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",isbn:"978-1-80356-363-3",printIsbn:"978-1-80356-362-6",pdfIsbn:"978-1-80356-364-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"969d1c6315b04584c2f011e03dad69c2",bookSignature:"Dr. Mansoor Zoveidavianpoor",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11929.jpg",keywords:"Drilling Performance, Drilling Tools, Well Design, Drilling Procedure, Rotary Drilling, Directional Drilling, Measuring-While-Drilling, Smart Well Technology, Environment Protection, Geothermal Drilling, Sustainable Drilling Fluids, Carbon Sequestration",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 18th 2022",dateEndSecondStepPublish:"March 18th 2022",dateEndThirdStepPublish:"May 17th 2022",dateEndFourthStepPublish:"August 5th 2022",dateEndFifthStepPublish:"October 4th 2022",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Zoveidavianpoor has over 18 years of multidisciplinary oil and gas experience, built upon his technical, operational, and management roles in the industry and academia. He is a member of the Society of Petroleum Engineers (SPE), the Energy Institute, UK and is registered as a chartered petroleum engineer. He has published more than 50 publications on International peer-reviewed Journals and conferences, has contributed to 5 textbooks, and served in many scientific committees.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"92105",title:"Dr.",name:"Mansoor",middleName:null,surname:"Zoveidavianpoor",slug:"mansoor-zoveidavianpoor",fullName:"Mansoor Zoveidavianpoor",profilePictureURL:"https://mts.intechopen.com/storage/users/92105/images/system/92105.jpg",biography:"Dr. Mansoor Zoveidavianpoor has over 24 years of experience, built upon his technical, operational, and management roles in the industry and academia. Mansoor holds a BSc degree in Geology, MSc, and Ph.D. degrees both in Petroleum Engineering. He was involved in different disciplines such as project management, geology, flow assurance, piping construction, artificial intelligence, environmental engineering, drilling and production engineering, He has lectured several courses at the University Technology Malaysia (UTM), Petroleum University of Technology (PUT), and Islamic Azad University (IAU). He is a member of the Society of Petroleum Engineers (SPE) and registered as a Chartered Petroleum Engineer at Energy Institute, and EIA subject specialist at DOE Malaysia. He has published more than 50 publications on International peer-reviewed Journals and conferences, has contributed to 5 textbooks, and served in many scientific committees. Currently, he is working as an Associate Professor at UTM and involved in several consultancies in petroleum engineering and energy transition. 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From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"79361",title:"Interaction of Bisphenol A with G Protein: Coupled Receptors - New Paradigms in Breast Cancer",doi:"10.5772/intechopen.101204",slug:"interaction-of-bisphenol-a-with-g-protein-coupled-receptors-new-paradigms-in-breast-cancer",body:'Significant evidence suggests that endocrine disruption is attributable not only to pharmaceutical products or rare contaminants, but also to exogenous chemical compounds ubiquitously found in everyday life of the modern world. Endocrine-disrupting chemicals (EDCs) enter the human body where they act similarly to endogenous hormones, altering endocrine homeostasis and causing adverse effects on human health [1, 2, 3, 4, 5, 6, 7]. Interestingly, the US Food and Drug Administration identified more than 1800 chemical disruptors of endocrine pathways involving estrogen, androgen, and thyroid hormones [8]. EDCs have been related to the development of disorders such as adulthood diabetes, poor semen quality, polycystic ovary syndrome, neurodegenerative disorders, and cancer [1, 8]. Changes in the physiological levels of hormones circulating in the human body may be involved in the high incidence of tumors of the reproductive system in both men and women [8]. Indeed, breast cancer is the most common cancer diagnosed in women worldwide that has been associated in a small percentage with genetic predisposition (
In 1891 Aleksandr Dianin, a Russian chemist from Saint Petersburg, combined phenol with acetone in the presence of an acid catalyst, synthesizing for the first time the chemical substance called 4,40-dihydroxy-2,2-diphenylpropane [10], a molecule that was later recognized by the name of bisphenol A [11]. In 1936, the English scientists Dodds and Lawson reported that BPA exhibited important estrogenic properties inducing complete cornification in vaginal smears of ovariectomized rats treated with this compound [12]. In the 1940s, BPA was basically considered a synthetic estrogen and its potential carcinogenic properties in humans started to be studied [13, 14]. Therefore, BPA is one of the first compounds of anthropogenic origin in which an endocrine-disrupting activity has been verified.
Later in the 1950s, it was found that the reaction of BPA with phosgene generated a polycarbonate, unalterable over time, easy to mold, versatile, and transparent. Due to these multiple qualities, together with its chemical stability, the industry began to use it rapidly and massively to manufacture all types of plastic containers [2]. Currently, BPA has been used to produce various electronic and construction products, automotive parts, medical and clinical articles, toys for children, hygiene and personal care items, and storage products. In addition, it is used for the inner lining of metal cans for preservation of food and beverages [2]. For this reason, BPA is today one of the most used chemical products worldwide. Several studies have suggested that the greatest human exposure to BPA (>90%) is likely to occur through food contamination and, to a lesser extent, by dust ingestion and absorption through the skin or dental surgeries [8].
The proestrogenic activity of BPA resurfaced in the early 1990s when a team led by David Feldman identified through mass spectrometry the presence of this molecule in a growth medium of yeast (
The continuous presence of BPA in our environment suggests that several routes of exposure may exist. Oral ingestion seems to be the main route, given the storage of food and liquids in plastic containers that include BPA among its major constituents, which also diffuses into the environment after exposure to high temperatures or frequent washing. The US EPA has established a safe daily intake of 50 g BPA/kg of body weight per day based on the assumption that the main source of exposure to BPA is through food ingestion [17]. Not only in humans but also in primates, ingested BPA is rapidly absorbed (5–15 min later) by the intestinal wall and is transformed into BPA glucuronide following its first passage through the intestine and liver; in addition, a small fraction of BPA is also transformed into a sulfate conjugate [4, 16, 18, 19]. Conjugated forms of BPA are estimated to have no endocrine activity [19, 20]. In murine models, and after oral administration of nanomolar doses of BPA, oxidation products of this compound have been found, suggesting the formation of secondary metabolites with greater estrogenic activity than the parent molecule [5]. BPA has a half-life between 4 and 5 h, and most of the conjugated forms are finally excreted through the urine [4, 5, 16]. Inhalation seems to be another route of entry, inducing cough, bronchospasm, and asthmatic attacks; similarly, eye exposure may cause conjunctivitis, itching, and periorbital edema whereas skin contact usually produces localized redness and inflammation [19].
BPA has been detected in all biological fluids, including serum, urine, cerebrospinal fluid, and milk, in most of today’s human populations. In fetal tissues, BPA has been found in concentrations similar to those present in maternal blood, showing that it can cross the transplacental barrier [19]. Furthermore, toxicological data indicates that human embryos and neonates, unlike adults, cannot conjugate BPA increasing its possibility to exert toxic effects [5]. Epidemiological and experimental studies suggest that embryonic exposure to BPA is in the long term related to the occurrence of a series of disorders, such as precocious puberty, infertility, metabolic disorders, and a series of hormone-dependent tumors, like breast cancer [1, 5, 17, 20, 21].
