Phytoestrogens in Human Osteosarcoma: Comparison
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Phytoestrogens are plant-derived bioactive compounds with estrogen-like properties.

Their potential health benefits, especially in cancer prevention and treatment, have been a subject

of considerable research in the past decade. Phytoestrogens exert their effects, at least in part,

through interactions with estrogen receptors (ERs), mimicking or inhibiting the actions of natural

estrogens. Recently, there has been growing interest in exploring the impact of phytoestrogens on

osteosarcoma (OS), a type of bone malignancy that primarily affects children and young adults and

is currently presenting limited treatment options. Considering the critical role of the estrogen/ERs

axis in bone development and growth, the modulation of ERs has emerged as a highly promising

approach in the treatment of OS. This review provides an extensive overview of current literature

on the effects of phytoestrogens on human OS models. It delves into the multiple mechanisms

through which these molecules regulate the cell cycle, apoptosis, and key pathways implicated in

the growth and progression of OS, including ER signaling. Moreover, potential interactions between

phytoestrogens and conventional chemotherapy agents commonly used in OS treatment will be

examined. Understanding the impact of these compounds in OS holds great promise for developing

novel therapeutic approaches that can augment current OS treatment modalities.

Phytoestrogens are plant-derived bioactive compounds with estrogen-like properties. Their potential health benefits, especially in cancer prevention and treatment, have been a subject of considerable research in the past decade. Phytoestrogens exert their effects, at least in part, through interactions with estrogen receptors (ERs), mimicking or inhibiting the actions of natural estrogens. There has been growing interest in exploring the impact of phytoestrogens on osteosarcoma (OS), a type of bone malignancy that primarily affects children and young adults and is currently presenting limited treatment options. Considering the critical role of the estrogen/ERs axis in bone development and growth, the modulation of ERs has emerged as a highly promising approach in the treatment of OS. It delves into the multiple mechanisms through which these molecules regulate the cell cycle, apoptosis, and key pathways implicated in the growth and progression of OS, including ER signaling. Moreover, potential interactions between phytoestrogens and conventional chemotherapy agents commonly used in OS treatment will be examined. Understanding the impact of these compounds in OS holds great promise for developing novel therapeutic approaches that can augment current OS treatment modalities.

  • osteosarcoma
  • phytoestrogens
  • anticancer effects

1. Introduction

Osteosarcoma (OS) is the most primary bone tumor and a major cause of cancer death during the second and third decades of life with a worldwide incidence of 3.4 cases per million people per year, for all races and both genders [1,2][1][2]. Current disease management strategies include the surgical resection of all clinically visible tumors and systemic front-line chemotherapy which uses high doses of methotrexate (MTX), cisplatin (CDDP), and doxorubicin (DOX). This determines an overall survival level of 65–70% at 5 years [3,4][3][4]. However, today, several patients continue to develop metastases with an elective site in the lung, which causes a high mortality rate. This means that 20–30% of patients are refractory to these conventional treatments [5]. This discomforting scenario is frequently attributed to the ineffectiveness of chemotherapy, which can be influenced by chemo-resistance phenomena [6]. In addition, chemotherapeutic agents often produce various side effects, including cardiotoxicity, hepatotoxicity, and renal toxicity, which contribute to the increased likelihood of OS recurrence and progression [7].
While there are an increasing number of targeted therapies being developed and an improvement in the survival rate of other cancers, OS still stands where it was decades ago. These unsatisfactory results mean that complementary and alternative treatment options merit more attention. In this regard, dietary supplements and phytotherapeutic agents, with high anticancer efficacy and nominal toxicity to normal tissues, have emerged as a promising avenue that is worth investigating [8].
Over the past decade, significant attention has been devoted to studying phytoestrogens through mechanistic in vitro research which, together with epidemiological observations, has provided evidence that supports their chemopreventive and chemotherapeutic effects in different types of malignancies, including breast, prostate, and colon cancer [8]. Phytoestrogens are found in various plants, especially soy and soy-based foods and herbal medicines [9]. They possess a structural similarity to the estrogen hormone, which enables them to interact with ERs in the body, exerting both estrogenic and anti-estrogenic effects [10,11,12][10][11][12]. This characteristic has sparked interest in gaining a better understanding of the potential influence of this class of plant substances on OS, considering that estrogen signaling can be implicated in the growth and progression of this malignancy [12,13,14][12][13][14]. In recent years, studies have shed light on the multifaceted effects of phytoestrogens on human OS cells. These compounds have been reported to exhibit both pro-apoptotic and anti-proliferative properties, suggesting their potential as therapeutic agents for OS [8,15][8][15]. Several underlying mechanisms have been proposed, including modulation of Ers, inhibition of angiogenesis, regulation of apoptosis-related proteins, and interference with cell signaling pathways involved in OS development, including the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and the mitogen-activated protein kinase (MAPK) signaling and Wnt/β-catenin pathway [15]. Phytoestrogens also possess antioxidant and anti-inflammatory properties, which contribute to their anticancer effects by attenuating oxidative stress and inflammation-mediated processes [8,15][8][15].

