.5274.501
58.
Kaushik S, Cuervo AM. Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis. Nat. Cell Biol. 2015;17:759-770.
Not in our library10.1038/ncb3166
59.
Kaushik S, Cuervo AM. The coming of age of chaperone-mediated autophagy. Nat. Rev. Mol. Cell Biol. 2018;19:365-381.
Not in our library10.1038/s41580-018-0001-6
60.
Kounakis K, Chaniotakis M, Markaki M, Tavernarakis N. Emerging roles of lipophagy in health and disease. Front. Cell Dev. Biol. 2019;7:1-8.
Not in our library10.3389/fcell.2019.00185
61.
Lu GD, et al. CCAAT/enhancer binding protein α predicts poorer prognosis and prevents energy starvation-induced cell death in hepatocellular carcinoma. Hepatology. 2015;61:965-978.
Not in our library10.1002/hep.27593
62.
Kaini RR, Sillerud LO, Zhaorigetu S, Hu CAA. Autophagy regulates lipolysis and cell survival through lipid droplet degradation in androgen-sensitive prostate cancer cells. Prostate. 2012;72:1412-1422.
Not in our library10.1002/pros.22489
63.
Assumpção JAF, Magalhães KG, Corrêa JR. The role of pparγ and autophagy in ros production, lipid droplets biogenesis and its involvement with colorectal cancer cells modulation. Cancer Cell Int. 2017;17:1-12.
Not in our library10.1186/s12935-016-0378-2
64.
Mukhopadhyay S, et al. ATG14 facilitated lipophagy in cancer cells induce ER stress mediated mitoptosis through a ROS dependent pathway. Free Radic. Biol. Med. 2017;104:199-213.
Not in our library10.1016/j.freeradbiomed.2017.01.007
65.
Bozza PT, Bakker-Abreu I, Navarro-Xavier RA, Bandeira-Melo C. Lipid body function in eicosanoid synthesis: an update. Prostaglandins Leukot. Ess. Fat. Acids. 2011;85:205-213.
Not in our library10.1016/j.plefa.2011.04.020
66.
Wang Dingzhi, DuBois Raymond N. Eicosanoids and cancer. Nature Reviews Cancer. 2010;10(3):181-193.
Not in our library10.1038/nrc2809
67.
Silva Adriana R., Pacheco Patricia, Vieira-de-Abreu Adriana, Maya-Monteiro Clarissa M., D'Alegria Barbara, Magalhães Kelly G., de Assis Edson F., Bandeira-Melo Christianne, Castro-Faria-Neto Hugo C., Bozza Patricia T. Lipid bodies in oxidized LDL-induced foam cells are leukotriene-synthesizing organelles: a MCP-1/CCL2 regulated phenomenon. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 2009;1791(11):1066-1075.
Not in our library10.1016/j.bbalip.2009.06.004
68.
Bozza PT, et al. Eosinophil lipid bodies: specific, inducible intracellular sites for enhanced eicosanoid formation. J. Exp. Med. 1997;186:909-920.
Not in our library10.1084/jem.186.6.909
69.
Yu W, et al. Co-compartmentalization of MAP kinases and cytosolic phospholipase A2 at cytoplasmic arachidonate-rich lipid bodies. Am. J. Pathol. 1998;152:759-769.
Not in our library
70.
Dvorak AM, et al. Ultrastructural immunogold localization of prostaglandin endoperoxide synthase (cyclooxygenase) to non-membrane-bound cytoplasmic lipid bodies in human lung mast cells, alveolar macrophages, type II pneumocytes, and neutrophils. J. Histochem. Cytochem. 1992;40:759-769.
Not in our library10.1177/40.6.1316915
71.
Dvorak AM, Weller PF, Harvey VS, Morgan ES, Dvorak HF. Ultrastructural localization of prostaglandin endoperoxide synthase (Cyclooxygenase) to isolated, purified fractions of guinea pig peritoneal macrophage and line 10 hepatocarcinoma cell lipid bodies. Int. Arch. Allergy Immunol. 1993;101:136-142.
Not in our library10.1159/000236511
72.
Bandeira-Melo Christianne, Paiva Ligia Almeida, Amorim Natália R. T., Weller Peter F., Bozza Patricia T. EicosaCell: An Imaging-Based Assay to Identify Spatiotemporal Eicosanoid Synthesis. Methods in Molecular Biology. 2017;127-141.
Not in our library10.1007/978-1-4939-6759-9_6
73.
Penrose H, et al. Epidermal growth factor receptor mediated proliferation depends on increased lipid droplet density regulated via a negative regulatory loop with FOXO3/Sirtuin6. Biochem Biophys. Res. Commun. 2016;469:370-376.
