Atherosclerosis, Diabetes Mellitus, and Cancer: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Vasiliki Katsi
,
Ilias Papakonstantinou
,
Konstantinos Tsioufis

The involvement of cardiovascular disease in cancer onset and development represents a contemporary interest in basic science. It has been recognized, from the most recent research, that metabolic syndrome-related conditions, ranging from atherosclerosis to diabetes, elicit many pathways regulating lipid metabolism and lipid signaling that are also linked to the same framework of multiple potential mechanisms for inducing cancer.

  • lipoprotein metabolism
  • cancer metabolism
  • endothelial dysfunction

1. Introduction

Atherosclerosis and cancer, among the most common human diseases, are determined by the result of underlying genetic predisposition and lifetime exposure to multiple factors that threaten a healthy life [1][2]. Atherosclerosis, a chronic inflammatory disease of the arterial wall, leads to the formation of atherosclerotic plaques and cardiovascular disease [3]. Atherosclerotic cardiovascular disease (ASCVD) is recognized to be substantially driven by important aspects of metabolic syndrome. Metabolic syndrome is characterized by a set of cardiovascular risk factors that include abdominal obesity, insulin resistance, impaired glucose metabolism, hypertension, and dyslipidemia [4]. Above all, the increased proportion of atherogenic small, dense low-density lipoproteins (LDLs) in metabolic syndrome, even though LDL-cholesterol levels may be optimal, reflects their direct involvement in the chronic inflammatory processes of atherosclerosis [5].
Clinical and epidemiological studies have linked defects in lipid metabolism to cancer and describe the association of several types of cancers with risk factors for cardiovascular disease [6][7][8]. Moreover, metabolic syndrome, as a cluster of risk factors for ASCVD and type 2 diabetes, has been substantially associated with the onset of malignancies [9]. For example, patients with metabolic syndrome have an increased risk of atherosclerosis-related cancer compared to metabolically healthy individuals and show an increased incidence and aggressiveness of tumor formation [10][11][12].
While the understanding of multiple factors continues to evolve, the interaction between metabolic syndrome, ASCVD, and cancer appears to be challenging to study, because ASCVD and cancer share multiple risk factors, and questions are raised about the actual contribution of each to cancer risk [13]. It is important to note that ASCVD risk factors like smoking, a diet high in saturated fat, a higher intake of sugar and high-glycemic-index foods, a sedentary lifestyle, and a lack of exercise are modifiable and subject to prevention [14]. How and to what extent these risk factors contribute to cancer is likely unknown. For instance, artificial sweeteners (especially aspartame and acesulfame-K), which are used in beverages, are associated with an increased cancer risk [15]. Similarly, human studies link the composition of dietary fat to the pathogenesis of cancer rather than the total fat content in isocaloric diets [16]. It is also likely that genetic predisposition, under the influence of environmental and atherogenic factors, may be implicated in both cardiovascular diseases and cancer and may be the initiating event in tumorigenesis–malignant transformation [17]. Moreover, while it has been shown that LDL retention is crucial for the initiation of atherosclerosis, its contribution to the malignancy of cancer is not known [18].
To uncover the processes that link ACVD and cancer, “chronic inflammation”, as the first step, is typically considered the leading mechanism [19][20]. Chronic inflammation, a container concept of different inflammatory networks, combines cellular and humoral pathways, which are also intertwined with additional molecular mechanisms and metabolic parameters [3][21][22].
First of all, the milestone event in atherosclerosis development is endothelial cell (EC) activation in susceptible vascular areas, regarded as “athero-prone”, at arterial branch points and curvatures, where blood flow turns from laminar and unidirectional to oscillatory, thus resulting in minimal but continuous shear stress on ECs [23]. At these sites of highly dynamic and inflamed endothelial microenvironments induced by hemodynamic stress, LDLs are deposited and are oxidized to form highly atherogenic oxidized LDL (oxLDL) [24]. LDL oxidation is mediated by reactive oxygen species (ROS) produced by oxidative phosphorylation (OXPHOS) in the mitochondria of damaged ECs [3][25]. Then, macrophages are chemoattracted and take up oxLDL with the help of scavenger receptors, forming foam cells. Foam cells secrete cytokines, which trigger a series of inflammatory reactions and progression to atheromatous plaques [26].
In addition to oxidation and chronic inflammation, angiogenesis has been demonstrated to be an important driving force of atherosclerosis and thus ASCVD. The predominant angiogenic mechanism in atherosclerotic lesions is sprouting angiogenesis from pre-existing vasa vasorum [25]. Angiogenic factors specific to atherosclerotic angiogenesis may include the vascular endothelial-specific growth factors VEGF-A, angiopoietins, and hypoxia-inducible factor-1α (HIF-1a) [25]. Furthermore, signaling pathways are activated by oxLDL and ROS in the subendothelial space to drive the expression of proinflammatory cytokines as mediators in atherosclerosis progression. Among them, toll-like receptor (TLR), NLRP3 inflammasome, Notch, and Wnt signaling, when dysregulated, play an important role [21]. Most of these signaling pathways interfere with transcription factors like nuclear transcription factor κB (NFκB), which mediates the production of interleukins related to inflammation and atherogenesis [27][28].
While the contribution of inflammation is central in cardiovascular diseases, the link between inflammation and cancer is less understood than the connection between inflammation and atherosclerosis. Inflammation has been recognized for its roles in cancer initiation, invasion, and progression [29][30][31]. The gain of oncogenes and loss of tumor suppressors are key characteristics of cancer cells. One of the most well-known oncogenic regulators, the tumor suppressor p53 can also regulate cellular metabolism [32]. In addition, deregulated NF-κB activity causes inflammation-related diseases, as well as cancers [33]. Moreover, the same molecular families of inflammation, specifically those targeting the pathways regulating lipid metabolism and atherogenesis, are elevated in many forms of cancer, and they provide growth signals that promote the proliferation of malignant cells [21][34].
The production of ROS, besides being an important aspect of ASCVD, also represents one of the hallmarks of tumors, as it occurs in response to the hypoxic (low oxygen level) tumor microenvironment (TME) [35]. This causes excessive abnormal angiogenesis, which plays a pivotal role in tumor progression, a process driven by the tissue hypoxia-triggered overproduction of VEGFs [36]. To increase oxygen delivery to the hypoxic environment, transcription factors are activated; among them, HIF-1a, which is also implicated in atherosclerotic angiogenesis, promotes alternative metabolic pathways that regulate the adaptation, survival, and aggressiveness of tumor cells [37]. Increased cancer risk is also associated with dysfunctional visceral fat, which plays a key role in the initiation and maintenance of chronic inflammation, fibrosis (extracellular matrix hypertrophy), and impaired angiogenesis, as well as consequent unresolved hypoxia [38]. In adipose tissue, lipids and accumulating lipid droplets (LDs) are common phenotypic features of dyslipidemia in metabolic syndrome [39]. Of interest, white adipose tissue (WAT) inflammation is associated with metabolic syndrome and pro-neoplastic genes [40]. Moreover, cancer cells exhibit the presence of abundant LDs, which suggests that the storage of lipids may be a common feature of malignancies [41].

2. Angiogenic Factors in Atherosclerotic Disease and Cancer

Angiogenesis is a normal physiological mechanism defined as the formation of new blood vessels and capillaries from already existing ones; this condition is called “sprouting” [42]. The angiogenic front of the sprouting vessel is characterized by two EC phenotypes, stalk and tip ECs, but the key event in sprouting angiogenesis is the selection of motile leading-edge tip cells [25][36]. Poorly perfused ECs exposed to high VEGF concentrations extend numerous filopodia and become tip cells, initiating sprouting angiogenesis. The degradation of the basal membrane and the detachment of mural cells then result in stalk cells [43]. While angiogenesis is considered an important mechanism for the development of atherosclerotic disease [25], it also represents one key event in several types of cancer [44]. This is because cancer is associated with a highly hypoxic state, which promotes hypoxic-tumor-derived transcription factors [45][46][47]. The most widely known angiogenic factors are the family of vascular endothelial growth factors (VEGF-A, VEGF-B), VEGF receptors (VEGFRs), and angiopoietins [48]. Other factors that promote angiogenesis and tumor expansion include HIF-1a (hypoxia-inducible factor-1a) and nuclear factor erythroid 2-related factor 2 (NRF2) [49]. The imbalance between angiogenic and antiangiogenic factors promotes an “angiogenic switch”, triggering blood vessel formation and angiogenesis [36].

2.1. Endothelial Growth Factor (VEGF) and VEGF Receptors (VEGFRs)

Endothelial growth factor (VEGF) promotes the proliferation, migration, and spread of endothelial cells and is an undisputed crucial player in EC activation for both physiological and pathological angiogenesis [36][50][51]. VEGF triggers cell responses by recruiting the tyrosine kinase receptors VEGFR1/Flt-1, VEGFR2/KDR/Flk1, and VEGFR3/Flt-4, and among them, VEGFR2 is the most potent mediator of changes that occur during VEGF-induced tip cell selection [43].

2.1.1. VEGF-Mediated Signaling

The activation of the VEGF receptor by its ligand promotes signaling pathways important to endothelial cell proliferation, including phosphoinositide-3-kinase (PI3K), protein kinase B (PKB/Akt), and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway (p38-MAPK/ERK1/2), facilitating the migration of inflammatory cells and the release of inflammatory cytokines and proteolytic enzymes into the extracellular matrix (ECM) [52][53]. Moreover, under hypoxic stress, DLL4-NOTCH reacts and represses VEGFA-VEGFR2 signaling, inhibiting their differentiation into tip cells [43][54].
Important cell receptors for VEGF/VEGFR signaling in angiogenesis include TFEB and Neuropilin 1 (NRP1). TFEB relies on the catalytic activity of VEGF receptor 2 (VEGFR2) to regulate EC proliferation [55][56]. Vascular NRP1, as a receptor, participates in distinct types of signaling pathways that control cell migration in angiogenesis and has been shown to synergize with VEGF-A as a co-receptor for VEGFR2 [52][57][58].

2.1.2. VEGF/VEGFR in Atherosclerosis

VEGF is part of the classical angiogenic factors that mediate atherosclerotic angiogenesis, in addition to its role in neovascularization, plaque growth/progression, and instability [25]. VEGF has a multifactorial influence on energy homeostasis, the lipidemic profile, insulin resistance, glucose sensitivity, and cardiac function [59]. The effects of VEGFs on the development of atherosclerosis are complex and diverse, but VEGF-A prevents the repair of endothelial damage, contributing to atherogenesis and promoting monocyte adhesion, transendothelial migration, and activation [58]. VEGF-A, as part of the VEGF-A/VEGFR-1-NRP1 signaling pathway, regulates chylomicrons entering the chylous duct; thus, dysregulation could cause the inhibition of chylomicron absorption [60]. Also, VEGF-A decreases the activity of plasma lipoprotein lipase (LPL), resulting in the accumulation of triglycerides in chylomicrons and very low-density lipoproteins, which results in atherosclerosis promotion [61]. On the other hand, VEGF-B is known for its lipid-lowering effect. Acting via VEGFR-1/AMPK and NRP-1, VEGF-B regulates the transcription of vascular fatty acid transporters, thus controlling the uptake of fatty acids from circulating lipids by ECs and their further transcytosis, followed by lipid utilization in mitochondria [62]. In addition, VEGF-B signaling impairs the recycling of low-density lipoprotein receptors (LDLRs) to the plasma membrane, leading to reduced cholesterol uptake and membrane cholesterol loading, which also leads to a decrease in glucose transporter 1 (GLUT1)-dependent endothelial glucose uptake [63].