2. Phytoestrogens: Chemical Classification and General Aspects

Phytoestrogens are produced by plants (more than 300 various species) as secondary metabolites which play crucial roles in various plant functions, such as defense against pathogens, pigmentation and protection from UV radiation, photosynthetic stress, and reactive oxygen species [16]. The quantity of phytoestrogens produced by a plant increases significantly during extreme growing conditions [17]. The human diet is rich in plant-containing phytoestrogens (i.e., vegetables, legumes, cereals, fruits, nuts, etc.), and beverages, such as wine, cider, beer, tea, and many more. Many edible plants contain multiple classes of phytoestrogens, adding to their diversity and potential health benefits [9]. Regarding their structural features, phytoestrogens represent a large and heterogenic class of non-steroidal substances characterized by a close structural similarity to the principal mammalian estrogen 17β-estradiol (E2) [11,12][11][12]. Shared structures include a phenolic ring and a pair of hydroxyl groups in opposite positions on the molecule (as in the case of E2 molecule), which are responsible for the interaction of phytoestrogens with the ligand-binding domain of ERα and ERβ. The exact position and number of these hydroxyl substituents is crucial in determining the binding affinity for the ERs and the activation of hormonal signaling [18,19][18][19]. The estrogenic or antiestrogenic properties of phytoestrogens in the target cells depend on their phenolic ring [20]. The phytoestrogens have been categorized into two main groups: flavonoids and non-flavonoids based on their chemical structure and properties. The classification and the basic structures of the most representative dietary phytoestrogens are illustrated in Figure 1.
Figure 1. Basic chemical structures of the major classes of phytoestrogens. The different types of phytoestrogens share a structural similarity with 17β-Estradiol. In green, the flavonoid skeleton showing rings A, B, and C and the numbering.

2.1. Flavonoids

Flavonoids are a large group of substituted phenolic compounds [22][21]. They share a common structure consisting of a fifteen-carbon skeleton composed of two benzene rings (A and B) connected by a heterocyclic pyran structure (C) in a C6–C3–C6 arrangement, as illustrated in Figure 1 [23][22]. The basic flavonoid skeleton can have numerous substituents, including hydroxyl groups typically found at positions 4′, 5′, and 7. Flavonoids can be further classified into different subclasses. Specifically, isoflavones are flavonoids, where the B ring is connected to the heterocyclic ring at the C3 position. On the other hand, flavonoids in which the B ring is linked at position 2 are divided into several subgroups, namely flavones, flavonols, flavanones, and catechins, depending on the degree of saturation and oxidation of the C ring (Figure 1). Coumestans are a distinct flavonoid which are characterized by a 1-benzoxolo (3,2-c)chromen-6-one structure formed by a benzoxole fused with a chromen-2-one [8]. The presence and position of hydroxyl groups and/or additional substituents contribute to the diversity of flavonoids and their biological activities [23,24,25][22][23][24]. Moreover, the addition of lipophilic prenyl side-chains can occur at different positions of the flavonoid skeleton, resulting in various prenylated derivatives with improved bioactivities and higher affinity to biological membranes. Prenylated flavonoids are much less common than flavonoids in nature [26][25]. Flavonoids are some of the most prevalent compounds found in fruits, vegetables, legumes, and tea and are generally concentrated in the fruit skin, bark, and flowers of plants [21][26]. Certain flavonoids, such as the flavonol quercetin, are found in all plant products (i.e., fruit, vegetables, cereals, leguminous plants, tea, and wine), but others are specific components of particular foods (i.e., flavanones in citrus fruit and isoflavones in soya). In most cases, food contains complex mixtures of flavonoids; for many food products, the composition is less known (for review, see [27]). In plants, most flavonoids are conjugated with one or more sugar residues linked to hydroxyl groups or aromatic carbons, so they mainly exist as glycosides [28].