To date, only a few studies have explored the effects produced by exposure to BPs, mainly BPA, during intrauterine or postnatal life together with their effects on general human health. Multiple metabolic disorders, polycystic ovary syndrome, spontaneous abortion, infertility, endometrial hyperplasia, hormone-dependent tumors, immunity alterations, cardiovascular pathologies, neurodegenerative disorders and obesity have so far been reported among their deleterious effects on human health [1]. Dumitrascu et al. in 2019 [1] highlighted that women suffering from polycystic ovary syndrome exhibited higher circulating levels of BPA and testosterone than healthy women and that high androgen levels decreased BPA clearance. Furthermore, they pointed out that women with endometriosis showed high levels of BPA in serum, suggesting an association between this compound and the disease. It has also been suggested that patients with high urinary levels of BPA have a high probability of implantation failure during
Structure of main bisphenols produced by industrial activity. BPA, bisphenol A; BPF, bisphenol F; BPAF, bisphenol AF; BPS, bisphenol S.
With regard to the risk of developing malignant neoplasms, the greatest association has been observed with breast, ovarian, and prostate cancer though the studies have not been conclusive [1]. To overcome the effects of BPA associated with an increased public concern about the risk of developing endocrine-related cancer due to exposure to BPA [24], the industry has replaced it with analogs such as BPS, BPB, BPF, or BPAF, which are now parts of products labeled as BPA-free [25]. Nevertheless,
Likewise, recent studies have shown that both BPA and BPS can contribute to breast cancer malignancy by disrupting the organization of acinar structures and by affecting the normal development of the mammary gland [9]. To date, the effects of BPA in eukaryotic cells have been reported to be mediated primarily by steroid receptors, including ERɑ and ERβ, estrogen-related receptors (ERR), androgen receptors (AR), and peroxisome proliferator-activated receptors (PPAR) [24]. Other interactions include signaling by stimulation of angiotensin (AT), α-adrenergic (AR,) or chemokine (CXC) receptors.
Although BPA does not possess the potency of estrogen, it is ubiquitously distributed in nature and its resistance to enzymatic or chemical degradation makes it even more dangerous. Breast cancer has a high mortality in women in many countries, and approximately 10% of these tumors are due to genetic influence whereas 90% are related to lifestyle or associated with negative elements present in the surrounding environment [1]. The most harmful effects attributed to EDCs would occur during breast development when this tissue is more susceptible to developing atypical differentiation.
Breast cell cultures developed in a 3D fashion are one of the most widely used models to gain a better understanding of the role of bisphenols in breast cancer. Using this approach and MCF-12A cells, which exhibit a typical luminal epithelial morphology, it was observed that low doses of BPA and BPS generated a disruption in the normal organization of the mammary acinus and promoted cell invasion [9]. Interestingly, mammospheres of MCF-7 cells (ERα-positive cell line) treated with 10 nM BPA displayed high expression of aldehyde dehydrogenase 1, a marker of breast stem cells, and SOX-2, a key transcription factor for cell pluripotentiality and self-renewal. That effects were not observed when MDA-MB-231 (ERα-negative cell line) was used instead of MCF-7 cells, suggesting that the receptors through which BPA modulates its signaling exhibit a different expression pattern in this kind of cancer, highlighting the implications of the heterogenicity of tumor mammary tissue when evaluating the effects of EDCs [34].
Evidence suggests that BPA may play an important role in the lifecycle and carcinogenesis of mammary epithelial cells and challenge us to continue studying its role in the origin and progression of breast cancer. One approach is to determine the relationship between BPA and G protein–coupled receptors (GPCRs) signaling, considering the recent evidence of the role of GPER-1 in breast cancer progression. Interestingly, approximately 20% of human neoplasms are related to some alteration in GPCRs [35]. The first relationship of GPCRs with tumorigenesis dates back to the 1980s, when a novel proto-oncogene called
The ability to receive and transmit a variety of external and internal signals is a fundamental feature to coordinate morphological and functional activities of multicellular organisms. The notion that receptive structures and substances mediate cellular responses was envisioned in 1897 by Paul Ehrlich with his “side chain” theory [38] and formulated more directly in 1905 by John Newport Langley [39]. However, at that time, the techniques to verify this hypothesis did not exist. It was not until the 1970s that Lefkowitz, using (−)[3H] alprenolol, a potent β-adrenergic antagonist, achieved the specific binding of this ligand to β-adrenergic receptors in frog red blood cells [40] and purified the β-adrenergic receptor (AR) by using affinity chromatography [41]. Since then, it has been demonstrated that the binding of a β-adrenergic agonist to its receptor leads to the activation of the heterotrimeric G protein with the subsequent production of cAMP [42]. The structure of this receptor was later investigated in more detail by Kobilka employing X-ray crystallography who found a surprising homology of β-adrenergic receptor with the previously described rhodopsin receptor [43, 44]. Elucidation of the structural and functional features of the β-adrenergic receptor, including its crystallization, constitutes one of the most relevant scientific milestones in recent times on the knowledge of GPCRs.
Currently, technical advances in molecular biology have made it possible to determine the genetic code of numerous receptor proteins, identifying their amino acidic sequence and allowing interesting evolutionary relationships. GPCRs represent approximately 4% of all genes encoded by the human genome, generating between 650 and 800 different types of GPCRs, constituting the most numerous family of membrane receptors, regulating a large number of physiological and pathological processes [39]. It is estimated that 60% of all commercially available drugs target at least one particular GPCR [45].
The most accepted classification of GPCRs is supported by the International Union of Basic and Clinical Pharmacology (IUPHAR), which based on structural and phylogenetic criteria has grouped them into the families of rhodopsin (family A), secretin (family B), and glutamate (family C) and into the adhesion receptor or frizzled/taste2 families [46]. The structural characteristics and the degree of homology between the different families make it possible to determine that all GPCRs in humans derive from a single common ancestor [46, 47]. GPCRs are characterized by having seven transmembrane helices, with an amino-terminal end located extracellularly and a carboxy-terminal end located toward the interior of the cell, in the vicinity of which the interaction with the heterotrimeric G protein occurs, promoting intracellular signaling events once the receptor is activated by its corresponding agonist [46]. It is estimated that GPCRs arose about 1200 million years ago, during the evolutionary separation of alveolates (organisms that do not have GPCRs in their genome) from fungi and plants (organisms that do present some types of GPCRs) [47, 48]. More than 80% of all GPCRs belong to the rhodopsin family, characterized by highly conserved motifs and significant structural and functional diversity [46, 47].
GPCRs are integral proteins of the plasma membrane that interact with a large number and variety of signals such as photons, ions, neurotransmitters, peptides, and hormones of different chemical nature [49]. Among the physiological responses triggered by GPCRs are the regulation of cell survival, motility, and cell proliferation [47]. It has been shown that in addition to classical nuclear ERα and ERβ receptors, endogenous estrogens can exert their biological activity by binding to cell membrane-sited receptors, particularly some of the large family of GPCRs [50, 51].
As mentioned before, BPA is one of the most studied xenoestrogens, initially developed as estrogen and now produced in large quantities and added to many consumer products such as coatings for cans, dental fillings, plastic bottles, feeding bottles, and some medical devices, causing ubiquitous human exposure. Indeed, more than 1 mg/kg of BPA has been detected in some foods, such as vegetables, probably due to leaks from plastic irrigation devices [24].