2.1.3. VEGF/VEGFR in Cancer

The expression of VEGF and VEGFRs is upregulated in solid tumors, and this significantly contributes to the formation of tumor blood vessels, leading to cancer development and dissemination [64]. Following the discovery that many tumors secrete VEGF, it is not unexpected that the VEGF pathway has been considered one of the most attractive targets for the development of antiangiogenic drugs [65]. The clinical benefit of drugs targeting the VEGF/VEGFR pathway, neutralizing monoclonal antibodies, has been modest for most tumor types; nevertheless, combinations of VEGF/VEGFR pathway inhibitors with immune checkpoint blockers have attained new interest [36][66].

2.2. Angiopoietins

Angiopoietins consist of a small group of secreted glycoproteins that are implicated not only in the normal process of angiogenesis, regulating vascular permeability and the growth, modification, and recovery of the blood vessels, but also in pathological vascular remodeling during inflammation, tumor angiogenesis, and metastasis [36][67]. In humans, angiopoietins constitute a small group of three secreted glycoproteins named Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), and Angiopoietin-4 (Ang-4) (the mouse ortholog is named Ang-3), which are ligands of the Tie-2 tyrosine kinase receptor [68]. Ang-1 is regarded as a strong Tie-2 agonist and promotes vessel maturation and survival through Tie-2 receptor phosphorylation and via the PI3K-Akt-mediated signaling pathway [69]. Ang-2 has been regarded as an antagonist of Tie-2 that competitively restrains Ang-1 binding. However, more recent studies imply that Ang-2 has a dual impact on angiogenesis since it acts either as a weak Tie-2 agonist or as a Tie-2 antagonist [36][70].

2.2.1. Angiopoietins in Atherosclerosis

Angiopoietin-1 may play a proatherogenic role, while angiopoietin-2, which acts as an antagonist of Angiopoietin-1, may inhibit atherosclerosis by limiting LDL oxidation [71]. In line with this remark, in hypercholesterolemic LDLR−/−Apolipoprotein B (ApoB)100/100 mice, anti-angiopoietin-2-blocking antibodies exerted an anti-atherogenic effect [72]. Moreover, in mice, Ang-2 showed increased expression in lesions with intraplaque hemorrhage compared to regions of the lesions without [73]. From other experiments in mice, when Ang-4 protein was injected twice a week into atherosclerotic ApoE−/−mice, Ang-4 reduced atherosclerotic plaque size and vascular inflammation and inhibited atherogenesis [74]. Another study showed that genetic ablation of Ang-4 in adipose tissue results in enhanced plasma lipoprotein lipase (LPL) activity, the rapid clearance of circulating triacylglycerols, increased lipolysis and fatty acid oxidation, and decreased synthesis, suggesting that a lack of Ang-4 in adipose tissue enhances the clearance of proatherogenic lipoproteins, attenuates inflammation, and reduces atherosclerosis. [75].

2.2.2. Angiopoietins in Cancer

It has been estimated that predominantly Ang-2 is extensively expressed in tumor endothelial cells and, in association with VEGF and other proangiogenic factors, triggers tumor angiogenesis [36]. This is accompanied by the proteolytic degradation of the basement membrane by matrix metalloproteinases (MMPs), which results in the loosening of endothelial cell–cell junctions [36]. Nowadays, it is well established that the serum levels of Ang-2 are significantly associated with the onset and progression of non-small-cell lung cancer (NSCLC) [67]. Ang-2 transcription augments the migration, invasion, and EMT of lung cancer cells [76]. While the role of Ang-4 (which acts as an agonist of the Tie-2 receptor) in tumor angiogenesis and invasion seems unclear, Ang-4 was recently shown to be associated with cancer progression by promoting glucose metabolism in colorectal cancer [77].

2.3. Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)

NRF2 belongs to the group of redox-sensitive transcription factors expressed in several tissues and, by promoting ROS detoxification, improves oxidative stress and maintains redox homeostasis [78]. Kelch-like ECH-associated protein 1 (KEAP1) is an inhibitor of NRF2 [79], while heme oxygenase-1 (HO-1) is a target of NRF2, which induces its expression [80].

2.3.1. NRF2 Signaling in Atherosclerosis

Based on the mentioned data, the NRF2 signaling pathway is currently considered an important defense mechanism against ASCVD; however, the mechanisms underlying the preventive effects of NRF2 are barely known. The nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (NRF2/HO-1) pathway confers antioxidant effects and plays a crucial protective role in cellular responses to oxidative stress, which is a risk factor for ASCVD, due to the degradation of pro-oxidant heme and the generation of antioxidants biliverdin and bilirubin [80].

2.3.2. NRF2 Signaling in Cancer

NRF2 has paradoxical roles in cancer biology, either acting as a tumor suppressor or exerting oncogenic effects [81]. There are also conflicting data as to whether NRF2 promotes or inhibits tumor initiation because no studies have demonstrated that NRF2-activating mutations alone are sufficient to initiate cancer [81]. It is known that cancer cells, to limit the damaging effects of ROS, utilize the transcription factor NRF2 to upregulate antioxidant proteins [82]. This may be mediated through the activation of the pentose phosphate pathway (PPP), a major glucose catabolic pathway, which redirects glucose and glutamine into anabolic processes, especially under the sustained activation of oncogenic signaling [83]. During the early phases of tumorigenesis, ROS appear to be mutagenic, and therefore, they support cell transformation into cancer cells [84]. Evidence indicates that ROS increase upon transformation, but their levels are kept in check by antioxidant systems, as orchestrated by NRF2 [85]. It is possible that limiting ROS is necessary for the initiation of cell transformation, whereas sustaining ROS levels promotes metastasis [82]. Likely, during tumor progression, a different type of ROS is being affected, and high levels of toxic ROS (that is, O2−, −OH, LOOH) may be a barrier to tumor initiation; thus, initiation requires the elevated expression of both NRF2 activation and TP53-induced glycolysis and apoptosis regulator (TIGAR) to support toxic ROS scavenging [82]. Robust evidence for the importance of ROS in cancer comes from human cancer genetic analysis and studies showing that loss-of-function mutations in cytoplasmic KEAP1 result in the activation of NRF2 in the context of other cancer-promoting mutations [86]. Hence, the NRF2 regulation of the antioxidant response by eliminating ROS and maintaining a normal redox state can have a detrimental impact on cancer treatment [87]. NRF2/KEAP1 may also protect against aberrant inflammation by regulating the uncontrolled activation of the NF-κB pathway, which can result in inflammatory cell damage and lead to malignant cell transformation [88]. NRF2 upregulates HO-1, which, besides removing toxic heme, produces biliverdin, iron ions, and carbon monoxide and thus exerts beneficial effects by protecting against oxidative injury, the regulation of apoptosis, and the modulation of inflammation, as well as the contribution to angiogenesis [89]. However, the role of HO-1 in tumorigenesis has not been systematically addressed, although emerging data show the multiple roles of HO-1 in tumorigenesis, from pathogenesis to the progression to malignancy, metastasis, and even resistance to therapy [90].

2.4. Hypoxia-Inducible Factor-1a/HIF-1a

Hypoxia-induced factor 1-alpha (HIF-1a), a heterodimeric protein part of the basic helix-loop-helix family, is regarded as the core molecule of an oxygen-sensing mechanism in the body, which is hypoxia [91][92].

2.4.1. HIF-1a in Atherosclerosis

HIF-1a in atherosclerosis exerts both detrimental and beneficial actions, depending on the cell type expressing HIF-1a [93]. OxLDLs can trigger HIF-1a activation through TLRs in macrophages, with consequences for interleukin-1β (IL-1β) production and the metabolic rewiring of macrophages with the induction of glycolysis (rather than OXPHOS) [93]. Overall, HIF-1a plays a key role in the critical steps of atherosclerosis development, acting on endothelial cells, vascular smooth muscle cells, and foam cell formation, and through the upregulation of VEGF, ROS, and the NF-kB pathways in endothelial cells, HIF-1a is able to cause endothelial cell dysfunction, angiogenesis, and inflammation [94].

2.4.2. HIF-1a in Cancer

HIF-1a, activated by hypoxia, is highly expressed in the TME and represents the main trigger for the growth of new blood vessels in malignant tumors [95]. HIF-1a induces the upregulation of angiogenic factors, VEGF/VEGFR, and angiopoietin with the Tie2 receptor at the transcriptional level, thereby promoting the formation of new blood vessels in cancer, leading to tumor growth, progression, and metastasis [49]. HIF-1a is also directly linked to leptin, which shows strong proangiogenic properties [96][97]. HIF-1a levels are regulated by multiple signaling pathways that play an important role in human cancer, among them the PI3K-Akt-mTOR signaling pathway [98]. PI3K/Akt signaling upregulates HIF-1a transcription and translation by PI3K/Akt signal, regardless of oxygen levels [99][100]. Both PI3K/Akt activity and HIF-1a expression are influenced by ROS. Collectively, these results suggest that ROS-induced high HIF-1a expression is, to a certain extent, mediated via PI3K/Akt activation [101]. HIF-1a is a key regulator of cancer metabolism. Deregulation of HIF-1a coupled with the abnormal expression of metabolic enzymes (pyruvate dehydrogenase complex) during cancer development might play a role in inducing the deviation of tumor cells from the default OXPHOS program to enter into a permanent aerobic glycolytic metabolic pathway as an adaptation to low oxygen tension, as the main metabolic pathway for generating ATP, even in the presence of oxygen [102].

3. The Role of Lipogenic Factors in Atherosclerosis and Cancer

Lipoproteins and lipid factors, important in the pathophysiology of atherosclerosis, that have been shown to play a pro-tumorigenic role in several cancers include oxidized LDL (oxLDL), Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1), Proprotein Convertase Subtilisin/Kexin type-9 serine protease (PCSK9), and other specific components, like fatty acid synthase (FASN) [103][104]. These specific components of the lipogenic machinery and cholesterol homeostasis are subject to the regulation of master transcriptional regulators, which may comprise sterol regulatory element-binding proteins (SREBPs) and liver X receptors (LXRs) [105].

3.1. Oxidized LDLs and LOX-1 Receptor

3.1.1. Oxidized LDLs

The oxidation of subendothelial LDL, oxLDL, is reported to be a major player in atherosclerosis development [106]. Also, oxLDL has been implicated in many aspects of cancer [103]. OxLDL upregulates HIF-1a expression and increases microRNA miR-210 expression, which leads to the downregulation of sprout-related EVH1 domain 2 (SPRED2), a protein that reduces cell migration, leading to a higher risk of vascular diseases [107]. Downregulation of SPRED2 has been detected in advanced human cancers and is associated with highly metastatic phenotypes [108][109]. OxLDL may disrupt the barrier integrity of the endothelium and represents one of the strongest triggering factors for the transition of endothelial cells into mesenchymal-like cells under pathological conditions, like in the context of atherosclerosis and cancer [110]. The induction of autophagy is an important additional mechanism by which oxLDL participates in cancer progression and promotes EMT when spreading outside the tumor mass [111]. This may be through oxLDL activation of the key metabolic enzyme proline oxidase (POX), which produces superoxide, which exerts its effect by regulating beclin-1 [112].