2.2. Non-Flavonoids

Non-flavonoids encompass a broad range of plant compounds that do not possess the characteristic flavonoid structure. Their structure consists of phenolic acids in either C6–C1 (benzoic acid) or C6–C3 (cinnamic acid) conformations and are mainly represented by lignans and stilbenes (Figure 1). Non-flavonoids may occur in the form of aglycones and glycosides [28]. Lignans are dimers of phenylpropanoid units connected via two specific carbons (C-2–C-2′) and are typically found in plant cell walls [29]. They are widespread and their content is high in common foods, including grains, nuts, seeds, vegetables, and drinks such as tea, coffee, or wine. Plant lignans are the principal source of dietary phytoestrogens in the Western diet [30]. Compounds, such as pinoresinol, lariciresinol, sesamin, enterolactone, and enterodiol can be found in this group [29]. Stilbenes are among the most relevant non-flavonoid phytoestrogens which consist of a 1,2-diphenylethylene nucleus that generates two isomers (cis and trans), with the trans-isomer being the most stable and biologically active [31,32][31][32]. More than 400 stilbene compounds have been identified in plants, with various structures ranging from monomers to octamers with different substituents, such as glycosyl, hydroxyl, methyl, or isopropyl radicals [31]. Monomeric stilbenes have been studied the most. These include resveratrol and polydatin (Section 7). They are naturally occurring in fruits, mostly in grapes, berries, and peanuts [33]. In general, the occurrence of stilbenes in the human diet is limited but represents an important part of phytoestrogen intake by people who follow a Mediterranean diet or who regularly drink wines.

2.3. Metabolism of Dietary Phytoestrogens

Each class of dietary phytoestrogens has its own structural particularities, and studies regarding their bioavailability and metabolism are still far from being completed. There is no relation between the quantity of phytoestrogens in food and their bioavailability in the human body. Indeed, the rate and extent of absorption of dietary phytoestrogens in the intestine is determined primarily by their chemical structure and by factors such as molecular size and solubility, extent of glycosylation, hydroxylation, acylation, and degree of polymerization [12,34][12][34]. Most ingested phytoestrogens (e.g., isoflavones, lignans, and stilbenes), are predominantly present as estrogenically inactive glycosides in plant material [35]. After ingestion, phytoestrogens undergo extensive metabolization mediated both by tissue enzymes and gut microbiota, either prior to absorption or during enterohepatic circulation. The intestinal flora is capable of transforming aglycones into bioactive metabolites that are more similar to estrogens, being able to interfere with the endogenous estrogen signaling and associated cellular processes. In some cases, these metabolites have greater biological activities and different impacts on targeted tissues than their parent precursors [36,37][36][37]. For a detailed background on the absorption and metabolism of different phytoestrogens, see ref. [38]. Thus, individual variability in gut microbiota can influence the metabolism of these estrogenic molecules, contributing to their intake and beneficial effects [39]. Consequently, the identification, quantification, and individual differences among phytoestrogen metabolites are important issues when researching the health effects of phytoestrogens in humans.