It is estimated that approximately 70% of breast carcinomas depend on estrogen and consequently are clinically classified as “hormone-sensitive breast cancer” or ERα-positive tumors. Interestingly, numerous reports indicate that xenoestrogens (chemicals that induce estrogen or antiestrogen responses) can disrupt normal estrogen-dependent signaling. Among the main xenoestrogens, BPA and some of the newly derived bisphenols stand out for their industrial origin and frequent occurrence in our “modern” society and ecosystems, generating a series of alterations in human beings and the environment. With no doubt, BPA is so far one of the most studied xenoestrogens though 17β-estradiol is the most potent form of estrogen when compared with BPA or other bisphenols [1, 50]. In men, estrogens favor serum levels of HDL cholesterol (high-density lipoproteins) to improve the cardiovascular condition and maintain bone mass and sperm maturation. In women, estrogens have strong effects on the female reproductive organs, including the breast, uterus, and menstrual cycle regulation. Moreover, altered estrogen balance is implicated in the pathophysiology of breast, ovarian, colorectal, prostate, and endometrial cancer. Similarly, estrogen unbalance has been implicated in metabolic, autoimmune, cardiovascular, neurodegenerative, and mood disorders [51].
BPA has long-term disruptive effects, even when contact has occurred during prenatal development. Intrauterine BPA exposure in pregnant Wistar rats alters the histoarchitecture of the mammary gland by increasing angiogenesis in female offsprings at postnatal day 50 or 110 [52]. Other studies, also using a murine model, indicate that prenatal exposure to BPA or its analogs, BPS and BPAF, induces accelerated development of the mammary gland, generating in the long term an increased susceptibility to spontaneous preneoplastic lesions, characterized by lobuloalveolar hyperplasia and perivascular inflammation [53].
As expected, the effects of BPA or other bisphenols have already been validated by studying their genomic activities on the pathways of nuclear estrogen receptors and it is only in the last years that the impact on GPCRs such as GPER-1, angiotensin, chemokines, and adrenergic receptors, as alternative estrogen-binding molecules, has begun to be elucidated [54]. Here, we present some evidence about interactions between BPs, GPCRs, breast cancer, and cancer progression.
Since the discovery of nuclear ERα by Jensen, the binding of estradiol to cell surface receptors was considered highly unlikely [50]. However, a series of investigations that demonstrated increased levels of cAMP shortly after estrogen stimulation, as well as increased cell proliferation of ERα-deficient cells following stimulation with 17β-estradiol, suggested the presence of a membrane-located receptor that was interacting functionally with estrogen [50, 55]. In 2002, the activity of a membrane estrogen receptor, provisionally called “ER-X,” was revealed, though its structure was not investigated [56]. Additionally, a glutamate receptor of the groups I and II sensitive to estrogen, whose activity was independent of Erα, was reported [57]. Given this background, several groups investigated an orphan membrane receptor called GPR30 (G protein-coupled receptor 30), described in 1997 by Carmeci et al., [58] which was strongly expressed in estrogen-sensitive breast cancer cells. In 2005, Thomas et al. demonstrated the specific binding of estrogen to GPR30 in SKBR3 breast cancer cells, a cell type that expresses GPR30 but not nuclear estrogen receptors [59]. In addition, Revankar et al. reported the localization of GPR30 in the endoplasmic reticulum and that its binding to estrogen increased intracellular calcium levels [60]. Subsequently, several groups, including ours, have described that GPR30 is primarily sited in the plasma membrane of breast cancer cells [50, 61]. Due to the ability of GPR30 to bind to estrogen, it was renamed as GPER-1 (G protein-coupled estrogen receptor 1) [61], a protein of 375 amino acids encoded by a gene located in chromosome 7p22.3 [61, 62]. GPER-1 activation triggers a non-genomic or “fast” intracellular signaling cascade characterized by cAMP production and increased intracellular calcium levels [63, 64], Src activation through Gβγ, with subsequent release of HB-EGF (heparin-binding EGF-like growth factor) and transactivation of EGFR (epidermal growth factor receptor) [61]. In addition, the activation of phospholipase C and cFos and several kinases such as ERK1/2 MAPK, PI3K (phosphoinositol 3-kinase), and Akt has also been described [50, 61, 63, 64].
In female GPER-1 null mice, an alteration of glucose homeostasis has been observed associated with a low release of insulin, reduced bone growth, and increased blood pressure [65] whereas male knock-out mice suffer deterioration of the cardiac function [66]. Furthermore, GPER-1 also modulates the immune system, inducing apoptosis of T cells and inhibiting the inflammatory process [67]. In summary, GPER-1 promotes a series of key biological functions attributed exclusively to nuclear α and β receptors in reproductive tissues, the cardiovascular system, the immune system, and the nervous system, among others [61]. GPER-1 has been linked to regulation of growth, migration, and survival of cancer cells [68] since it is expressed in ERα-positive and -negative breast tumors and their corresponding human breast cancer cell lines [50]. Clinical investigations have shown that patients with GPER-1 positive breast tumors and four to six months of tamoxifen treatment developed resistance to therapy and suffered an increase in breast tumor mass and reduced survival [68, 69, 70]. GPER-1 activation also produces an increase in the number of breast cancer stem cells (CSCs) by activating the TAZ protein (transcriptional coactivator with PDZ-binding motif), one of the components of the Hippo signaling pathway [71]. The ability to reprogram CSCs is also attributed to elevated TAZ in breast cancer [72]. A recent investigation using tumor cells isolated from ERα/PR-positive breast tumors showed that silencing of GPER-1 generated,
In general, xenoestrogens have been shown to have similar binding affinities for ERα, ERβ, and GPER-1. Interestingly, the phytoestrogen genistein and BPA have high affinity for GPER-1 [75]. It has been shown that nanomolar concentrations of BPA stimulate the proliferation of TM4 mouse Sertoli cells. Exposure of TM4 cells to ICI 182,780 or G15 (a GPER-1 antagonist) abolished the proliferative response promoted by BPA, pointing out a strong dependence from ERα/ERβ and GPER-1 [76]. In addition, it has been shown that BPA can produce a hypothalamic disrupting effect, particularly on the gonadotropin-releasing hormone (GnRH) release axis and, therefore, on the reproductive cycle in humans [77]. Moreover, nanomolar concentrations of BPA induce through GPER-1 and αvβ3 integrin, which acts as a vitronectin receptor, the proliferation of male germ cells [78].