Not in our library10.1016/j.bbrc.2015.11.119
74.
D’Avila H, et al. Mycobacterium bovis bacillus Calmette-Guerin induces TLR2-mediated formation of lipid bodies: intracellular domains for eicosanoid synthesis in vivo. J. Immunol. 2006;176:3087-3097.
Not in our library10.4049/jimmunol.176.5.3087
75.
Plotkowski MC, et al. Lipid body mobilization in the ExoU-induced release of inflammatory mediators by airway epithelial cells. Micro. Pathog. 2008;45:30-37.
Not in our library10.1016/j.micpath.2008.01.008
76.
Pacheco P, et al. Monocyte chemoattractant protein-1/CC chemokine ligand 2 controls microtubule-driven biogenesis and leukotriene B4-synthesizing function of macrophage lipid bodies elicited by innate immune response. J. Immunol. 2007;179:8500-8508.
Not in our library10.4049/jimmunol.179.12.8500
77.
Kim Sun-Hee, Roszik Jason, Cho Sung-Nam, Ogata Dai, Milton Denái R., Peng Weiyi, Menter David G., Ekmekcioglu Suhendan, Grimm Elizabeth A. The COX2 Effector Microsomal PGE2 Synthase 1 is a Regulator of Immunosuppression in Cutaneous Melanoma. Clinical Cancer Research. 2018;25(5):1650-1663.
Not in our library10.1158/1078-0432.ccr-18-1163
78.
Sanin David E., Matsushita Mai, Klein Geltink Ramon I., Grzes Katarzyna M., van Teijlingen Bakker Nikki, Corrado Mauro, Kabat Agnieszka M., Buck Michael D., Qiu Jing, Lawless Simon J., Cameron Alanna M., Villa Matteo, Baixauli Francesc, Patterson Annette E., Hässler Fabian, Curtis Jonathan D., O’Neill Christina M., O’Sullivan David, Wu Duojiao, Mittler Gerhard, Huang Stanley Ching-Cheng, Pearce Erika L., Pearce Edward J. Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to Prostaglandin E2. Immunity. 2018;49(6):1021-1033.e6.
Not in our library10.1016/j.immuni.2018.10.011
79.
Veglia Filippo, Tyurin Vladimir A., Blasi Maria, De Leo Alessandra, Kossenkov Andrew V., Donthireddy Laxminarasimha, To Tsun Ki Jerrick, Schug Zach, Basu Subhasree, Wang Fang, Ricciotti Emanuela, DiRusso Concetta, Murphy Maureen E., Vonderheide Robert H., Lieberman Paul M., Mulligan Charles, Nam Brian, Hockstein Neil, Masters Gregory, Guarino Michael, Lin Cindy, Nefedova Yulia, Black Paul, Kagan Valerian E., Gabrilovich Dmitry I. Fatty acid transport protein 2 reprograms neutrophils in cancer. Nature. 2019;569(7754):73-78.
Not in our library10.1038/s41586-019-1118-2
80.
Human Pancreatic Carcinoma-Associated Fibroblasts Promote Expression of Co-inhibitory Markers on CD4+ and CD8+ T-Cells · 2019
No notice
81.
NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control · 2018
No notice
82.
Binnewies Mikhail, Roberts Edward W., Kersten Kelly, Chan Vincent, Fearon Douglas F., Merad Miriam, Coussens Lisa M., Gabrilovich Dmitry I., Ostrand-Rosenberg Suzanne, Hedrick Catherine C., Vonderheide Robert H., Pittet Mikael J., Jain Rakesh K., Zou Weiping, Howcroft T. Kevin, Woodhouse Elisa C., Weinberg Robert A., Krummel Matthew F. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nature Medicine. 2018;24(5):541-550.
Not in our library10.1038/s41591-018-0014-x
83.
Hirata Eishu, Sahai Erik. Tumor Microenvironment and Differential Responses to Therapy. Cold Spring Harbor Perspectives in Medicine. 2017;7(7):a026781.
Not in our library10.1101/cshperspect.a026781
84.
Zhang Y, et al. Fatty acid-binding protein E-FABP restricts tumor growth by promoting IFN-responses in tumor-associated macrophages. Cancer Res. 2014;74:2986-2998.
Not in our library10.1158/0008-5472.can-13-2689
85.
Saponin-based adjuvants induce cross-presentation in dendritic cells by intracellular lipid body formation · 2016
No notice
86.
Exogenous lipid uptake induces metabolic and functional reprogramming of tumor-associated myeloid-derived suppressor cells · 2017
Not checked
87.
Caspase-1 cleaves PPARγ for potentiating the pro-tumor action of TAMs · 2017
No notice
88.