3.1.2. LOX-1 Receptor

The majority of the atherogenic effects of oxLDL on endothelial function are regulated through the expression and activation of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1) [107]. LOX-1 belongs to class E scavenger receptors (SRs) and has the ability to bind to dysfunctional lipids, like oxLDL, fundamental in atherosclerosis and other diseases, like obesity, hypertension, and cancer [113]. LOX-1 is upregulated by many inflammatory mediators and proatherogenic stimuli but has no known enzymatic or catalytic activity, and ligand binding has been shown to trigger intracellular signaling [18][114]. To date, evidence suggests that LOX-1 is involved in a plethora of processes relevant to the pathogenesis of certain malignancies and may play a causative role in tumor initiation and progression [107]. LOX-1 overexpression mediates VEGF induction and HIF-1a activation, promoting neoangiogenic and EMT processes in glioblastoma, osteosarcoma prostate, colon, breast, lung, and pancreatic tumors [115]. In endothelial cells, the binding of oxLDL to LOX-1 increases ROS formation, the PI3K/Akt cascade, and NFkB activation [115][116].

3.2. PCSK9 Pathway

3.2.1. Role of PCSK9 in Atherosclerosis

Proprotein convertase subtilisin/kexin type-9 (PCSK9), a serine protease, is now identified as an important and major player in the pathophysiology of atherosclerosis and promotes the onset and progression of CVD [117]. PCSK9 is activated when intracellular cholesterol is reduced and binds to LDL-Rs, redirecting them to lysosomes for cleavage instead of recycling them back to the cell surface, promoting a subsequent increase in LDL-cholesterol (LDL-C) levels [118]. Beyond cholesterol metabolism, other physiological processes are also regulated by PCSK9, such as adipogenesis modulation, the immune response, and interaction with many other cellular receptors, including LOX-1 [119].
PCSK9 can mediate oxLDL-induced inflammation by enhancing the expression of LOX-1, which can increase the uptake of oxLDLs that induce inflammation via activation of NF-kB. PCSK9 can also increase the expression of TLR4, which activates NF-kB to upregulate the expression of inflammatory cytokines, like interleukin 6 (IL-6) [117]. Silencing PCSK9 reduced the expression of inflammatory genes by blocking the TLR4/NFkB pathway in macrophages [120]. PCSK9 increases oxLDL uptake and activates ROS [121]. Given these observations, PCSK9 is clearly involved in the inflammatory response of atherosclerosis.

3.2.2. Role of PCSK9 in Cancer

The recent literature illustrates that PCSK9 is highly expressed and strongly associated with the incidence and progression of most cancers [122]. Τhe use of PCSK9 small interfering RNA (PCSK9i) also enhanced the efficacy of immune therapy targeted at the checkpoint protein PD-1 [123]. Additionally, PCSK9 inhibition has demonstrated the potential to induce cancer cell apoptosis through several pathways, increase the efficacy of a class of existing anticancer therapies, and boost the host immune response to cancer [124]. Hence, a novel application of PCSK9 inhibitors in cancer and metastasis could be considered. However, due to poor data on the effectiveness and safety of PCSK9 inhibitors in cancer, the impact of PCSK9 inhibition on these pathological conditions is still unknown [125].

3.3. Sterol Regulatory Element-Binding Proteins (SREBPs)

Sterol regulatory element-binding proteins (SREBPs) are transcription factors for cholesterol production and absorption, and they regulate one of the critical transcription pathways involved in cholesterol homeostasis [126]. Generally, SREBP-1 activates the synthesis of fatty acids and triglycerides, while SREBP-2 increases the synthesis of cholesterol [127]. Activation of SREBP transcription leads to the increased expression of microRNA-33, specifically miR-33a and miR-33b, which are located within intron 16 of SREBP-2 and intron 17 of SREBP-1, respectively [128]. The co-expression of the two miR-33 forms, along with their host genes, can function in a synergistic manner to further facilitate lipid homeostasis [129]. miRNAs are small non-coding RNAs that are key regulators of metabolism and play an important role in cancer by actually downregulating SREBPs in cancer cells [130][131].
The activation of SREBP-1 and -2 ultimately upregulates the expression of enzymes in lipogenesis pathways and the expression of LDLRs, promoting fatty acid and cholesterol synthesis, while LDLR upregulation increases cholesterol uptake [132]. SREBP-1 and -2 also regulate the expression of PCSK9 [133]. SREBP2 was identified as a potent activator of the NLRP3 inflammasome in ECs [134]. In support of the above finding, SREBPs may exacerbate the initiation and progression of atherosclerosis [135].

SREBPs in Human Cancers

SREBPs are significantly upregulated in human cancers and mediate a mechanistic link between lipid metabolism reprogramming and malignancy [136]. SREBPs are activated in a lipid-independent manner in cancer by the PI3K/Akt/mTOR/SREBP1 signaling pathway, which is often abnormally activated in tumor cells. Activation of the PI3K/Akt/mTOR signaling pathway induces the transcription of SREBPs, which subsequently promotes cholesterol uptake and synthesis to meet the demand of cancer cells [107]. Moreover, PI3K/Akt/mTOR/SREBP1 signaling protects cancer cells by inhibiting ferroptosis, an iron-dependent form of cell death caused by the accumulation of phospholipid peroxides [137]. SREBP1 inhibits ferroptosis in cancer cells by upregulating its transcriptional target SCD1 and producing monounsaturated fatty acids [138]. In situations in which lipids and/or oxygen is limited, SREBP2 and its downstream targets, including mevalonate-pathway enzymes, are significantly upregulated [139]. The upstream mevalonate pathway is oncogenic in a variety of cancers, mainly in brain tumors like glioblastoma, and requires the oncogene MYC for its upregulation [140][141]. This upregulation of the mevalonate pathway further upregulates the microRNA miR-33b; however, it is still not entirely clear whether the lipid accumulation induced by microRNAs through SREBPs has a direct link to the cancer cell phenotype [138]. Whereas oncogene activity promotes cholesterol upregulation, tumor suppressors have the opposite effect. For example, the well-known tumor suppressor p53 upregulates ABCA1, thereby restricting SREBP2 maturation and repressing the mevalonate pathway [142].

3.4. Other Lipogenic Factors in Atherosclerosis and Cancer

Specific components of the lipogenic machinery have been shown to play a pro-tumorigenic role in several cancers. These master transcriptional regulators governing cholesterol homeostasis and lipid metabolism are indispensable for tumor progression and include those discussed below.

3.4.1. Fatty Acid Synthase (FASN)

Fatty acid synthase (FASN) or fatty acid translocase or cluster of differentiation 36 (CD36) is a transmembrane glycoprotein that acts as a downstream molecular complex that facilitates intercellular cholesterol and free fatty acid (FFA) transport [143]. FASN is one of the key components that link lipid synthesis, oxidative stress, and ROS formation, as shown in p53-deficient colorectal cancer cells, where ROS-mediated FASN stabilization promotes lipid synthesis and tumor growth [144]. FASN also acts as a signal-transducing receptor for oxLDL [145]. Once FFAs are taken up into the cell, they can be stored in lipid droplets and used for fatty acid β-oxidation and energy production [145]. This may be regulated through the liver kinase B1/LKB1-AMPK pathway [143]. In addition to the exogenous uptake and release of FFAs, FASN could induce insulin resistance and β-cell dysfunction [146]. FASN, as a key downstream target of SREBP, brings fatty acids into cancer cells and is upregulated in breast, prostate, ovarian, stomach, and colorectal cancers and also in many other types of cancers [147].

3.4.2. Further FASN Role in Cancer

High CD36/FASN expression is associated with a poor prognosis in cancers, such as breast, ovarian, gastric, and prostate cancer [148]. Increased FASN expression correlates with established oncogenic events, like human epidermal growth factor receptor 1,2 (HER1/2) amplification in breast cancer, which in turn induces the expression of FASN via activation of PI3K/Akt pathways, resulting in positive feedback to maintain elevated levels of FASN in cancer cells [149]. FASN upregulation and overexpression in cancer cells lead to increased lipid synthesis, in addition to mTOR activation, resulting in increased protein synthesis. FASN also favors the activity of the PPP (pentose phosphate pathway) enzyme PGDH by increasing the pool of NADP+, a co-substrate of the latter. PPP upregulation concomitantly increases DNA/RNA synthesis [150]. The uptake of FFAs (such as oleate and palmitate) via FASN activates oncogenic signaling pathways in liver cancer cells, thereby promoting EMT [151]. FASN/CD36 can also activate the Wnt signaling pathway to promote metastasis through EMT [143].

3.4.3. Liver X Receptors/LXRs

Liver X receptors (LXRs) are transcription factors that belong to the nuclear hormone receptor family. They play a role in lipid metabolism regulation. They act as cholesterol and glucose sensors, ultimately promoting the loss of cellular cholesterol and regulating insulin sensitivity and whole-body homeostasis [152]. LXRs counterbalance the activity of SREBPs, which enhances lipid uptake and biogenesis to maintain cholesterol homeostasis, reversing cholesterol transport and limiting lipid uptake when cellular lipid stores are high [152]. LXRs are nuclear receptors that also modulate intracellular cholesterol levels by upregulating the transcription of efflux proteins such as ATP-binding cassette subfamily A member 1 (ABCA1) and ATP-binding cassette subfamily G member 1 (ABCG1), which are cell membrane proteins that allow cholesterol efflux from cells. ABCA1 is required for high-density lipoprotein (HDL) biogenesis, efflux of cholesterol from macrophages, and reverse transport of cholesterol to the liver [152]. Thus, LXR activity within lesions is atheroprotective [153][154]. Recent studies have demonstrated that TIGAR, which protects against glycolysis and oxidative stress, is associated with ASCVD by upregulating ABCA1 and ABCG1, also interfering with LXR expression via ROS [155]. The activation of LXRs also results in an increase in HIF-1a transcriptional activity [93].
In cancer, LXRs contribute to the development of glioblastoma, a highly lethal brain cancer, which significantly depends on cholesterol and is overly sensitive to LXR-agonist-induced cell death [156]. Also, upregulation of ABCA1 and ABCG1 by LXR agonists has induced apoptosis in prostate and breast cancer cell lines [157]. In tumor immunotherapy, LXR activation therapy produces a strong anti-tumor response in mice and enhances the activation of T cells in various immunotherapy studies, suggesting the LXR/ApoE axis as a target for improving the efficacy of tumor immunotherapy [158]. LXRs contribute to the development of colorectal cancer, along with the enzyme Stearoyl-CoA Desaturase 1 (SCD1), which is directly regulated by LXRs [159]. TIGAR inhibition repressed SCD1 expression in a redox- and AMPK-dependent manner, and TIGAR also induces ferroptosis resistance in colorectal cancer cells via the ROS/AMPK/SCD1 signaling pathway [160].