A study using triple-negative breast cancer cells (TNBC) showed that BPS trigger cancer cells migration, through activation of the GPER/Hippo-YAP signaling pathway. The dephosphorylation of YAP (yes-associated protein) promotes its accumulation in the nucleus, upregulating
The inflammatory response is an important component of many diseases, including metabolic diseases and cancer. Notably, BPA and BPS promote persistent inflammatory states through increased expression of IL-19, EGFR, and TGF-β, among other regulatory molecules [82, 83]. Interestingly, biological fluids from cancer patients contain elevated levels of the bioactive peptide hormones known as kinins [84], and the kinin B1 receptor (B1R), another member of the GPCR family stimulated by kinin B1R agonists (Lys-des[Arg9]bradykinin or des[Arg9]bradykinin), is expressed in ductal breast carcinoma
Specific angiotensin-binding sites in tissues were discovered in the 1960s by Merlin Bumpus, following tracking of radioactive angiotensin infused into live rats [88]. The physiological relevance of this finding was related to the best-known responses triggered by angiotensins, such as vasoconstriction or aldosterone secretion [88, 89]. Subsequently, the specific and saturable binding of radiolabeled angiotensin was demonstrated in homogenates, subcellular fractions, and tissues of several species, including humans [90]. Additionally, pharmacological experiments showed different tissue responses to angiotensin and the presence of different types of angiotensin receptor (AT) proteins [91, 92]. The classification of angiotensin receptors was initially somewhat confusing, but today two types of receptors are formally recognized and called AT1 and AT2 [93, 94, 95]. The human AT1 receptor is encoded by a single gene located on the q arm, band 22 of chromosome 3 and its distribution is quite wide in adult tissues [89, 94]. AT1 activation triggers an intracellular signaling cascade that promotes the phosphorylation of proteins that participate in smooth muscle contraction, aldosterone secretion, cell growth, and cell proliferation [96]. By comparison, the gene that encodes the AT2 receptor is located on the X chromosome [93], expressing itself predominantly during intrauterine development though its levels have been found to increase due to stress or tissue damage [96]. Physiologically, the activity of AT2 receptor antagonizes that of the AT1 receptor [94, 96]. Since their discovery, angiotensin receptors have been considered important therapeutic targets for hypertension, heart and kidney failure, and other types of vascular diseases [10]. Moreover, angiotensin receptors have also been involved in the development of different types of metabolic and neoplastic diseases.
One of the most important theories elaborated to explain the origin and persistence of cancer in modern societies deals with CSCs, key cellular players first isolated in the 1990s by John E. Dick from human acute myeloid leukemia cells [97]. So far, CSCs have been identified in different types of tumors as a subpopulation of cancer cells with self-renewal and multipotency properties, capable of initiating and maintaining carcinogenesis, through clones with different degrees of differentiation, and responsible for resistance to treatment strategies, metastases, and disease relapse [34, 98]. Recent evidence indicates that the RAS pathway is crucial for an appropriate tumor microenvironment and maintenance and differentiation of CSCs [36, 97, 98, 99].
Overexpression of the AT2 receptor stimulates the differentiation of mesenchymal stem cells [99], and signaling via AT1 or AT2 receptors can condition the hematopoietic lineage [98]. Expression of angiotensin receptors and other members of the RAS pathway in CSCs suggests that new therapeutic routes may emerge for several types of cancer [10, 100, 101, 102]. Human embryonic cells exposed to low concentrations of BPA upregulate the expression of Oct4 and Nanog proteins, two early differentiation markers of mammary epithelial cells [103]. Another possible regulator of CSCs, activated by BPA, is bone morphogenetic protein [104]; it has been suggested that bone morphogenetic protein 2 initiates the transformation of stem cells toward a malignant phenotype [105]. Similarly, the presence of angiotensin II has been verified in breast cancer epithelial cells [102, 106] and the stroma [102] and overexpression of AT1 receptor in MCF-7 cells has been associated with an increased capacity for cell migration, invasion, proliferation [101, 107], and release of MMP-9 [107], responses associated with phosphorylation of ERK1/2 MAPK [107]. Interestingly, most of the effects of angiotensin II on cell proliferation and activation of the Ras-Raf-MAPK pathway and the transcription factors NF-κB and CREB can be inhibited by an AT1 interfering RNA, plus treatment with irbesartan, an AT1 pharmacological antagonist [107]. On the other hand, a study in nonmetastatic operable breast tumors determined the presence of AT2 receptors in up to 35% of cases whereas tumors expressing the AT1 receptor corresponded to stage III and showed an increased number of mitosis and vascularization [108].
Considering that inflammation and increased angiogenesis are two events directly associated with angiotensin receptors’ dysregulation, these receptors have been proposed to contribute significantly to the development of neoplasia, especially if we consider the possibility that they could be activated by bisphenols [107, 108, 109].
Evolutionarily, it is estimated that the origin of the chemokine system dates back about 650 million years ago [110]. This system has undergone great structural and functional diversification, contributing to the physiological activity of the different tissues of vertebrates [110, 111]. The first chemokine was described in 1977 by identifying the sequence and activity of platelet factor 4 (PF-4) [112]. In 1985, gamma interferon, another chemokine with high homology with PF-4 and proinflammatory activity, was discovered [113]. Subsequently, Yoshimura et al. isolated and described a monocyte chemotactic protein (MCP-1), which is currently recognized as one of the most potent monocyte activators [114]. Initially, chemokines were given names associated with their biological activity, but in order to limit the generation of a diversity of names due to the increasing amount of chemokines discovered, a nomenclature was created in the year 2000 [115]. Currently, chemokines are characterized by the presence of four cysteine residues involved in their 3-dimensional shape; chemokines are classified into four main subfamilies: CC, CXC, XC, and CX3C followed by a number (the “X” corresponds to an amino acid that can change) [115].
At the beginning of the 1990s it was determined that stimulation of leukocytes by proinflammatory chemokines induced a transient increase in intracellular calcium levels [116, 117]; this observation constituted one of the first indications of chemokine receptors’ activity such as GPCRs-dependent chemokines [111, 115]. Initially it was thought that the activity of chemokine receptors was limited to modulation of certain aspects of the immune response, such as the recruitment of neutrophils during acute inflammation or of monocytes during chronic inflammation. However, it is currently considered that practically any cell type in the body can express chemokine receptors and not just leukocytes [111, 118]. Similarly, it is estimated that around 20 chemokine receptors can recognize the more than 50 chemokines studied so far [118, 119]. This opens a range of biological responses commanded by chemokine receptors and accounts for versatility of these receptors in their interaction with chemokines including a role in the pathophysiology of cancer. The first investigation that evidenced this activity used a model of murine lymphoma and demonstrated the association between MCP-1 (current CCL2) with promotion of tissue invasion [120]. Following this finding, the activity of chemokine receptors in the initiation and progression of different types of cancers has been demonstrated [111, 121]. In breast cancer, chemokine receptors can downregulate the immune response, favoring tumor progression [119, 121] by promoting tumor growth and survival signals [119]. The chemokine system has also been related to the maintenance of CSCs, through modulation of tumor microenvironment [111, 119, 121]. Although there are still many factors to be clarified, it has been established that the chemokine system significantly strengthens carcinogenic activity by promoting angiogenesis. Actually, the chemokine receptors expressed in endothelial cells and displaying high proangiogenic activity are CXCR2 (whose ligands are CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8), and CXCR1 (whose ligand is CXCL8, one of the most potent angiogenic molecules) [119]. Additionally, it is known that CXCL8 induces higher levels of MMP-2 and MMP-9 and of VEGF, supporting its role in cancer cell migration and metastasis [111]. Recently, CXCL1-3 has been negatively correlated with the prognosis and survival of breast cancer patients [122]. Furthermore, a phytoestrogen, called quercetin (a flavonoid found in high concentrations in fruits and vegetables), has been found to have an inhibitory effect on cell proliferation, promoting apoptosis in MDA-MB-231 and MCF-7 cells and increasing CXCL1-2 secretion [122].