Wu H, et al. Oleate but not stearate induces the regulatory phenotype of myeloid suppressor cells. Sci. Rep. 2017;7:7498.
Not in our library10.1038/s41598-017-07685-9
89.
Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer · 2017
No notice
90.
Goswami, S. & Sharma-Walia, N. Crosstalk between osteoprotegerin (OPG), fatty acid synthase (FASN) and, cycloxygenase-2 (COX-2) in breast cancer: implications in carcinogenesis. Oncotarget10.18632/oncotarget.9835 (2016).
Not in our library10.18632/oncotarget.9835
91.
Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 2017;14:399-416.
Not in our library10.1038/nrclinonc.2016.217
92.
Lipid droplet‐dependent fatty acid metabolism controls the immune suppressive phenotype of tumor‐associated macrophages · 2019
No notice
93.
Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat. Immunol. 2018;19:108-119.
Not in our library10.1038/s41590-017-0022-x
94.
Hossain F, et al. Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies. Cancer Immunol. Res. 2015;3:1236-1247.
Not in our library10.1158/2326-6066.cir-15-0036
95.
Condamine T, et al. Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci. Immunol. 2016;1:aaf8943-aaf8943.
Not in our library10.1126/sciimmunol.aaf8943
96.
Reactive Oxygen Species as Regulators of MDSC-Mediated Immune Suppression · 2018
No notice
97.
Goc J, et al. Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells. Cancer Res. 2014;74:705-715.
Not in our library10.1158/0008-5472.can-13-1342
98.
Shi Y, et al. Suppression of vascular endothelial growth factor abrogates the immunosuppressive capability of murine gastric cancer cells and elicits antitumor immunity. FEBS J. 2014;281:3882-3893.
Not in our library10.1111/febs.12923
99.
McDonnell AM, et al. Tumor-infiltrating dendritic cells exhibit defective cross-presentation of tumor antigens, but is reversed by chemotherapy. Eur. J. Immunol. 2015;45:49-59.
Not in our library10.1002/eji.201444722
100.
Mature dendritic cells correlate with favorable immune infiltrate and improved prognosis in ovarian carcinoma patients · 2018
No notice
101.
Bougnères Laurence, Helft Julie, Tiwari Sangeeta, Vargas Pablo, Chang Benny Hung-Junn, Chan Lawrence, Campisi Laura, Lauvau Gregoire, Hugues Stephanie, Kumar Pradeep, Kamphorst Alice O., Dumenil Ana-Maria Lennon, Nussenzweig Michel, MacMicking John D., Amigorena Sebastian, Guermonprez Pierre. A Role for Lipid Bodies in the Cross-presentation of Phagocytosed Antigens by MHC Class I in Dendritic Cells. Immunity. 2009;31(2):232-244.
Not in our library10.1016/j.immuni.2009.06.022
102.
Herber DL, et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nat. Med. 2010;16:880-886.
Not in our library10.1038/nm.2172
103.
Ramakrishnan R, et al. Oxidized lipids block antigen cross-presentation by dendritic cells in cancer. J. Immunol. 2014;192:2920-2931.
Not in our library10.4049/jimmunol.1302801
104.
Ovarian Cancer-Intrinsic Fatty Acid Synthase Prevents Anti-tumor Immunity by Disrupting Tumor-Infiltrating Dendritic Cells · 2018
No notice
105.
Oxidative Stress, Tumor Microenvironment, and Metabolic Reprogramming: A Diabolic Liaison · 2012
No notice
106.
Chen P, et al. Preoperative serum lipids as prognostic predictors in esophageal squamous cell carcinoma patients with esophagectomy. Oncotarget. 2017;8:41605-41619.
Not in our library10.18632/oncotarget.15651
107.
Zhang Y, et al. Association of serum lipids and severity of epithelial ovarian cancer: an observational cohort study of 349 Chinese patients. J. Biomed. Res. 2018;32:336-342.
Not in our library10.7555/jbr.32.20170096
108.
Sood, D. et al. 3D extracellular matrix microenvironment in bioengineered tissue models of primary pediatric and adult brain tumors. Nat. Commun. 10.1038/s41467-019-12420-1 (2019).
Not in our library10.1038/s41467-019-12420-1
109.
Bozza PT, Viola JP. Lipid droplets in inflammation and cancer. Prostaglandins Leukot. Essent. Fat. Acids. 2010;82:243-250.
Not in our library10.1016/j.plefa.2010.02.005
110.
Cruz, A. L. S. et al. Cell cycle progression regulates biogenesis and cellular localization of lipid droplets. Mol. Cell. Biol. 1–20 10.1128/MCB.00374-18 (2019).
Not in our library10.1128/mcb.00374-18
111.