3.4.4. Stearoyl-CoA Desaturase (SCD)

Desaturation is indispensable in cancer to avoid lipotoxicity under conditions of nutrient stress [147]. Desaturases are controlled by SREBP [147] and by LXRs [159]. In particular, the Stearoyl-CoA desaturase-1 (SCD1) enzyme is a central regulator of lipid metabolism and fat storage. SCD1 catalyzes the generation of monounsaturated fatty acids (MUFAs), which are major components of triglycerides stored in lipid droplets, to form new saturated fatty acid (SFA) substrates—making it a key enzyme involved in finely tuning the MUFA-to-SFA ratio [161].
SCD1 plays an important role in cancer, promoting cell proliferation and metastasis [162]. Its inhibition reduces the MUFA/SFA ratio and contributes to the induction of ferroptosis in tumor cells [163]. Intriguingly, despite LXR agonists eliciting great interest as a promising therapeutic target for cancer, LXR’s ability to induce SCD1 and new fatty acid synthesis represents a major obstacle in the development of new effective treatments [159].

3.4.5. Acetyl-CoA Synthetase 2 (ACSS2)

The acetyl-CoA synthetase (ACSS) enzyme is the sole known mammalian enzyme that can catalyze the conversion of free acetate into acetyl coenzyme A (acetyl-CoA) for lipid synthesis. When cellular cholesterol levels fall below the threshold, proteases begin to act on SREBPs and promote the expression of genes related to cholesterol and fatty acid synthesis, like ACSS2 [164]. SREBP cooperates with the transcription factor LXR, accentuating the importance of ACSS2 in lipid synthesis [164].
More recently, ACSS2 was identified to facilitate the adaptation of cancer cells in the TME by promoting the acetylation of histones and transcription factors and therefore influencing metabolic reprogramming and cell cycle progression in tumors [34][165]. Of interest, to upregulate histone acetylation, ACSS2 forms a complex with TFEB [166]. In addition, studies on tumors have shown that, in cancer cells, ACSS2 interacts with oncoprotein interferon regulatory factor 4 (IRF4) and enhances IRF4 stability and IRF4-mediated gene transcription through the activation of acetylation [167]. Moreover, ACSS2 expression inversely correlates with overall survival in patients with triple-negative breast cancer, liver cancer, glioma, or lung cancer [34].

4. The Role of Adiposity in Cancer

Human adipose tissue plays functional roles related to triglyceride storage, as well complementary physiological roles in the endocrine system [168]. Adipocyte tissue and its microenvironment may play a role in carcinogenesis, the development of metastases, and the progression of the disease [169]. However, the underlying mechanism resulting in carcinogenesis is complex and not yet fully understood. The main components of the adipose organ include both white adipose tissue (WAT) and brown adipose tissue (BAT) [168][170].

4.1. White Adipose Tissue (WAT)

White adipose tissue (WAT) serves many physiological functions, including the storage of lipids for fatty acid supply in a state of energy deprivation, and is involved in a wide array of biological processes that modulate whole-body metabolism and insulin resistance [168]. It stores food calories, creates a layer of thermal insulation, and provides mechanical protection, which is important for resisting infection and injury [171]. Distributed throughout the body, WAT is found near various invasive solid cancers in humans, such as breast, prostate, colon, and kidney cancers and melanoma, and serves as a tremendous reservoir of lipids for cancer cells [170]. However, while the effect of WAT on cancer progression is established and a direct carcinogenic role for WAT cannot be ruled out, there is still a debate about whether WAT actually promotes cancer initiation and, if it does, what mechanisms are involved. A paradigm is that the inflammatory WAT milieu creates an environment in which ROS production is elevated to a level at which genomic instability ensues; however, the role of WAT-generated ROS in tumor initiation remains hypothetical [172]. An antioxidant capacity level that does not cause cell death (redox homeostasis) and mitochondrial function in WAT may be improved by chronic exercise [173]. At this point, there is a clear need to better understand the changes in WAT and the resulting changes in other organs, which underlie cancer progression in obesity, and to understand the role of the conversion of WAT into beige/brown adipose tissue (BAT) in the cancer process [174].

4.2. Brown Adipose Tissue (BAT)

Conversely, BAT is a tissue designed for maintaining body temperature at significantly higher levels than ambient temperatures through heat production, primarily via non-shivering thermogenesis [170]. Mediated by the expression of tissue-specific uncoupling protein 1 (UCP1) within the abundant mitochondria, which contributes to its brown appearance, BAT functions to facilitate adaptive thermogenesis, with the uncoupling of ATP production and substrate oxidation [175]. BAT is located in the deep neck region, along large blood vessels, and in the supraclavicular area, and it combusts through β-oxidation of triglyceride-derived fatty acids and glucose, consuming them to produce heat [170]. Naturally, the most potent activator of BAT is cold exposure, which increases sympathetic outflow toward beta-adrenergic receptors in BAT, as was shown by novel experimental evidence from mice, where the exposure of tumor-bearing mice to cold conditions markedly inhibited the growth of various types of solid tumors, including clinically untreatable cancers, such as pancreatic cancers [176]. Research into the bi-directional interactions between adipocytes and cancer cells suggests that adipocytes supply cancer cells with fatty acids for energy production, regardless of which adipose tissue depot they reside in, and cancer cells adapt to the adipose tissue microenvironment by upregulating lipid utilization machinery. However, the association of BAT activation with cancer progression that is evident in rodent models has not yet been tested for clinical relevance. Moreover, it does appear that adipocytes from obese individuals have a more robust tumor-promoting role [38]

4.3. Dysfunctional Adiposity and Cancer: The Role of LD Accumulation

Lipid droplets (LDs), also known as lipid bodies or liposomes, are cellular organelles originating from the endoplasmic reticulum, which supplies them with most of their constituent molecules and has a leading role in their biogenesis [177]. They are ubiquitous in cells but are constitutively expressed in fat-storing adipocytes, where they accumulate neutral lipids, including triacylglycerol (TAG) and cholesterol esters (CEs), including fatty acids [178]. LDs are coated with peripheral and integral proteins classified as members of the perilipin (PLIN)-ADRP-TIP47 family or the cell death-inducing DFF45-like effector (CIDE) family lipid metabolism enzymes involved in maintaining lipid homeostasis, such as diacylglycerol acyltransferases 1 and 2 (DGAT1 and DGAT2) [179]. Tyrosine kinase (TKR) ephrin receptor (EPHB2) directly regulates these key proteins involved in maintaining lipid homeostasis [180].
In cancer, LDs appear as metabolic determinants, and their accumulation is now recognized as a key feature of cancer cells. They function in multiple ways to promote cancer progression; however, the mechanisms controlling LD accumulation in cancer are mostly unknown. In particular, LDs release fatty acids to generate acyl-CoA and channel them to mitochondria to produce energy through fatty acid oxidation to boost cancer cell proliferation and metastasis. Moreover, acetyl-CoA can produce NADPH, which acts as a hydrogen donor to maintain redox homeostasis and prevent cell death induced by excessive ROS accumulation [181]. LDs play a vital role in ameliorating endoplasmic reticulum (ER) stress caused by abundant newly synthesized unfolded proteins (UPR) in cancer cells, and the mitochondrial UPR regulates many genes involved in protein folding, ROS defenses, metabolism, the assembly of iron–sulfur clusters, and the modulation of the innate immune response [177][178][182]. In this way, cancer cells employ lipid droplets to ensure redox balance, to initiate autophagy, and to recycle materials from destroyed organelles under metabolic stress, thereby minimizing stress and preventing apoptosis and ferroptosis caused by lipotoxicity and fostering tumor progression. As regulators of (poly)unsaturated fatty acid trafficking, lipid droplets are also emerging as modulators of lipid peroxidation and sensitivity to ferroptosis [183]. Interestingly, tumorigenicity, invasion, and metastasis, as well as chemoresistance, are controlled by a subpopulation of aggressive tumoral cells named cancer stem cells (CSCs), suggesting that LDs may be fundamental elements for stemness in cancer [184]. CSCs are highly tumorigenic and possess a self-renewal capacity and tumor-initiating properties. Among cancers in which lipid molecules are important for CSC tumorigenicity, glioblastoma is recognized as a malignant brain tumor with abundant LDs [184].