It has been suggested that early exposure to BPA can cause deleterious immunological effects, creating over time the organic conditions for development of a variety of disorders during adulthood; thus, bisphenols can dysregulate the chemokine network altering homeostasis of the immune system. A study in which a low dose of BPA was administered intratracheally in six-week-old male mice suggests that BPA exacerbates the allergic process of the airways through the expression of CXCR4 receptors in antigen-presenting cells [123]. Additionally, it has been estimated that 10 μM BPA, BPS, and BPAF increase secretion levels of chemokines, such as CXCL8 (IL-8), reducing the viability of human macrophages [124]; this effect is partially reversed by exposure to genistein (one of the most common phytoestrogens) [124].
Notably, 17β-estradiol increases the expression of CXC12 and its receptor CXCR4 in MCF-7 cells but inhibits the expression of CXCR7, the other receptor for this chemokine. Overexpression of CXC12 and CXCR4 is important for the increase in the proliferation rate of breast cancer cells stimulated with 17β-estradiol. By contrast, high levels of CXCR7 are related to the basal growth of tumor cells [125]. These effects can be explained molecularly by the regulatory effect of 17β-estradiol on the level of chromatin compaction in the promoters of genes related to chemokines.
Furthermore, the activity of the chemokine network has been associated with a series of estrogenic compounds in estrogen-sensitive breast cancer cells. Genistein and BPA (in addition to estrogen) have been shown to stimulate CXC12 synthesis and secretion in T47D breast cancer cells [126]. Similarly, it has been observed that BPAF stimulates proliferation of T47D cells, in a dose-dependent manner, promoting transcription and secretion of CXCL12, while the use of a shRNA or selective inhibition of CXCL12 significantly reduced the activity of CXCL12 and cell proliferation [127]. Dysregulation of the chemokine network by BPs has been associated, in humans and animals, with a variety of adverse effects both on the development and on the structure of the mammary gland, highlighting the generation of intraductal hyperplasia and carcinoma
In perspective, the set of experimental results indicates that bisphenols, particularly BPA and BPAF, target the mammary gland, affecting the expression of chemokine receptors and their ligands, alterations that have been associated with changes in normal development. Although an important part of the research indicates a possible cross-talk between nuclear estrogen receptors, GPCRs and bisphenols to alter homeostasis of the chemokine system, this interactions have so far not been directly addressed and remain largely unknown.
Epinephrine and norepinephrine bind to specific GPCRs referred to as adrenergic receptors, modulating physiological responses such as metabolism, vascular tone, and cell proliferation. These receptors are classified into three types, which are subdivided into the following subtypes: α1-adrenergic (α1A, α1B, α1D), α2-adrenergic (α2A, α2B, α2C), and β-adrenergic (β1, β2, β3) [130, 131]. In general, α-adrenergic receptors have a vasoconstrictive effect and produce excitation in the uterus, heart, and blood vessels and have a relaxing effect in the intestine [132]. On the other hand, β-adrenergic receptors have a vasodilator effect, but a vasoconstrictor activity in the uterus and an excitatory effect in the myocardium [131, 132]. By binding to catecholamines, AR activate various signaling pathways that depend on heterotrimeric G proteins, which use phospholipase C and adenyl cyclase to produce second messengers that activate cytosolic kinases, which by translocating to the nucleus modulate different transcription factors [133]. Two single nucleotide polymorphisms of the α2-adrenergic receptor gene (rs1800544 and rs553668) have been considered as useful tools to predict the severity of invasive breast cancer and their relation with metabolic alterations [130]. Presence of AR has been described in human epithelial breast cells [134, 135] and in adipocytes of breast tissue [131, 136]. Furthermore, stimulation of α and β AR by catecholamines has been shown to stimulate proliferation and migration of non-tumor (MCF-10A) and neoplastic (MCF-7 and MDA-MB-231) breast epithelial cells, generating an increase in cAMP levels, effects that are reversed by the use of AR antagonists [135, 136].
Prenatal exposure of mice to BPA (10 μg/kg body weight) and its binding to α2-adrenergic receptors changed the binding affinity of adrenaline to α2-adrenergic receptors in the locus coeruleus and the medial preoptic area of the brain and eliminated the behavioral differences between males and females related to emotion and anxiety [137]. Other studies have indicated that intrauterine exposure to BPA can alter the programming of most sensitive brain regions to steroids, differentially affecting men and women [51, 138]. On the other hand, both BPA and BPS have been shown to promote lipid accumulation and differentiation of murine 3 T3-L1 adipocytes in a dose-dependent manner though BPS displayed more adipogenicity than BPA [136]. Interestingly, it has been established that alterations in the typical responses of the sympathetic nervous system and its signaling pathways alter the normal metabolic balance, generating conditions for the establishment of disorders, such as obesity and type II diabetes mellitus, and consequently increasing the risk for cancer development [133].
Although there is no conclusive evidence to establish a direct relationship between bisphenols exposure and activation of AR in the context of breast cancer, experimental evidence indicates that they are involved in the development of breast cancer at a systemic level mediated by the sympathetic nervous system and through activation of α and β adrenergic receptors that are expressed in a great variety of cell types, including epithelial cells and adipocytes of the breast. On the other hand, interactions of AR with BPA in cells of the nervous system and with BPA and BPS during adipogenesis suggest that there exists a disruptor axis in sympathetic and metabolic activity to favor the development of neoplasia [136].
Although the concern about the deleterious effects of BPA on health has been recognized by the industry, in particular its relationship with cancer, the generation of new analogs such as BPB, BPF, and BPAF, which are part of products labeled as BPA-free, has not solved the problem [129]. Indeed,
Potential effects of bisphenols on GPCRs to favor development and progression of breast cancer. BPA, BPAF, BPS, bisphenols A, AF and S; GPER-1, G protein coupled estrogen receptor 1; AT, angiotensin; Erα, estrogen receptor alpha; TDP, 4,4′-thiodiphenol; ROS, reactive oxygen species.
More studies regarding the effects of bisphenols on angiotensin, adrenergic, chemokines, B1R, or even GPER-1 receptors are necessary to determine the real risks of these compounds for human health and the particular risk of developing cancer.
Understanding the role of endocrine disruptors and the mechanisms involved in their action is crucial to prevent the harm that bisphenols may cause in the population and to improve public health approaches to control cancer as well as some chronic diseases that afflict adult life.
Tumor angiogenesis or aberrant vascularization is considered a critical hallmark of tumor progression that is inevitable for tumor growth and metastatic spread [1]. This complex multistep process of new vasculature formation from pre-existing blood vessels is triggered by numerous signals from tumor cells in a phase of rapid growth [1]. The expression and secretion of various activators and inhibitors of angiogenesis are regulated by gene mutation (e.g., oncogenes and tumor-suppressor genes), and microenvironmental factors such as hypoxia and accumulation of different metabolites [2, 3]. As the growing tumor requires more blood vessels for nutrition and oxygen supply, angiogenic pathways are induced by tilting the balance toward pro-angiogenic molecules (angiogenic switch) to drive new blood vessel growth [3].