3. Phytoestrogen Mechanisms of Action—Anticancer Related Effects

In recent years, significant efforts have been made to elucidate the molecular mechanisms underlying the biological effects of phytoestrogens in both physiological and pathological conditions. The bioavailability and metabolism of phytoestrogens, as well as their effects on enzymes, nuclear receptors, and intracellular transduction mechanisms, play a crucial role in determining the overall impact of these compounds on cancer risk and progression [8]. However, the debate surrounding these effects persists, and further clarification is still needed. Phytoestrogens show a complex mode of action via interaction with the ER subtypes (i.e., ERα and ERβ), acting as either estrogen, triggering receptor pathways, or anti-estrogens, blocking normal estrogenic activity [10,40,41][10][40][41]. The dichotomy of ER modulating action induced by phytoestrogens led to the insertion of these compounds into the class of selective ER modulators (SERMs) [42,43,44,45][42][43][44][45] and probably provides an explanation regarding the conflicting evidence about the risks and benefits of these molecules on human health [46]. The activation of ER signaling pathways plays a vital role in the malignant progression of multiple cancers by comprehensively regulating downstream genes. The two ER subtypes have been described with different tissue distribution and ligand-binding affinities. ERα is mainly found in breast and uterine tissues and has been associated with pro-oncogenic responses while ERβ is the predominant isoform in the brain, bones, and blood vessels and is related to tumor-suppressive responses [19,47][19][47]. The alteration of the ERα/ERβ ratio in the affected tissues is one of the main reasons for the variability of estrogen-dependent cancer biology [48] and correlates with the response to the treatments and prognosis [49,50][49][50]. Phytoestrogens are known to bind ERs with much lower affinities than that of E2 (from 1/100 to 1/10,000), suggesting their weak estrogenic activities [19,47,51][19][47][51]. The actions of phytoestrogens via ERs can be mediated by genomic and/or non-genomic mechanisms, in a dose- and tissue-specific manner [52,56][52][53]. The ER-mediated genomic effects of phytoestrogens result in the regulation of target genes, which include anti-inflammatory, anti-apoptotic, metabolic, and mitochondrial genes, as well as an improvement in mitochondrial biogenesis and function, which leads to increased resistance to stress [57,58][54][55] (Figure 2).
Figure 2. Intracellular mediators of the effects of phytoestrogens on cancer cells. Phytoestrogen can interact with the two types of ER, the intracellular ERα and Erβ, and membrane-associated mERs and GPER, activating downstream genomic and non-genomic effects which ultimately affect cell cancer phenotypes. The genomic pathway can involve ER interactions with other transcription factors (TFs), such as CREB, AP-1, Sp1, and NF-κB. Phytoestrogens can also act through ER-independent mechanisms which induce oxidative stress-mediated signaling by generating ROS, as well as interacting with other nuclear receptors, such as PPARs and ERRα/γ.
Phytoestrogens also modulate several therapeutically important oncogenic signaling pathways, including the epithelial–mesenchymal transition (EMT) and MAPK-associated pathways [46[46][56],59], and recruit transcription factors, such as response element binding protein (CREB), the activator protein 1 (AP-1), the stimulating protein 1 (Sp1), and the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), which are correlated with cell cycle regulation, angiogenesis, metastasis, and apoptosis [60][57]. Besides nuclear events mediated by intracellular ER binding, many of these compounds also exert non-genomic effects through the activation of the membrane-associated ERs (mERs) and/or G-protein-coupled estrogen receptor 1 (GPER1/GPR30), which are involved in a diverse array of disorders, including cancer [61,62,63][58][59][60]. Among the membrane-initiated non-genomic effects is the activation of signaling