This entry is adapted from the peer-reviewed paper 10.3390/ijms241411786

References

  1. DiRenzo, D.; Owens, G.K.; Leeper, N.J. “Attack of the Clones”: Commonalities Between Cancer and Atherosclerosis. Circ. Res. 2017, 120, 624–626.
  2. Tapia-Vieyra, J.V.; Delgado-Coello, B.; Mas-Oliva, J. Atherosclerosis and Cancer; A Resemblance with Far-reaching Implications. Arch. Med. Res. 2017, 48, 12–26.
  3. Libby, P. The changing landscape of atherosclerosis. Nature 2021, 592, 524–533.
  4. Silveira Rossi, J.L.; Barbalho, S.M.; Reverete de Araujo, R.; Bechara, M.D.; Sloan, K.P.; Sloan, L.A. Metabolic syndrome and cardiovascular diseases: Going beyond traditional risk factors. Diabetes Metab. Res. Rev. 2022, 38, e3502.
  5. Iqbal, J.; Al Qarni, A.; Hawwari, A.; Alghanem, A.F.; Ahmed, G. Metabolic Syndrome, Dyslipidemia and Regulation of Lipoprotein Metabolism. Curr. Diabetes Rev. 2018, 14, 427–433.
  6. Lau, E.S.; Paniagua, S.M.; Liu, E.; Jovani, M.; Li, S.X.; Takvorian, K.; Suthahar, N.; Cheng, S.; Splansky, G.L.; Januzzi, J.L., Jr.; et al. Cardiovascular Risk Factors are Associated with Future Cancer. JACC CardioOncol. 2021, 3, 48–58.
  7. Duarte, C.W.; Lindner, V.; Francis, S.A.; Schoormans, D. Visualization of Cancer and Cardiovascular Disease Co-Occurrence With Network Methods. JCO Clin. Cancer Inform. 2017, 1, 1–12.
  8. Neshat, S.; Rezaei, A.; Farid, A.; Sarallah, R.; Javanshir, S.; Ahmadian, S.; Chatrnour, G.; Daneii, P.; Heshmat-Ghahdarijani, K. The tangled web of dyslipidemia and cancer: Is there any association? J. Res. Med. Sci. 2022, 27, 93.
  9. Esposito, K.; Chiodini, P.; Colao, A.; Lenzi, A.; Giugliano, D. Metabolic syndrome and risk of cancer: A systematic review and meta-analysis. Diabetes Care 2012, 35, 2402–2411.
  10. Zhong, L.; Liu, J.; Liu, S.; Tan, G. Correlation between pancreatic cancer and metabolic syndrome: A systematic review and meta-analysis. Front. Endocrinol. 2023, 14, 1116582.
  11. Zhou, Z.; Zhang, Y.; Li, Y.; Jiang, C.; Wu, Y.; Shang, L.; Huang, Y.; Cheng, S. Metabolic syndrome is a risk factor for breast cancer patients receiving neoadjuvant chemotherapy: A case-control study. Front. Oncol. 2023, 12, 1080054.
  12. Lu, B.; Qian, J.M.; Li, J.N. The metabolic syndrome and its components as prognostic factors in colorectal cancer: A meta-analysis and systematic review. J. Gastroenterol. Hepatol. 2023, 38, 187–196.
  13. Handy, C.E.; Quispe, R.; Pinto, X.; Blaha, M.J.; Blumenthal, R.S.; Michos, E.D.; Lima, J.A.C.; Guallar, E.; Ryu, S.; Cho, J.; et al. Synergistic Opportunities in the Interplay Between Cancer Screening and Cardiovascular Disease Risk Assessment: Together We Are Stronger. Circulation 2018, 138, 727–734.
  14. Lechner, K.; von Schacky, C.; McKenzie, A.L.; Worm, N.; Nixdorff, U.; Lechner, B.; Kränkel, N.; Halle, M.; Krauss, R.M.; Scherr, J.; et al. Lifestyle factors and high-risk atherosclerosis: Pathways and mechanisms beyond traditional risk factors. Eur. J. Prev. Cardiol. 2020, 27, 394–406.
  15. Debras, C.; Chazelas, E.; Srour, B.; Druesne-Pecollo, N.; Esseddik, Y.; Szabo de Edelenyi, F.; Agaësse, C.; De Sa, A.; Lutchia, R.; Gigandet, S.; et al. Artificial sweeteners and cancer risk: Results from the NutriNet-Santé population-based cohort study. PLoS Med. 2022, 19, e1003950.
  16. Bojková, B.; Winklewski, P.J.; Wszedybyl-Winklewska, M. Dietary Fat and Cancer-Which Is Good, Which Is Bad, and the Body of Evidence. Int. J. Mol. Sci. 2020, 21, 4114.
  17. Pfeffer, T.J.; Pietzsch, S.; Hilfiker-Kleiner, D. Common genetic predisposition for heart failure and cancer. Gemeinsame genetische Prädisposition für Herzinsuffizienz und Krebs. Herz 2020, 45, 632–636.
  18. Tsumita, T.; Maishi, N.; Annan, D.A.; Towfik, M.A.; Matsuda, A.; Onodera, Y.; Nam, J.M.; Hida, Y.; Hida, K. The oxidized-LDL/LOX-1 axis in tumor endothelial cells enhances metastasis by recruiting neutrophils and cancer cells. Int. J. Cancer 2022, 151, 944–956.
  19. Koene, R.J.; Prizment, A.E.; Blaes, A.; Konety, S.H. Shared Risk Factors in Cardiovascular Disease and Cancer. Circulation 2016, 133, 1104–1114.
  20. Alfaddagh, A.; Martin, S.S.; Leucker, T.M.; Michos, E.D.; Blaha, M.J.; Lowenstein, C.J.; Jones, S.R.; Toth, P.P. Inflammation and cardiovascular disease: From mechanisms to therapeutics. Am. J. Prev. Cardiol. 2020, 4, 100130.
  21. Kong, P.; Cui, Z.Y.; Huang, X.F.; Zhang, D.D.; Guo, R.J.; Han, M. Inflammation and atherosclerosis: Signaling pathways and therapeutic intervention. Signal. Transduct. Target. Ther. 2022, 7, 131.
  22. Hanahan, D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022, 12, 31–46.
  23. Gimbrone, M.A., Jr.; García-Cardeña, G. Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis. Cardiovasc. Pathol. 2013, 22, 9–15.
  24. Libby, P.; Buring, J.E.; Badimon, L.; Hansson, G.K.; Deanfield, J.; Bittencourt, M.S.; Tokgözoğlu, L.; Lewis, E.F. Atherosclerosis. Nat. Rev. Dis. Primers. 2019, 5, 56.
  25. Camaré, C.; Pucelle, M.; Nègre-Salvayre, A.; Salvayre, R. Angiogenesis in the atherosclerotic plaque. Redox Biol. 2017, 12, 18–34.
  26. Soehnlein, O.; Libby, P. Targeting inflammation in atherosclerosis—From experimental insights to the clinic. Nat. Rev. Drug Discov. 2021, 20, 589–610.
  27. Fan, X.; Li, Q.; Wang, Y.; Zhang, D.M.; Zhou, J.; Chen, Q.; Sheng, L.; Passerini, A.G.; Sun, C. Non-canonical NF-κB contributes to endothelial pyroptosis and atherogenesis dependent on IRF-1. Transl. Res. 2023, 255, 1–13.
  28. Fiordelisi, A.; Iaccarino, G.; Morisco, C.; Coscioni, E.; Sorriento, D. NFkappaB is a Key Player in the Crosstalk between Inflammation and Cardiovascular Diseases. Int. J. Mol. Sci. 2019, 20, 1599.
  29. McAllister, S.S.; Weinberg, R.A. Tumor-host interactions: A far-reaching relationship. J. Clin. Oncol. 2010, 28, 4022–4028.
  30. Greten, F.R.; Grivennikov, S.I. Inflammation and Cancer: Triggers, Mechanisms, and Consequences. Immunity 2019, 51, 27–41.
  31. Zhao, H.; Wu, L.; Yan, G.; Chen, Y.; Zhou, M.; Wu, Y.; Li, Y. Inflammation and tumor progression: Signaling pathways and targeted intervention. Signal Transduct. Target. Ther. 2021, 6, 263.
  32. Lacroix, M.; Riscal, R.; Arena, G.; Linares, L.K.; Le Cam, L. Metabolic functions of the tumor suppressor p53: Implications in normal physiology, metabolic disorders, and cancer. Mol. Metab. 2020, 33, 2–22.
  33. Yu, H.; Lin, L.; Zhang, Z.; Zhang, H.; Hu, H. Targeting NF-κB pathway for the therapy of diseases: Mechanism and clinical study. Signal Transduct. Target. Ther. 2020, 5, 209.
  34. Cheng, C.; Geng, F.; Cheng, X.; Guo, D. Lipid metabolism reprogramming and its potential targets in cancer. Cancer Commun. 2018, 38, 27.
  35. Weinberg, F.; Ramnath, N.; Nagrath, D. Reactive Oxygen Species in the Tumor Microenvironment: An Overview. Cancers 2019, 11, 1191.
  36. Jászai, J.; Schmidt, M.H.H. Trends and Challenges in Tumor Anti-Angiogenic Therapies. Cells 2019, 8, 1102.
  37. Bui, B.P.; Nguyen, P.L.; Lee, K.; Cho, J. Hypoxia-Inducible Factor-1: A Novel Therapeutic Target for the Management of Cancer, Drug Resistance, and Cancer-Related Pain. Cancers 2022, 14, 6054.
  38. Mukherjee, A.; Bilecz, A.J.; Lengyel, E. The adipocyte microenvironment and cancer. Cancer Metastasis Rev. 2022, 41, 575–587.
  39. Geltinger, F.; Schartel, L.; Wiederstein, M.; Tevini, J.; Aigner, E.; Felder, T.K.; Rinnerthaler, M. Friend or Foe: Lipid Droplets as Organelles for Protein and Lipid Storage in Cellular Stress Response, Aging and Disease. Molecules 2020, 25, 5053.
  40. Moukarzel, L.A.; Ferrando, L.; Stylianou, A.; Lobaugh, S.; Wu, M.; Nobre, S.P.; Iasonos, A.; Zoppoli, G.; Giri, D.D.; Abu-Rustum, N.R.; et al. Impact of obesity and white adipose tissue inflammation on the omental microenvironment in endometrial cancer. Cancer 2022, 128, 3297–3309.
  41. Wu, X.; Geng, F.; Cheng, X.; Guo, Q.; Zhong, Y.; Cloughesy, T.F.; Yong, W.H.; Chakravarti, A.; Guo, D. Lipid Droplets Maintain Energy Homeostasis and Glioblastoma Growth via Autophagic Release of Stored Fatty Acids. iScience 2020, 23, 101569.
  42. Carmeliet, P. Mechanisms of angiogenesis and arteriogenesis. Nat. Med. 2000, 6, 389–395.
  43. Filippini, A.; Tamagnone, L.; D’Alessio, A. Endothelial Cell Metabolism in Vascular Functions. Cancers 2022, 14, 1929.
  44. Teleanu, R.I.; Chircov, C.; Grumezescu, A.M.; Teleanu, D.M. Tumor Angiogenesis and Anti-Angiogenic Strategies for Cancer Treatment. J. Clin. Med. 2019, 9, 84.
  45. Liao, D.; Johnson, R.S. Hypoxia: A key regulator of angiogenesis in cancer. Cancer Metastasis Rev. 2007, 26, 281–290.
  46. Marmé, D. Tumor Angiogenesis: A Key Target for Cancer Therapy. Oncol. Res. Treat. 2018, 41, 164.
  47. Ricciuti, B.; Foglietta, J.; Bianconi, V.; Sahebkar, A.; Pirro, M. Enzymes involved in tumor-driven angiogenesis: A valuable target for anticancer therapy. Semin. Cancer Biol. 2019, 56, 87–99.