High expression levels of pro-angiogenic factors reflect the tumor aggressiveness [4]. Within the angiogenic cascade, a diverse group of mediators are shown in Figure 1. These molecules participate in the establishment of new tumor vessels in various ways. Among them, vascular endothelial growth factor (VEGF), also called VEGF-A, is key “molecular player” that modifies the endothelial barriers [3]. Moreover, VEGF as master regulator of angiogenesis in tumor tissues and its receptors, particularly VEGFR-2, have been implicated in tumor vascularization [3]. Namely, activation of VEGF/VEGFR-2 signaling pathways triggers an angiogenic program in the endothelial cells (ECs) [3]. Thus, VEGF binds to its cognate receptor that results in autophosphorylation of specific tyrosine residues of VEGFR-2, and consequential activation of multiple downstream signaling networks in the vascular endothelial cells through the recruiting of the MAP kinase (ERK1/2 and p38), PI3K, AKT, PLC-γ, and JAK-STAT [5, 6, 7]. The final result is the activation of full range of biological responses that modulate angiogenesis, including vascular permeability as well as endothelial cell proliferation, survival, adhesion, and migration.
Pro-angiogenic mediators implicated in the tumor angiogenesis. Plethora of mediators that promotes tumor angiogenesis can be categorized into several groups. VEGFs-vascular endothelial factors; FGFs-fibroblast growth factors; PDGFs-platelet-derived growth factor; EGFs-epidermal growth factor; TGFs-transforming growth factors; MMPs-matrix metalloproteinases; uPA-urokinase-type plasminogen activator; TNF-α-tumor necrosis factor-α; NO-nitric oxide; PGE2-prostaglandin E2; S1P-sphingosine-1-phosphate.
It is well established that VEGF is multifunctional molecule. VEGF has been first identified as vascular permeability factor, which exerts potent ability to increase vascular permeability, resulting in leakage of plasma protein and other molecules out of blood vessels [8]. Furthermore, VEGF is a potent mitogen that is highly specific for ECs and stimulates cell proliferation through VEGFR-2-mediated activation of the RAS/RAF/ERK/MAPK pathway [9]. Acting as survival factor for ECs, VEGF increases expression of the anti-apoptotic proteins Bcl-2 and A1 in the ECs [10]. On the other hand, VEGF also participates in tumor angiogenesis through increased migration and invasion of ECs by enhancing of matrix metalloproteinases (MMPs) release [3], and further amplifying angiogenesis by enhanced recruitment and homing of bone marrow derived vascular precursor cells [11]. PI3K/AKT signaling promotes VEGF-mediated invasion and metastasis of ECs [12].
VEGF expression is tightly regulated by plethora of transcriptional regulators, such as transcription factor called hypoxia-inducible factor (HIF). Beside them, VEGF signaling is also upregulated by multiple stimuli, including cytokines and galectins by tumor microenvironments. We discuss the role of IL-17 and Galectin-3 in mediating angiogenesis, either directly or indirectly
The tumor microenvironment represents a complex ecosystem involving interactions between tumor cells, ECs, epithelial cells, immune cells, fibroblasts, and the extracellular matrix, as well as secreted cytokines and growth factors. All of these factors provide essential support for the tumor progression. The dynamic cross-talk between angiogenesis and tumor microenvironment is important to further accelerate tumor growth and metastasis [13]. Thus, released angiogenic factors can promote tumor immunosuppression by inhibiting maturation of dendritic cells, increasing mobilization of immunosuppressive cells, and suppressing CD8 + T cell activity [14]. The tumor microenvironment, in turn, produces numerous soluble molecules and growth factors that stimulate angiogenesis, thus forming a vicious circle for tumor progression [15]. Increasing evidence suggests that Galectin-3 and IL-17 are the significant pieces of that puzzle that shape angiogenesis and tumor progression in many ways (Figure 2).
Pro-angiogenic effects of Galectin-3 and IL-17 as a part of tumor progression machinery. Many cells and soluble mediators create tumor microenvironment characterized by hypoxia, chronic inflammation, and immunosuppression. Galectin-3 participates in all steps of angiogenic cascade
Galectin-3, a unique chimaera-type member of the lectin family with selectivity for β-galactosides, is a versatile galectin involved in fundamental biological processes as well as various pathological circumstances [16, 17]. This evolutionary conserved molecule is usually overexpressed in variety types of tumor [18]. The ECs, immune cells, mesenchymal stem cells (MSCs), cancer-associated fibroblasts (CAFs), and myofibroblasts also produce and secrete Galectin-3 [19, 20, 21]. Galectin-3 expression is higher in endothelial progenitor cells as compared with normal ECs [22]. However, the tumor microenvironment, for example, tumor cells, inflammatory cells, and/or specific glycan-ligands on galectin-binding proteins, alters endothelial Galectin-3 expression as it provide most of the signals to which the ECs respond [23, 24]. Accordingly, pro-inflammatory cytokine IL-1β increases Galectin-3 expression by ECs [25]. ECs not only have a pivotal role in angiogenesis, but also they facilitate tumor invasion by secreting growth factors and extracellular matrix proteinases [26]. Released molecules sequentially increase chances that tumor cells enter to the circulation and metastasis [26].
Depending on cell types and cellular localization, Galectin-3 drives force in the diverse processes critical in tumor biology, including apoptosis, invasion, metastasis, immune surveillance, gene expression, and inflammation [27]. The cytoplasmic Galectin-3 blocks apoptotic machinery in tumor cells [16] through several mechanisms [28]. Galectin-3 secreted by tumor cells contributes to immunosuppression within the tumor microenvironment by polarizing to pro-tumor phenotype of tumor-associated macrophages 2 (TAM2), restricting T cell receptor clustering, and triggering apoptosis of CD8 + T lymphocytes, further facilitating tumor escape [29]. The upregulation of Galectin-3 by TAMs in the hypoxic regions of breast cancer promotes tumor cell migration and invasion and TAMs-mediated metastasis, as well as angiogenesis [30]. Expression of Galectin-3 in CAFs in breast cancer has been associated with distant metastasis [31]. Galectin-3 is also found in extracellular vesicles released by tumor cells, and it seems that this galectin is critical regulator in cell-cell and cell-extracellular matrix interactions [32]. Endothelial Galectin-3 expression in the lungs cooperates with poly-N-acetyl-lactosamine on N-glycans of B16-F1 murine melanoma cells, as a ligand for Galectin-3 [33]. Our data demonstrated that host-derived Galectin-3 facilitates B16-F1 cell adhesion to the metastatic target and interferes with efficiency of the antitumor immune response, thereby accelerating melanoma metastasis [34].
Tumor angiogenesis and chronic inflammation are closely related and often share common signaling pathways and molecules [35]. In addition to angiogenesis, Galectin-3 participates in shaping of tumor inflammatory microenvironment likely through the recruitment of inflammatory cells and modification of their polarization [36], as well as the production of pro-inflammatory cytokines that have been implicated in tumor promotion (Figure 2, [37]). Overexpressed pro-inflammatory IL-1, IL-6, and TNF-α contribute to various steps of tumor progression [38]. This cytokine network, required for the establishment of chronic inflammation in the tumor microenvironment, facilitates tumor growth and metastasis, enhances angiogenesis, and inhibits immune surveillance [39]. In particular, tumor-infiltrating Th17 lymphocytes orchestrate the maintenance of chronic inflammation. IL-6, TGF-β, and IL-1β are pivotal drivers of development of Th17 cells that secrete IL-17 and other cytokines. Although IL-23 is not required for triggering Th17 differentiation, it is essential for the function, survival, and expansion of Th17 lymphocytes in the inflamed tissue [40]. To increase inflammation, IL-17 induces mobilization, recruitment, and activation of different immune cells [40]. Interestingly, the finding of correlation between serum Galectin-3 levels and IL-17 production in patients with colorectal carcinoma has suggested that Galectin-3 may be one of the important modulators in the regulation of inflammatory conditions (Figure 2, [41]).