cascades, such as the mitogen-activated protein extracellular kinase/extracellular signal-regulated kinase (MEK/ERK) and PI3K pathways, which affect cancer cell apoptosis and proliferation [10,64][10][61]. In addition, they can exert estrogenic activity by cross-talk with many other pathways, including those related to membrane-associated growth factor receptors, such as the human epidermal growth factor receptor (EGFR/HER) and the insulin-like growth factor 1-receptor (IGF1R) [65][62], as well as nuclear receptors, including [66][63] peroxisome proliferator-activated receptors (PPARs) [67][64] and estrogen-related receptor alpha/gamma (ERRα/γ) (Figure 2) [68][65]. Moreover, phytoestrogens can promote apoptosis and prevent the reproduction of malignant cells by blocking neo-angiogenesis, tyrosine-kinase, and topoisomerase proteins [69][66]. Several studies have also reported that, in addition to the classical estrogen receptor signaling and the genomic and non-genomic effects mentioned above, some phytoestrogens, including genistein and resveratrol, exert their anticancer effects by the epigenetic mechanism, such as the modulation of the chromatin structure [42,70][42][67] and the regulation of different cancer-associated miRNAs [71[68][69],72], suggesting new therapeutic strategies for cancer. Phytoestrogens are mostly known for their potent antioxidant activity, i.e., another biological activity that indirectly reduces the risk of various degenerative diseases linked to oxidative stress, including cancer [73][70]. The chemical structures of these compounds consist of a long-conjugated system that includes phenolic groups. This structural arrangement confers them significant antioxidant properties [8], which have been linked to their chemoprevention potential, particularly in Asian populations. It is worth noting that in these populations, there is a correlation between soy consumption and a reduced occurrence of estrogen-related cancers [8,24][8][23]. On the other hand, at high concentrations, phytoestrogens may have pro-oxidant effects and induce cell death. Flavonoids autoxidize in aqueous medium and may form highly reactive radicals in the presence of transition metals. This effect has been described for several compounds, including genistein [74,75][71][72] and resveratrol [76][73], suggesting that a combination of phytoestrogens with anti-cancer treatments may render cancer cells more sensitive to treatment, in part by increasing the production of reactive oxygen species (ROS). However, given the high concentration of these compounds required for these activities, their impact on cancer onset and progression appears to be related to other cellular effects besides the modulation of oxidative stress [77,78][74][75]. Some phytoestrogens have also been shown to possess anti-inflammatory properties and modulate immune responses. They can inhibit the production of inflammatory mediators and reduce the expression of pro-inflammatory genes, contributing to their potential as anticancer agents [8,15][8][15]. As a whole, phytoestrogens exert a plethora of effects through multiple synergistic signaling pathways, which contribute to the outcome of phytoestrogen exposure on health and/or cancer cells. The specific effects of phytoestrogen exposure on cancer initiation, progression, and development may differ depending on the ERα/ERβ ratio in the affected tissue and the different selectivity and concentration of phytoestrogens [48]. In this regard, the majority of reported findings indicate distinct effects at low and high concentrations of phytoestrogens, which may be attributed to the capacity of these molecules to interact with and modulate ERs, thereby influencing endocrine functions [79][76]. Indeed, some studies have raised concerns about the potential adverse effects of soy products, particularly in high doses or when consumed by individuals with hormone-sensitive cancers [10,42][10][42]. Hence, it is crucial to gain a comprehensive understanding of how phytoestrogens interact with the ERs to fully evaluate their toxicologic and pharmacologic properties.