  48. Mukwaya, A.; Jensen, L.; Lagali, N. Relapse of pathological angiogenesis: Functional role of the basement membrane and potential treatment strategies. Exp. Mol. Med. 2021, 53, 189–201.
  49. Qi, S.; Deng, S.; Lian, Z.; Yu, K. Novel Drugs with High Efficacy against Tumor Angiogenesis. Int. J. Mol. Sci. 2022, 23, 6934.
  50. Carmeliet, P. VEGF as a key mediator of angiogenesis in cancer. Oncology 2005, 69, 4–10.
  51. Goel, H.L.; Mercurio, A.M. VEGF targets the tumour cell. Nat. Rev. Cancer 2013, 13, 871–882.
  52. Zalpoor, H.; Aziziyan, F.; Liaghat, M.; Bakhtiyari, M.; Akbari, A.; Nabi-Afjadi, M.; Forghaniesfidvajani, R.; Rezaei, N. The roles of metabolic profiles and intracellular signaling pathways of tumor microenvironment cells in angiogenesis of solid tumors. Cell Commun. Signal. 2022, 20, 186.
  53. Hoeben, A.; Landuyt, B.; Highley, M.S.; Wildiers, H.; Van Oosterom, A.T.; De Bruijn, E.A. Vascular endothelial growth factor and angiogenesis. Pharmacol. Rev. 2004, 56, 549–580.
  54. Zhou, B.; Lin, W.; Long, Y.; Yang, Y.; Zhang, H.; Wu, K.; Chu, Q. Notch signaling pathway: Architecture, disease, and therapeutics. Signal Transduct Target Ther. 2022, 7, 95.
  55. Doronzo, G.; Astanina, E.; Bussolino, F. The Oncogene Transcription Factor EB Regulates Vascular Functions. Front. Physiol. 2021, 12, 640061.
  56. Ariano, C.; Riganti, C.; Corà, D.; Valdembri, D.; Mana, G.; Astanina, E.; Serini, G.; Bussolino, F.; Doronzo, G. TFEB controls integrin-mediated endothelial cell adhesion by the regulation of cholesterol metabolism. Angiogenesis 2022, 25, 471–492.
  57. Plein, A.; Fantin, A.; Ruhrberg, C. Neuropilin regulation of angiogenesis, arteriogenesis, and vascular permeability. Microcirculation 2014, 21, 315–323.
  58. Dabravolski, S.A.; Khotina, V.A.; Omelchenko, A.V.; Kalmykov, V.A.; Orekhov, A.N. The Role of the VEGF Family in Atherosclerosis Development and Its Potential as Treatment Targets. Int. J. Mol. Sci. 2022, 23, 931.
  59. Kafyra, M.; Kalafati, I.P.; Gavra, I.; Siest, S.; Dedoussis, G.V. Associations of VEGF-A-Related Variants with Adolescent Cardiometabolic and Dietary Parameters. Nutrients 2023, 15, 1884.
  60. Hokkanen, K.; Tirronen, A.; Ylä-Herttuala, S. Intestinal lymphatic vessels and their role in chylomicron absorption and lipid homeostasis. Curr. Opin. Lipidol. 2019, 30, 370–376.
  61. Zhou, Y.; Zhu, X.; Wang, H.; Duan, C.; Cui, H.; Shi, J.; Shi, S.; Yuan, G.; Hu, Y. The Role of VEGF Family in Lipid Metabolism. Curr. Pharm. Biotechnol. 2023, 24, 253–265.
  62. Hagberg, C.E.; Falkevall, A.; Wang, X.; Larsson, E.; Huusko, J.; Nilsson, I.; van Meeteren, L.A.; Samen, E.; Lu, L.; Vanwildemeersch, M. Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 2010, 464, 917–921.
  63. Moessinger, C.; Nilsson, I.; Muhl, L.; Zeitelhofer, M.; Heller Sahlgren, B.; Skogsberg, J.; Eriksson, U. VEGF-B signaling impairs endothelial glucose transcytosis by decreasing membrane cholesterol content. EMBO Rep. 2020, 21, e49343.
  64. Apte, R.S.; Chen, D.S.; Ferrara, N. VEGF in Signaling and Disease: Beyond Discovery and Development. Cell 2019, 176, 1248–1264.
  65. Kamal, M.A.; Akhtar, S. Tumor Angiogenesis and VEGFR-2: Mechanism, Pathways and Current Biological Therapeutic Interventions. Curr. Drug Metab. 2021, 22, 50–59.
  66. Patel, S.A.; Nilsson, M.B.; Le, X.; Cascone, T.; Jain, R.K.; Heymach, J.V. Molecular Mechanisms and Future Implications of VEGF/VEGFR in Cancer Therapy. Clin. Cancer Res. 2023, 29, 30–39.
  67. Tsakogiannis, D.; Nikolakopoulou, A.; Zagouri, F.; Stratakos, G.; Syrigos, K.; Zografos, E.; Koulouris, N.; Bletsa, G. Update Overview of the Role of Angiopoietins in Lung Cancer. Medicina 2021, 57, 1191.
  68. Saharinen, P.; Eklund, L.; Alitalo, K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat. Rev. Drug Discov. 2017, 16, 635–661.
  69. Solimando, A.G.; Summa, S.; Vacca, A.; Ribatti, D. Cancer-Associated Angiogenesis: The Endothelial Cell as a Checkpoint for Immunological Patrolling. Cancers 2020, 12, 3380.
  70. Ricard, N.; Bailly, S.; Guignabert, C.; Simons, M. The quiescent endothelium: Signalling pathways regulating organ-specific endothelial normalcy. Nat. Rev. Cardiol. 2021, 18, 565–580.
  71. Ahmed, A.; Fujisawa, T. Multiple roles of angiopoietins in atherogenesis. Curr. Opin. Lipidol. 2011, 22, 380–385.
  72. Theelen, T.L.; Lappalainen, J.P.; Sluimer, J.C.; Gurzeler, E.; Cleutjens, J.P.; Gijbels, M.J.; Biessen, E.A.; Daemen, M.J.; Alitalo, K.; Ylä-Herttuala, S. Angiopoietin-2 blocking antibodies reduce early atherosclerotic plaque development in mice. Atherosclerosis 2015, 241, 297–304.
  73. de Vries, M.R.; Parma, L.; Peters, H.A.B.; Schepers, A.; Hamming, J.F.; Jukema, J.W.; Goumans, M.J.T.H.; Guo, L.; Finn, A.V.; Virmani, R.; et al. Blockade of vascular endothelial growth factor receptor 2 inhibits intraplaque haemorrhage by normalization of plaque neovessels. J. Intern. Med. 2019, 285, 59–74.
  74. Cho, D.I.; Ahn, M.J.; Cho, H.H.; Cho, M.; Jun, J.H.; Kang, B.G.; Lim, S.Y.; Yoo, S.J.; Kim, M.R.; Kim, H.S.; et al. ANGPTL4 stabilizes atherosclerotic plaques and modulates the phenotypic transition of vascular smooth muscle cells through KLF4 downregulation. Exp. Mol. Med. 2023, 55, 426–442.
  75. Aryal, B.; Singh, A.K.; Zhang, X.; Varela, L.; Rotllan, N.; Goedeke, L.; Chaube, B.; Camporez, J.P.; Vatner, D.F.; Horvath, T.L.; et al. Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis. JCI Insight 2018, 3, e97918.
  76. Dong, Z.; Chen, J.; Yang, X.; Zheng, W.; Wang, L.; Fang, M.; Wu, M.; Yao, M.; Yao, D. Ang-2 promotes lung cancer metastasis by increasing epithelial-mesenchymal transition. Oncotarget 2018, 9, 12705–12717.
  77. Mizuno, S.; Seishima, R.; Yamasaki, J.; Hattori, K.; Ogiri, M.; Matsui, S.; Shigeta, K.; Okabayashi, K.; Nagano, O.; Li, L.; et al. Angiopoietin-like 4 promotes glucose metabolism by regulating glucose transporter expression in colorectal cancer. J. Cancer Res. Clin. Oncol. 2022, 148, 1351–1361.
  78. Jaramillo, M.C.; Zhang, D.D. The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev. 2013, 27, 2179–2191.
  79. Pouremamali, F.; Pouremamali, A.; Dadashpour, M.; Soozangar, N.; Jeddi, F. An update of Nrf2 activators and inhibitors in cancer prevention/promotion. Cell Commun. Signal. 2022, 20, 100.
  80. Kishimoto, Y.; Kondo, K.; Momiyama, Y. The Protective Role of Heme Oxygenase-1 in Atherosclerotic Diseases. Int. J. Mol. Sci. 2019, 20, 3628.
  81. Occhiuto, C.J.; Moerland, J.A.; Leal, A.S.; Gallo, K.A.; Liby, K.T. The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis. Mol. Cells 2023, 46, 176–186.
  82. Martínez-Reyes, I.; Chandel, N.S. Cancer metabolism: Looking forward. Nat. Rev. Cancer 2021, 21, 669–680.
  83. Mitsuishi, Y.; Taguchi, K.; Kawatani, Y.; Shibata, T.; Nukiwa, T.; Aburatani, H.; Yamamoto, M.; Motohashi, H. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012, 22, 66–79.
  84. Fendt, S.M.; Frezza, C.; Erez, A. Targeting Metabolic Plasticity and Flexibility Dynamics for Cancer Therapy. Cancer Discov. 2020, 10, 1797–1807.
  85. DeNicola, G.M.; Karreth, F.A.; Humpton, T.J.; Gopinathan, A.; Wei, C.; Frese, K.; Mangal, D.; Yu, K.H.; Yeo, C.J.; Calhoun, E.S.; et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 2011, 475, 106–109.
  86. Sayin, V.I.; LeBoeuf, S.E.; Papagiannakopoulos, T. Targeting Metabolic Bottlenecks in Lung Cancer. Trends Cancer 2019, 5, 457–459.
  87. Panieri, E.; Buha, A.; Telkoparan-Akillilar, P.; Cevik, D.; Kouretas, D.; Veskoukis, A.; Skaperda, Z.; Tsatsakis, A.; Wallace, D.; Suzen, S.; et al. Potential Applications of NRF2 Modulators in Cancer Therapy. Antioxidants 2020, 9, 193.
  88. Wardyn, J.D.; Ponsford, A.H.; Sanderson, C.M. Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways. Biochem. Soc. Trans. 2015, 43, 621–626.
  89. Loboda, A.; Damulewicz, M.; Pyza, E.; Jozkowicz, A.; Dulak, J. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: An evolutionarily conserved mechanism. Cell. Mol. Life Sci. 2016, 73, 3221–3247.
  90. Chiang, S.K.; Chen, S.E.; Chang, L.C. The Role of HO-1 and Its Crosstalk with Oxidative Stress in Cancer Cell Survival. Cells 2021, 10, 2401.
  91. Pezzuto, A.; Carico, E. Role of HIF-1 in Cancer Progression: Novel Insights. A Review. Curr. Mol. Med. 2018, 18, 343–351.
  92. Acker, T.; Plate, K.H. Role of hypoxia in tumor angiogenesis-molecular and cellular angiogenic crosstalk. Cell Tissue Res. 2003, 314, 145–155.
  93. Thomas, C.; Leleu, D.; Masson, D. Cholesterol and HIF-1α: Dangerous Liaisons in Atherosclerosis. Front. Immunol. 2022, 13, 868958.
  94. Jain, T.; Nikolopoulou, E.A.; Xu, Q.; Qu, A. Hypoxia inducible factor as a therapeutic target for atherosclerosis. Pharmacol. Ther. 2018, 183, 22–33.