IL-17A (commonly referred to as IL-17) is the first discovered and best characterized member of the IL-17 family. Currently, six structurally related cytokines of IL-17 family have been identified (IL-17A to IL-17F) [42]. It is well documented that IL-17 plays protective role in infections, but here, we will review the multifunctional impacts of IL-17 on tumor biology.
IL-17 is mostly produced and secreted by Th17 lymphocytes, but it can be also produced by a broad spectrum of other cell populations [42]. Many studies describe the Th17-rich microenvironment in various types of tumor and that Th17 lymphocytes are endowed with a unique functional plasticity [40, 43]. Tumor cells, CAFs, and myeloid-derived suppressor cells (MDSCs) have been found to produce cytokine milieu that elicits recruitment and/or generation of Th17 lymphocytes [44, 45]. In addition, metabolic conditions present in the tumor milieu including indoleamine 2,3-dioxygenase (IDO) and hypoxia drive the differentiation of CD4 + T lymphocytes toward the Th17 lineage [46, 47]. Type 17 CD8 + T cytotoxic (Tc17) lymphocytes among tumor-infiltrating lymphocytes (TILs) were detected in nasopharyngeal [48] and gastric cancer [49]. Further, the main IL-17-producing cells in breast cancer are tumor-infiltrating γδT cells [50], and it seems that these TILs can promote the breast cancer progression [51]. NKT cells and group 3 innate lymphoid cells (ILC3s) represent other innate lymphocytes capable to produce IL-17 in the tumor microenvironment [52]. On the other hand, IL-17R is widely expressed in ECs, epithelial cells, fibroblasts, hematopoietic cells [53], and tumor cells [54], which implicates pleiotropic effects of IL-17 in the tumor microenvironment.
It seems that IL-17, as Roman god Janus, exerts two opposite faces in the tumor: “dark face” that drives tumor progression and “light face” responsible for the development of effective antitumor immunity. By
The critical events during angiogenic cascade such as activation, proliferation, and migration of ECs, as well as sprouting and tube formation, largely depend on Galectin-3 [66]. Initially, it has been observed that soluble Galectin-3 affects the migration of human umbilical vein endothelial cells (HUVECs) and capillary tube formation indicating its potential as chemoattractant for ECs [19]. This result has been confirmed by the increased tumor angiogenesis in the presence of Galectin-3
Ever since, Galectin-3 has been widely recognized as powerful pro-angiogenic molecule acting through various receptors on the ECs, subsequently activating distinct signaling pathways involved in tumor angiogenesis (Figure 2). Interactions between Galectin-3 and different integrins expressed on ECs supposed to be critical in controlling endothelial cell migration and adhesion. Pericyte-derived neural/glial antigen 2 (NG2) proteoglycan, Galectin-3, and α3β1 integrin form the membrane complex that triggers intracellular signaling involved in endothelial cell motility [69]. The blocking antibodies specific for αVβ3, α5β1, and α2β1 integrins interfere with endothelial cell adhesion to Galectin-3-coated surface [70]. In addition to integrins, Galectin-3 on endothelial cell migration markedly depends on direct binding to the membrane highly glycosylated cell adhesion molecule CD146, also known as melanoma cell adhesion molecule [71]. CD146 has been recognized as VEGFR-2 co-receptor and a potential target for anti-angiogenic therapy in tumors [72]. The interaction between Galectin-3 and CD146 is also responsible for secretion of pro-metastatic cytokines by ECs indicating that this axis regulates distinct events during tumor progression [73]. Galectin-3 interacts with glycoprotein endoglin expressed predominantly by ECs as a component of TGF-β receptor complex [74]. Endoglin is abundantly expressed by proliferating ECs indicating an important role of TGF-β/endoglin signaling in tumor vasculature formation [75]. Therefore, thanks to its carbohydrate-binding capacity, Galectin-3 interacts with different molecules expressed by ECs in tumor microenvironment. Moreover, truncated Galectin-3, containing CRD domain, interacts more efficiently with ECs in comparison with full-length molecule [76, 77]. Apart from CRD domain, it seems that angiostimulatory effect of Galectin-3 also depends on its N-terminal tail [78]. Full-length Galectin-3, including its ability to oligomerize through N-terminal domain, appears to be necessary to affect migration of ECs and capillary tube formation [78]. Taken together, angiostimulatory effect of Galectin-3 on distinct events during angiogenesis has been mediated by different parts of the molecule in both carbohydrate dependent and independent manner [68].
Further investigation of the molecular mechanisms responsible for Galectin-3 pro-angiogenic actions in tumors documented its involvement in modulation of VEGF and basic fibroblast growth factor (bFGF) signaling pathways. Galectin-3 binds N-glycans of integrin αvβ3
Galectin-3 has been described as a regulator of Jagged-1 (JAG1)/NOTCH1 signaling axis involved in tumor vasculature formation, in particular sprouting angiogenesis [83]. Under hypoxic condition, secreted Galectin-3 directly binds Notch ligand JAG1 in ECs thus activating pro-angiogenic JAG1/NOTCH1 signaling pathway. Galectin-3 prolongs the half-life of JAG1 over the Delta-like-4 (DLL4) thus affecting the balance between these molecules with opposite functions during angiogenic cascade [83, 84]. Interestingly, the proposed mechanism seems to be independent of VEGF/VEGFR signaling thus revealing novel potential targets in anti-angiogenic therapy.
In addition, Galectin-3 promotes the progression of hepatocellular carcinoma, including angiogenesis, through upregulation of β-catenin signaling [85]. Given its presence in different cellular compartments including nucleus, as well as its pleiotropic functions, Galectin-3 interferes with β-catenin pathway known to be active in various types of tumor. Galectin-3 activates PI3K/AKT signaling thus enhancing the phosphorylation and inactivation of key molecule of β-catenin degradation complex known as glycogen synthase kinase-3β (GSK-3β) [85, 86]. Subsequently, β-catenin accumulates in the nucleus and regulates the expression of genes involved in Galectin-3-mediated angiogenesis and epithelial-mesenchymal transition (EMT) [85].
Exosomes are vesicles secreted by living cells that participate in intercellular communication during essential processes such as proliferation, apoptosis, migration, and angiogenesis [87]. A highly glycosylated protein named lectin galactoside-binding soluble 3 binding protein (LGALS3BP), as a ligand for Galectin-3, has been previously recognized as a modulator of breast cancer angiogenesis that elevates VEGF expression via PI3K/AKT signaling pathway [88]. It has been shown recently that exosomes highly containing LGALS3BP affect endometrial cancer growth and angiogenesis [89]. The exosomes delivering LGALS3BP induce tumor cell proliferation and migration and HUVEC angiogenesis by triggering PI3K/AKT/VEGF signaling pathway [89].