4. Molecular Basis of Osteosarcoma Pathogeneses

The difficulty in establishing an efficacious OS therapy is linked to the unclear specific markers for diagnosis and treatment. It is also due to the complexity of the OS genome, low incidence of this tumor, and significant biologic differences between OS subtypes. Nevertheless, the heterogeneity in the genotype of OS has translated into several expression profiles of macromolecular biomarkers, which are helpful in the clinic [2,80,81,82][2][77][78][79]. There are many genetic mutations observed in OS patients. The p53 and retinoblastoma (Rb) genes are well-known tumor-suppressor genes. Both germline and somatic mutations of the p53 and Rb genes have been proven to be involved in OS pathogenesis [82,83,84][79][80][81]. Inherited cancer predisposition syndromes, such as Li–Fraumeni, hereditary retinoblastoma, Rothmund–Thomson, Bloom, or Werner syndrome, may also influence the high appearance of this kind of tumor in young patients [83,85,86,87,88][80][82][83][84][85]. Among other genes mutated in more than 10% of OS cases, c-Myc plays a role in OS development and promotes cell invasion by activating MEK–ERK pathways. A high expression of c-Myc in OS tumors correlates with the formation of metastasis and poor prognosis [89][86]. Several studies have consistently demonstrated that OS cells have the capacity to develop and secrete a range of growth factors that exert autocrine and paracrine effects. Vascular endothelial growth factor (VEGF), transforming growth factor (TGF), IGF-I and IGF-II, and connective tissue growth factor (CTGF) are deregulated in OS, which leads to tumor progression and growth in target cells [82,90,91,92][79][87][88][89]. Parathyroid hormone-related peptide (PTHrP) and its receptor have also been implicated in OS progression and metastasis development, with PTHrP conferring OS chemoresistance by blocking signaling via p53 [93][90]. Epigenetic events have emerged as significant risk factors for OS, since the DNA methylation pattern of specific genes or gene regions and histone modifications may be involved in tumor development [94][91]. In addition, a variety of studies have found abnormally expressed levels of micro-RNAs (miRs), which have the potential to become prognostic biomarkers of OS. Overexpression of this molecule results in proliferation, migration, and invasion of tumor cells [68,95][65][92]. Among the miRNAs deregulated in osteosarcoma are miR-421, miR-16, miR-200b, and miR-101 [81,96,97][78][93][94]. OS is a highly metastatic tumor, and pulmonary metastases are the most common cause of death [82,98][79][95]. The ability of OS cells to metastasize has been found to be correlated with multiple processes and various cytophysiological changes, including changing the adhesion capabilities between cells and the extracellular matrix (ECM) and disrupting intercellular interactions [99,100][96][97]. Degradation of the ECM and components of the basement membrane caused by the concerted action of proteinases, such as matrix metalloproteinases (MMPs), cathepsins, and the plasminogen activator (PA), can play a critical role in OS invasion and metastasis [100][97]. Moreover, in metastatic forms of OS, some specific genetic changes have been observed, which include upregulation of the Wnt/β-catenin and Src pathways, the neurogenic locus notch homolog protein 1 and 2 (Notch1/Notch2) receptors [101,102][98][99] together with the downregulation of the Fas/Fas ligand pathway (a cell death pathway), which increases the metastatic potential of human OS [103,104][100][101]. In both primary bone cancer and bone metastases, the bone remodeling process creates a favorable environment for tumor establishment and progression. Osteoblasts and osteoclasts are the primary regulators of bone metabolism [105][102]. Specifically, osteoblasts secrete multiple components of ECM and MMPs in the OS niche, which are rich promoters of OS development. Moreover, osteoclasts play a pivotal role as bone-resorbing cells, and significant osteolysis exhibited in some OS cases can be directly attributed to the heightened activity of osteoclasts [100][97]. It has been demonstrated that OS is a condition characterized by deregulation in the signaling triad, i.e., the receptor activator of nuclear factor kB Ligand (RANKL), its receptors RANK, and osteoprotegerin (OPG) [106,107][103][104]. In its canonical function, RANKL, which is secreted by osteoblasts, induces bone destruction by mature osteoclasts. In response, osteoblasts secrete the OPG–RANKL decoy receptor and in this way inhibit osteoclast differentiation and resultant bone resorption [106,108][103][105]. The RANKL/OPG ratio in the blood is increased in high-grade OS, leading to the establishment of a vicious cycle between pathological bone remodeling and OS growth [108][105]. RANKL/RANK-signaling regulates OS cell migration and tissue-specific metastatic behavior in the lungs, but has no direct impact on OS-associated bone destruction and does not impact OS cell proliferation [106,109][103][106]. Thus, osteoclast pathways of differentiation, maturation, and activation constitute another compelling therapeutic target since the inhibition of bone resorption at the tumor–bone interface may lead to reduced local OS invasion [106][103]. Among the possible mechanisms that contribute to OS development in the bone microenvironment are alterations in the osteogenic pathway, which lead to the differentiation of mesenchymal stem cells (MSCs) into mature osteoblasts [81,110][78][107]. Defects in osteogenic differentiation or exposure to new non-native stimuli, such as pro-inflammatory cytokines and pro-tumor agents, may cause an imbalance between cell differentiation and proliferation, thus contributing to a malignant phenotype. OS cells share more characteristics with undifferentiated osteo-progenitors than with differentiated osteoblasts, including a high proliferative capacity and resistance to apoptosis. Indeed, osteogenic regulators associated with mature osteoblast phenotypes, such as CTGF, RUNX2, alkaline phosphatase (ALP), osteopontin (OPN), and osteocalcin (OCN), are very lowly expressed in both primary OS tumors and OS cell lines [111][108]. Although not well understood, some of the potential defects in the MSC differentiation cascade may include genetic and/or epigenetic changes in Wnt signaling, Rb, and p53. These alterations may lead to uncontrolled cell proliferation and disrupted differentiation, thus producing a tumorigenic phenotype [81,110][78][107]. Interestingly, treatments of human OS cells with therapeutic agents, such as peroxisome proliferator-activated receptor (PPAR) agonists [111][108], growth factors (e.g., PTHrP) [112][109], and SERMs [113][110], enable terminal differentiation and subsequent tumor inhibition. Hence, a better understanding of the relationship between defects in osteogenic differentiation and tumor development is of fundamental importance for the treatment of OS and promoting differentiation offers a potential for disease control.

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