  95. Lv, X.; Li, J.; Zhang, C.; Hu, T.; Li, S.; He, S.; Yan, H.; Tan, Y.; Lei, M.; Wen, M.; et al. The role of hypoxia-inducible factors in tumor angiogenesis and cell metabolism. Genes Dis. 2016, 4, 19–24.
  96. Gonzalez-Perez, R.R.; Xu, Y.; Guo, S.; Watters, A.; Zhou, W.; Leibovich, S.J. Leptin upregulates VEGF in breast cancer via canonic and non-canonical signalling pathways and NFkappaB/HIF-1alpha activation. Cell. Signal. 2010, 22, 1350–1362.
  97. Erkasap, N.; Ozyurt, R.; Ozkurt, M.; Erkasap, S.; Yasar, F.; Ihtiyar, E.; Ciftci, E.; Canaz, F.; Colak, E. Role of Notch, IL-1 and leptin expression in colorectal cancer. Exp. Ther. Med. 2021, 21, 600.
  98. Hoxhaj, G.; Manning, B.D. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat. Rev. Cancer 2020, 20, 74–88.
  99. Su, X.; Yang, Y.; Guo, C.; Zhang, R.; Sun, S.; Wang, Y.; Qiao, Q.; Fu, Y.; Pang, Q. NOX4-derived ROS mediates TGF-beta1-induced metabolic reprogramming during epithelial-Mesenchymal transition through the PI3K/AKT/HIF-1alpha pathway in Glioblastoma. Oxidative Med. Cell. Longev. 2021, 2021, 5549047.
  100. Yeh, Y.H.; Hsiao, H.F.; Yeh, Y.C.; Chen, T.W.; Li, T.K. Infammatory interferon activates HIF-1alpha-mediated epithelial-to-mesenchymal transition via PI3K/AKT/mTOR pathway. J. Exp. Clin. Cancer Res. 2018, 37, 70.
  101. Dong, S.; Liang, S.; Cheng, Z.; Zhang, X.; Luo, L.; Li, L.; Zhang, W.; Li, S.; Xu, Q.; Zhong, M.; et al. ROS/PI3K/Akt and Wnt/β-catenin signalings activate HIF-1α-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer. J. Exp. Clin. Cancer Res. 2022, 41, 15.
  102. Nagao, A.; Kobayashi, M.; Koyasu, S.; Chow, C.C.T.; Harada, H. HIF-1-Dependent Reprogramming of Glucose Metabolic Pathway of Cancer Cells and Its Therapeutic Significance. Int. J. Mol. Sci. 2019, 20, 238.
  103. Bitorina, A.V.; Oligschlaeger, Y.; Shiri-Sverdlov, R.; Theys, J. Low profile high value target: The role of OxLDL in cancer. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2019, 1864, 158518.
  104. Zhang, Z.; Hu, Y.; Chen, Y.; Chen, Z.; Zhu, Y.; Chen, M.; Xia, J.; Sun, Y.; Xu, W. Immunometabolism in the tumor microenvironment and its related research progress. Front. Oncol. 2022, 12, 1024789.
  105. Huang, B.; Song, B.L.; Xu, C. Cholesterol metabolism in cancer: Mechanisms and therapeutic opportunities. Nat. Metab. 2020, 2, 132–141.
  106. Wang, D.; Yang, Y.; Lei, Y.; Tzvetkov, N.T.; Liu, X.; Yeung, A.W.K.; Xu, S.; Atanasov, A.G. Targeting Foam Cell Formation in Atherosclerosis: Therapeutic Potential of Natural Products. Pharmacol. Rev. 2019, 71, 596–670.
  107. Deng, C.F.; Zhu, N.; Zhao, T.J.; Li, H.F.; Gu, J.; Liao, D.F.; Qin, L. Involvement of LDL and ox-LDL in Cancer Development and Its Therapeutical Potential. Front. Oncol. 2022, 12, 803473.
  108. Gao, T.; Yang, X.; Fujisawa, M.; Ohara, T.; Wang, T.; Tomonobu, N.; Sakaguchi, M.; Yoshimura, T.; Matsukawa, A. SPRED2: A Novel Regulator of Epithelial-Mesenchymal Transition and Stemness in Hepatocellular Carcinoma Cells. Int. J. Mol. Sci. 2023, 24, 4996.
  109. Wang, H.; Liu, S.; Kong, F.; Xiao, F.; Li, Y.; Wang, H.; Zhang, S.; Huang, D.; Wang, L.; Yang, Y. Spred2 inhibits epithelial-mesenchymal transition of colorectal cancer cells by impairing ERK signaling. Oncol. Rep. 2020, 44, 174–184.
  110. Xu, S.; Ilyas, I.; Little, P.J.; Li, H.; Kamato, D.; Zheng, X.; Luo, S.; Li, Z.; Liu, P.; Han, J.; et al. Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies. Pharmacol. Rev. 2021, 73, 924–967.
  111. Yin, S.; Yang, S.; Pan, X.; Ma, A.; Ma, J.; Pei, H.; Dong, Y.; Li, S.; Li, W.; Bi, X. MicroRNA-155 promotes ox-LDL-induced autophagy in human umbilical vein endothelial cells by targeting the PI3K/Akt/mTOR pathway. Mol. Med. Rep. 2018, 18, 2798–2806.
  112. Zabirnyk, O.; Liu, W.; Khalil, S.; Sharma, A.; Phang, J.M. Oxidized Low-Density Lipoproteins Upregulate Proline Oxidase to Initiate ROS-Dependent Autophagy. Carcinogenesis 2010, 31, 446–454.
  113. Duprat, F.; Robles, C.; Castillo, M.P.; Rivas, Y.; Mondaca, M.; Jara, N.; Roa, F.; Bertinat, R.; Toledo, J.; Paz, C.; et al. LOX-1 Activation by oxLDL Induces AR and AR-V7 Expression via NF-κB and STAT3 Signaling Pathways Reducing Enzalutamide Cytotoxic Effects. Int. J. Mol. Sci. 2023, 24, 5082.
  114. Akhmedov, A.; Sawamura, T.; Chen, C.H.; Kraler, S.; Vdovenko, D.; Lüscher, T.F. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): A crucial driver of atherosclerotic cardiovascular disease. Eur. Heart J. 2021, 42, 1797–1807.
  115. Murdocca, M.; De Masi, C.; Pucci, S.; Mango, R.; Novelli, G.; Di Natale, C.; Sangiuolo, F. LOX-1 and cancer: An indissoluble liaison. Cancer Gene Ther. 2021, 28, 1088–1098.
  116. Balzan, S.; Lubrano, V. LOX-1 receptor: A potential link in atherosclerosis and cancer. Life Sci. 2018, 198, 79–86.
  117. Momtazi-Borojeni, A.A.; Sabouri-Rad, S.; Gotto, A.M.; Pirro, M.; Banach, M.; Awan, Z.; Barreto, G.E.; Sahebkar, A. PCSK9 and inflammation: A review of experimental and clinical evidence. Eur. Heart J. Cardiovasc. Pharmacother. 2019, 5, 237–245.
  118. Farnier, M. PCSK9: From discovery to therapeutic applications. Arch. Cardiovasc. Dis. 2014, 107, 58–66.
  119. Seidah, N.G.; Garçon, D. Expanding Biology of PCSK9: Roles in Atherosclerosis and Beyond. Curr. Atheroscler. Rep. 2022, 24, 821–830.
  120. Tang, Z.H.; Peng, J.; Ren, Z.; Yang, J.; Li, T.T.; Li, T.H.; Wang, Z.; Wei, D.H.; Liu, L.S.; Zheng, X.L.; et al. New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-κB pathway. Atherosclerosis 2017, 262, 113–122.
  121. Scalise, V.; Sanguinetti, C.; Neri, T.; Cianchetti, S.; Lai, M.; Carnicelli, V.; Celi, A.; Pedrinelli, R. PCSK9 Induces Tissue Factor Expression by Activation of TLR4/NFkB Signaling. Int. J. Mol. Sci. 2021, 22, 12640.
  122. Alannan, M.; Seidah, N.G.; Merched, A.J. PCSK9 in Liver Cancers at the Crossroads between Lipid Metabolism and Immunity. Cells 2022, 11, 4132.
  123. Liu, X.; Bao, X.; Hu, M.; Chang, H.; Jiao, M.; Cheng, J.; Xie, L.; Huang, Q.; Li, F.; Li, C.Y. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. Nature 2020, 588, 693–698.
  124. Oza, P.P.; Kashfi, K. The evolving landscape of PCSK9 inhibition in cancer. Eur. J. Pharmacol. 2023, 949, 175721.
  125. Mahboobnia, K.; Pirro, M.; Marini, E.; Grignani, F.; Bezsonov, E.E.; Jamialahmadi, T.; Sahebkar, A. PCSK9 and cancer: Rethinking the link. Biomed. Pharmacother. 2021, 140, 111758.
  126. De Bose-Boyd, R.A.; Ye, J. SREBPs in Lipid Metabolism, Insulin Signaling, and Beyond. Trends Biochem. Sci. 2018, 43, 358–368.
  127. Goldstein, J.L.; De Bose-Boyd, R.A.; Brown, M.S. Protein sensors for membrane sterols. Cell 2006, 124, 35–46.
  128. Najafi-Shoushtari, S.H.; Kristo, F.; Li, Y.; Shioda, T.; Cohen, D.E.; Gerszten, R.E.; Näär, A.M. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 2010, 328, 1566–1599.
  129. Moore, K.J.; Rayner, K.J.; Suarez, Y.; Fernandez-Hernando, C. The role of microRNAs in cholesterol efflux and hepatic lipid metabolism. Annu. Rev. Nutr. 2011, 31, 49–63.
  130. Fernández-Hernando, C.; Suárez, Y.; Rayner, K.J.; Moore, K.J. MicroRNAs in lipid metabolism. Curr. Opin. Lipidol. 2011, 22, 86–92.
  131. Budakoti, M.; Panwar, A.S.; Molpa, D.; Singh, R.K.; Büsselberg, D.; Mishra, A.P.; Coutinho, H.D.M.; Nigam, M. Micro-RNA: The darkhorse of cancer. Cell. Signal. 2021, 83, 109995.
  132. Xu, H.; Zhou, S.; Tang, Q.; Xia, H.; Bi, F. Cholesterol metabolism: New functions and therapeutic approaches in cancer. Biochim. Biophys. Acta Rev. Cancer 2020, 1874, 188394.
  133. Seidah, N.G.; Prat, A. The Multifaceted Biology of PCSK9. Endocr. Rev. 2022, 43, 558–582.
  134. Chen, Z.; Martin, M.; Li, Z.; Shyy, J.Y. Endothelial dysfunction: The role of sterol regulatory element-binding protein-induced NOD-like receptor family pyrin domain-containing protein 3 inflammasome in atherosclerosis. Curr. Opin. Lipidol. 2014, 25, 339–349.
  135. Peng, C.; Lei, P.; Li, X.; Xie, H.; Yang, X.; Zhang, T.; Cao, Z.; Zhang, J. Down-regulated of SREBP-1 in circulating leukocyte is a risk factor for atherosclerosis: A case control study. Lipids Health Dis. 2019, 18, 177.
  136. Li, Y.; Wu, S.; Zhao, X.; Hao, S.; Li, F.; Wang, Y.; Liu, B.; Zhang, D.; Wang, Y.; Zhou, H. Key events in cancer: Dysregulation of SREBPs. Front. Pharmacol. 2023, 14, 1130747.
  137. Chen, X.; Kang, R.; Kroemer, G.; Tang, D. Broadening horizons: The role of ferroptosis in cancer. Nat. Rev. Clin. Oncol. 2021, 18, 280–296.
  138. Yi, J.; Zhu, J.; Wu, J.; Thompson, C.B.; Jiang, X. Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis. Proc. Natl. Acad. Sci. USA 2020, 117, 31189–31197.