Kurat Christoph F., Wolinski Heimo, Petschnigg Julia, Kaluarachchi Supipi, Andrews Brenda, Natter Klaus, Kohlwein Sepp D. Cdk1/Cdc28-Dependent Activation of the Major Triacylglycerol Lipase Tgl4 in Yeast Links Lipolysis to Cell-Cycle Progression. Molecular Cell. 2009;33(1):53-63.
Not in our library10.1016/j.molcel.2008.12.019
112.
Patel D, et al. A late G1 lipid checkpoint that is dysregulated in clear cell renal carcinoma cells. J. Biol. Chem. 2017;292:936-944.
Not in our library10.1074/jbc.m116.757864
113.
Qi W, et al. Tumor suppressor FOXO3 mediates signals from the EGF receptor to regulate proliferation of colonic cells. Am. J. Physiol. Gastrointest. Liver Physiol. 2010;300:G264-G272.
Not in our library10.1152/ajpgi.00416.2010
114.
Qi W, et al. FOXO3 growth inhibition of colonic cells is dependent on intraepithelial lipid droplet density. J. Biol. Chem. 2013;288:16274-16281.
Not in our library10.1074/jbc.m113.470617
115.
Yu W, Cassara J, Weller PF. Phosphatidylinositide 3-kinase localizes to cytoplasmic lipid bodies in human polymorphonuclear leukocytes and other myeloid-derived cells. Blood. 2000;95:1078-1085.
Not in our library10.1182/blood.v95.3.1078.003k16_1078_1085
116.
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Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance · 2018
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130.
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Association of tamoxifen resistance and lipid reprogramming in breast cancer · 2018
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Lipid Droplets: A New Player in Colorectal Cancer Stem Cells Unveiled by Spectroscopic Imaging · 2014
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Ueyama Hiroya. A white opaque substance-positive gastric hyperplastic polyp with dysplasia. World Journal of Gastroenterology. 2013;19(26):4262.
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Ueo Tetsuya, Yonemasu Hirotoshi, Yao Kenshi, Ishida Tetsuya, Togo Kazumi, Yanai Yuka, Fukuda Masahide, Motomura Mitsuteru, Narita Ryoich, Murakami Kazunari. Histologic differentiation and mucin phenotype in white opaque substance-positive gastric neoplasias. Endoscopy International Open. 2015;03(06):E597-E604.
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Hisabe Takashi, Yao Kenshi, Imamura Kentaro, Ishihara Hiroshi, Yamasaki Kazutomo, Yasaka Tatsuhisa, Matsui Toshiyuki, Iwashita Akinori. Novel Endoscopic Findings as Visualized by Magnifying Endoscopy with Narrow-Band Imaging: White Opaque Substance Is Present in Colorectal Hyperplastic Polyps. Digestion. 2015;93(2):127-131.
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187.
Imamura Kentaro, Yao Kenshi, Hisabe Takashi, Nambu Masami, Ohtsu Kensei, Ueo Tetsuya, Yano Shinji, Ishihara Hiroshi, Nagahama Takashi, Kanemitsu Takao, Yamasaki Kazutomo, Matsui Toshiyuki, Tanabe Hiroshi, Iwashita Akinori, Daa Tsutomu, Yokoyama Shigeo, Matsunaga Kazuhisa, Enjoji Munechika. The nature of the white opaque substance within colorectal neoplastic epithelium as visualized by magnifying endoscopy with narrow-band imaging. Endoscopy International Open. 2016;04(11):E1151-E1157.
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Kawasaki Keisuke, Eizuka Makoto, Nakamura Shotaro, Endo Masaki, Yanai Shunichi, Akasaka Risaburo, Toya Yosuke, Fujita Yasuko, Uesugi Noriyuki, Ishida Kazuyuki, Sugai Tamotsu, Matsumoto Takayuki. Association between white opaque substance under magnifying colonoscopy and lipid droplets in colorectal epithelial neoplasms. World Journal of Gastroenterology. 2017;23(47):8367-8375.
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Ueo Tetsuya, Yonemasu Hirotoshi, Yada Naomi, Yano Shinji, Ishida Tetsuya, Urabe Masaki, Takahashi Ken, Nagamatsu Hideyasu, Narita Ryoichi, Yao Kenshi, Daa Tsutomu, Yokoyama Shigeo. White opaque substance represents an intracytoplasmic accumulation of lipid droplets: Immunohistochemical and immunoelectron microscopic investigation of 26 cases. Digestive Endoscopy. 2012;25(2):147-155.
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190.
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Hisabe T, et al. Novel endoscopic findings as visualized by magnifying endoscopy with narrow-band imaging: white opaque substance is present in colorectal hyperplastic polyps. Digestion. 2015;93:127-131.
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Not in our library10.1159/000477910

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