The complex interplay between immunosuppression and angiogenesis is the integral part of tumor progression [29]. TAMs are the critical participants in tumor progression involved in the creation of immunosuppressive microenvironment thus enhancing metastasis and angiogenesis [90]. TAMs produce various pro-angiogenic molecules including growth factors (e.g., VEGF), chemokines, cytokines, as well as MMPs [90]. Galectin-3 promotes alternative activation of TAMs toward their pro-tumorigenic M2 phenotype (Figure 2, [29]). Increased angiogenesis in tumor is strongly associated with macrophage influx driven by elevated Galectin-3 expression [36]. Furthermore, Galectin-3 deficiency in both tumor tissue and stroma impairs angiogenesis
Collectively, thanks to its distinctive structure, Galectin-3 engages plenty of ligands both intracellularly and extracellularly, further interfering with various signaling pathways that regulate tumor angiogenesis. As a potential orchestrator of angiogenic cascade, Galectin-3 may be successfully targeted for anti-angiogenic tumor therapy.
Apart from galectins, certain cytokine network within the tumor microenvironment contributes to angiogenesis mainly through sophisticated interplay between different cells and extracellular matrix components as well as stimulation of key pro-angiogenic mediator productions.
The data from human subjects have indicated the strong association between increased angiogenicity and high frequency of tumor-infiltrating Th17 lymphocytes [92, 93]. IL-17 overexpression has been associated with higher microvascular density (MVD) in tumors [92]. In general, IL-17 indirectly amplifies angiogenesis mostly by inducing VEGF upregulation, as well as another angiogenic factors by tumor cells and CAFs [94, 95, 96]. Also, IL-17 induces the recruitment of inflammatory cells with angiogenic phenotype (e.g., macrophages and neutrophils) and immunosuppressive cells to the tumor microenvironment, which contributes to different points of angiogenesis in many ways (Figure 2, [59, 97]). Even though the IL-17 overexpression has been detected in tumors, mechanisms of IL-17 that contribute to angiogenesis are still unclear. IL-17/IL-17RA axis promotes the activation of JAK-STAT3 signaling pathway resulting in phosphorylation and nuclear translocation of STAT3 [98]. STAT3 is important regulator of VEGF expression [96]. Furthermore, IL-17-mediated tumor angiogenesis involves the activation of STAT3/GIV (Gα-interacting vesicle-associated protein, Girdin) signaling pathway and subsequent upregulation of its downstream target VEGF [99]. Wu et al. [96] determined that IL-17 induces VEGF upregulation and neovascularization through STAT3-mediated signaling pathway in tumor cells that could be blocked by JSI-124, an inhibitor of phosphorylated STAT3. In addition, other mediators such as granulocyte colony-stimulating factor (G-CSF), EGF, FGF, PDGF, and IL-6 exhibit their pro-angiogenic functions
IL-17 stimulates the production of IL-8 [102]. IL-8 acts directly on ECs by promoting their proliferation, survival, and migration, as well as indirectly by increasing the recruitment of neutrophils that are important source of angiogenic factors in tumor microenvironment [103]. IL-17 activates ECs to produce pro-inflammatory chemokines and cytokines, including CXCL1, IL-8, and granulocyte macrophage-colony-stimulating factor (GM-CSF), thus promoting neutrophil recruitment and adhesion to ECs [98]. It is well known that neutrophils release plethora of molecules that promotes angiogenesis. In particular, neutrophil-derived MMP-9 is critical for catalyzing angiogenic switch in tumor cells and releasing of sequestered growth factors (e.g., VEGF), as well as remodeling of extracellular matrix (ECM) components during angiogenesis [104].
Accumulation of neutrophils has been associated with higher MVD and therefore more aggressive phenotype of gastric cancer [105]. IL-17 enhances the production of many angiogenic CXC chemokines including CXCL1, CXCL5, CXCL6, and CXCL8 (IL-8) [106, 107]. Among these, CXCL1 and CXCL5 are the important chemoattractants for neutrophils [108]. The listed chemokines also promote CXCR2-dependent angiogenesis by stimulating the migration and proliferation of ECs [107]. On the other hand, IL-17 facilitates recruitment and activation of MDSCs in tumor microenvironment [109]. Apart from immunosuppressive activity, MDSCs modulate angiogenesis
Increased IL-17 and IL-23 mRNA expression has been associated with invasive gastric cancer [111]. We have shown that serum levels of IL-17 and IL-23 are significantly elevated in patients with colorectal carcinoma, but only IL-23 significantly correlated with overexpression of VEGF [112, 113]. It seems that IL-23 induces tumor-associated inflammation and angiogenesis thus promoting tumor growth [114]. IL-23-induced differentiation of Th17 lymphocytes suggests the possible indirect role of IL-23 in angiogenesis in IL-17-dependent manner (Figure 2).
There is evidence of tightly relationship between IL-17 and IL-33. Serum IL-33 has been associated with elevated IL-17 levels in patients with autoimmune hepatitis [115]. In addition, intestinal epithelial cells-derived IL-33 stimulates the recruitment of Th17 lymphocytes as the main cellular source of IL-17 in the small intestine [116]. Further, IL-6 can be critical trigger of IL-17 production, suggesting that the IL-33/IL-6/IL-17 axis plays a potential role in tumor biology [117]. It is well known that IL-33 is another pro-inflammatory cytokine with strong pro-angiogenic capacity (Figure 2). Similar to IL-17, IL-33 promotes the production of different pro-angiogenic factors, including VEGF and IL-8 [118]. It appears that IL-33 increases endothelial cell proliferation and vascular permeability [119]. Milosavljevic et al. [120] have found significantly higher expression of IL-33, IL-33 receptor, and VEGF in breast cancer. IL-33 and IL-33R expression correlated with VEGF expression in tumor tissue. VEGF expression positively correlated with MVD implicating that IL-33/IL-33R pathway is involved in breast cancer growth [120]. Further, tumor-derived IL-33 induces the recruitment of CD11b + Gr1+ and CD11b + F4/80+ myeloid cells to the tumor microenvironment further contributing to angiogenesis
Angiogenesis is complex and dynamic process in which more actors take part. To date, several anti-angiogenic agents, mainly acting
MCP is specifically inhibitor of Galectin-3, which significant decreases the MVD, suggesting that targeting Galectin-3 may open novel perspectives to interfere with tumor angiogenesis [67]. On the other hand, anti-angiogenic treatments have therapeutic limitations including varying degrees of response and resistance due to VEGF-independent mechanisms. Thus, VEGF blockade creates hypoxic conditions in the tumor, which in turn causes increased invasion and poorer survival by inducting of HIF-1α-dependent c-Met overexpression [126]. In hypoxic areas, tumor cells also survive oxygen-depleted environment by upregulating Galectin-3 expression, which may in turn increase tumor aggressiveness [127]. The simultaneous blockade of VEGF and Galectin-3 could be providing a more potent antitumor effect, which is mediated by, among others, anti-angiogenic mechanisms.
Finally, due to the fact that multiple actors are involved in tumor angiogenesis, Galectin-3 and IL-17 targeting is likely to improve the efficacy of current anti-angiogenic tumor therapy.
This work was supported by a grant from the Ministry of Education, Science and Technological Development, Serbia (ON175069 and ON175071), a bilateral project with People’s Republic of China (06/2018) and by the Faculty of Medical Sciences of the University of Kragujevac, Serbia (JP16/19).
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My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. 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Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. 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