  139. Lewis, C.A.; Brault, C.; Peck, B.; Bensaad, K.; Griffiths, B.; Mitter, R.; Chakravarty, P.; East, P.; Dankworth, B.; Alibhai, D.; et al. SREBP maintains lipid biosynthesis and viability of cancer cells under lipid- and oxygen-deprived conditions and defines a gene signature associated with poor survival in glioblastoma multiforme. Oncogene 2015, 34, 5128–5140.
  140. Mullen, P.J.; Yu, R.; Longo, J.; Archer, M.C.; Penn, L.Z. The interplay between cell signalling and the mevalonate pathway in cancer. Nat. Rev. Cancer 2016, 16, 718–731.
  141. Wang, X.; Huang, Z.; Wu, Q.; Prager, B.C.; Mack, S.C.; Yang, K.; Kim, L.J.Y.; Gimple, R.C.; Shi, Y.; Lai, S.; et al. MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor-Initiating Cells. Cancer Res. 2017, 77, 4947–4960.
  142. Moon, S.H.; Huang, C.H.; Houlihan, S.L.; Regunath, K.; Freed-Pastor, W.A.; Morris, J.P., 4th; Tschaharganeh, D.F.; Kastenhuber, E.R.; Barsotti, A.M.; Culp-Hill, R.; et al. p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression. Cell 2019, 176, 564–580.e19.
  143. Wang, J.; Li, Y. CD36 tango in cancer: Signaling pathways and functions. Theranostics 2019, 9, 4893–4908.
  144. Han, Z.; Liu, M.; Xie, Y.; Zeng, K.; Zhan, Z.; Chen, Y.; Wang, L.; Chen, X.; Luo, Y.; Zeng, Y.; et al. Derepression of the USP22-FASN axis by p53 loss under oxidative stress drives lipogenesis and tumorigenesis. Cell Death Discov. 2022, 8, 445.
  145. Sazaki, I.; Sakurai, T.; Yamahata, A.; Mogi, S.; Inoue, N.; Ishida, K.; Kikkai, A.; Takeshita, H.; Sakurai, A.; Takahashi, Y.; et al. Oxidized Low-Density Lipoproteins Trigger Hepatocellular Oxidative Stress with the Formation of Cholesteryl Ester Hydroperoxide-Enriched Lipid Droplets. Int. J. Mol. Sci. 2023, 24, 4281.
  146. Menendez, J.A.; Vazquez-Martin, A.; Ortega, F.J.; Fernandez-Real, J.M. Fatty acid synthase: Association with insulin resistance, type 2 diabetes, and cancer. Clin. Chem. 2009, 55, 425–438.
  147. Peck, B.; Schulze, A. Lipid Metabolism at the Nexus of Diet and Tumor Microenvironment. Trends Cancer 2019, 5, 693–703.
  148. Chae, H.S.; Hong, S.T. Overview of Cancer Metabolism and Signaling Transduction. Int. J. Mol. Sci. 2022, 24, 12.
  149. Vazquez-Martin, A.; Colomer, R.; Brunet, J.; Lupu, R.; Menendez, J.A. Overexpression of fatty acid synthase gene activates HER1/HER2 tyrosine kinase receptors in human breast epithelial cells. Cell Prolif. 2008, 41, 59–85.
  150. Vanauberg, D.; Schulz, C.; Lefebvre, T. Involvement of the pro-oncogenic enzyme fatty acid synthase in the hallmarks of cancer: A promising target in anti-cancer therapies. Oncogenesis 2023, 12, 16.
  151. Nath, A.; Li, I.; Roberts, L.R.; Chan, C. Elevated free fatty acid uptake via CD36 promotes epithelial—Mesenchymal transition in hepatocellular carcinoma. Sci. Rep. 2015, 5, 14752.
  152. Bilotta, M.T.; Petillo, S.; Santoni, A.; Cippitelli, M. Liver X Receptors: Regulators of Cholesterol Metabolism, Inflammation, Autoimmunity, and Cancer. Front. Immunol. 2020, 11, 584303.
  153. Lee, S.D.; Tontonoz, P. Liver X receptors at the intersection of lipid metabolism and atherogenesis. Atherosclerosis 2015, 242, 29–36.
  154. Wang, S.; Smith, J.D. ABCA1 and nascent HDL biogenesis. Biofactors 2014, 40, 547–554.
  155. Zhao, Z.W.; Zhang, M.; Zou, J.; Wan, X.J.; Zhou, L.; Wu, Y.; Liu, S.M.; Liao, L.X.; Li, H.; Qin, Y.S. TIGAR mitigates atherosclerosis by promoting cholesterol efflux from macrophages. Atherosclerosis 2021, 327, 76–86.
  156. Pirmoradi, L.; Seyfizadeh, N.; Ghavami, S.; Zeki, A.A.; Shojaei, S. Targeting cholesterol metabolism in glioblastoma: A new therapeutic approach in cancer therapy. J. Investig. Med. 2019, 67, 715–719.
  157. Lin, C.Y.; Gustafsson, J.Å. Targeting liver X receptors in cancer therapeutics. Nat. Rev. Cancer 2015, 15, 216–224.
  158. Tavazoie, M.F.; Pollack, I.; Tanqueco, R.; Ostendorf, B.N.; Reis, B.S.; Gonsalves, F.C.; Kurth, I.; Andreu-Agullo, C.; Derbyshire, M.L.; Posada, J.; et al. LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer. Cell 2018, 172, 825–840.e18.
  159. Piccinin, E.; Cariello, M.; Moschetta, A. Lipid metabolism in colon cancer: Role of Liver X Receptor (LXR) and Stearoyl-CoA Desaturase 1 (SCD1). Mol. Asp. Med. 2021, 78, 100933.
  160. Liu, M.Y.; Li, H.M.; Wang, X.Y.; Xia, R.; Li, X.; Ma, Y.J.; Wang, M.; Zhang, H.S. TIGAR drives colorectal cancer ferroptosis resistance through ROS/AMPK/SCD1 pathway. Free Radic. Biol. Med. 2022, 182, 219–231.
  161. Ravaut, G.; Légiot, A.; Bergeron, K.F.; Mounier, C. Monounsaturated Fatty Acids in Obesity-Related Inflammation. Int. J. Mol. Sci. 2020, 22, 330.
  162. Ascenzi, F.; De Vitis, C.; Maugeri-Saccà, M.; Napoli, C.; Ciliberto, G.; Mancini, R. SCD1, autophagy and cancer: Implications for therapy. J. Exp. Clin. Cancer Res. 2021, 40, 265.
  163. Tesfay, L.; Paul, B.T.; Konstorum, A.; Deng, Z.; Cox, A.O.; Lee, J.; Furdui, C.M.; Hegde, P.; Torti, F.M.; Torti, S.V. Stearoyl-CoA Desaturase 1 Protects Ovarian Cancer Cells from Ferroptotic Cell Death. Cancer Res. 2019, 79, 5355–5366.
  164. Huang, Z.; Zhang, M.; Plec, A.A.; Estill, S.J.; Cai, L.; Repa, J.J.; McKnight, S.L.; Tu, B.P. ACSS2 promotes systemic fat storage and utilization through selective regulation of genes involved in lipid metabolism. Proc. Natl. Acad. Sci. USA 2018, 115, E9499–E9506.
  165. Ling, R.; Chen, G.; Tang, X.; Liu, N.; Zhou, Y.; Chen, D. Acetyl-CoA synthetase 2(ACSS2): A review with a focus on metabolism and tumor development. Discov. Oncol. 2022, 13, 58.
  166. Li, X.; Qian, X.; Lu, Z. Local histone acetylation by ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Autophagy 2017, 13, 1790–1791.
  167. Li, Z.; Liu, H.; He, J.; Wang, Z.; Yin, Z.; You, G.; Wang, Z.; Davis, R.E.; Lin, P.; Bergsagel, P.L.; et al. Acetyl-CoA Synthetase 2: A Critical Linkage in Obesity-Induced Tumorigenesis in Myeloma. Cell Metab. 2021, 33, 78–93.e7.
  168. White, U. Adipose tissue expansion in obesity, health, and disease. Front. Cell Dev. Biol. 2023, 11, 1188844.
  169. Pallegar, N.K.; Christian, S.L. Adipocytes in the Tumour Microenvironment. Adv. Exp. Med. Biol. 2020, 1234, 1–13.
  170. Cypess, A.M. Reassessing Human Adipose Tissue. N. Engl. J. Med. 2022, 386, 768–779.
  171. Barthelemy, J.; Bogard, G.; Wolowczuk, I. Beyond energy balance regulation: The underestimated role of adipose tissues in host defense against pathogens. Front. Immunol. 2023, 14, 1083191.
  172. Lengyel, E.; Makowski, L.; DiGiovanni, J.; Kolonin, M.G. Cancer as a Matter of Fat: The Crosstalk between Adipose Tissue and Tumors. Trends Cancer 2018, 4, 374–384.
  173. Matta, L.; de Faria, C.C.; De Oliveira, D.F.; Andrade, I.S. Exercise Improves Redox Homeostasis and Mitochondrial Function in White Adipose Tissue. Antioxidants 2022, 11, 1689.
  174. Mu, W.J.; Zhu, J.Y.; Chen, M.; Guo, L. Exercise-Mediated Browning of White Adipose Tissue: Its Significance, Mechanism and Effectiveness. Int. J. Mol. Sci. 2021, 22, 11512.
  175. Oeckl, J.; Janovska, P.; Adamcova, K.; Bardova, K.; Brunner, S.; Dieckmann, S.; Ecker, J.; Fromme, T.; Funda, J.; Gantert, T.; et al. Loss of UCP1 function augments recruitment of futile lipid cycling for thermogenesis in murine brown fat. Mol. Metab. 2022, 61, 101499.
  176. Seki, T.; Yang, Y.; Sun, X.; Lim, S.; Xie, S.; Guo, Z.; Xiong, W.; Kuroda, M.; Sakaue, H.; Hosaka, K.; et al. Brown-fat-mediated tumour suppression by cold-altered global metabolism. Nature 2022, 608, 421–428.
  177. Antunes, P.; Cruz, A.; Barbosa, J.; Bonifácio, V.D.B.; Pinto, S.N. Lipid Droplets in Cancer: From Composition and Role to Imaging and Therapeutics. Molecules 2022, 27, 991.
  178. Olzmann, J.A.; Carvalho, P. Dynamics and functions of lipid droplets. Nat. Rev. Mol. Cell Biol. 2019, 20, 137–155.
  179. Morales, P.E.; Bucarey, J.L.; Espinosa, A. Muscle Lipid Metabolism: Role of Lipid Droplets and Perilipins. J. Diabetes Res. 2017, 2017, 1789395.
  180. Morales, A.; Greenberg, M.; Nardi, F.; Gil, V.; Hayward, S.W.; Crawford, S.E.; Franco, O.E. Loss of ephrin B2 receptor (EPHB2) sets lipid rheostat by regulating proteins DGAT1 and ATGL inducing lipid droplet storage in prostate cancer cells. Lab. Investig. 2021, 101, 921–934.
  181. Luo, W.; Wang, H.; Ren, L.; Lu, Z.; Zheng, Q.; Ding, L.; Xie, H.; Wang, R.; Yu, C.; Lin, Y.; et al. Adding fuel to the fire: The lipid droplet and its associated proteins in cancer progression. Int. J. Biol. Sci. 2022, 18, 6020–6034.
  182. Sun, N.; Youle, R.J.; Finkel, T. The mitochondrial basis of aging. Mol. Cell 2016, 61, 654–666.
  183. Petan, T. Lipid Droplets in Cancer. Rev. Physiol. Biochem. Pharmacol. 2023, 185, 53–86.
  184. Royo-García, A.; Courtois, S.; Parejo-Alonso, B.; Espiau-Romera, P.; Sancho, P. Lipid droplets as metabolic determinants for stemness and chemoresistance in cancer. World J. Stem Cells. 2021, 13, 1307–1317.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback