Eicosanoid là gì

Disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer”
Disruption of homeostasis-induced signaling & crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer”
Article Number9Number of page(s)34SectionLife Sciences - MedicineDOIhttps://doi.org/10.1051/fopen/2018008Published online25 April 2019

1 Theodor-Billroth-Academy®, Germany, USA 2 INCORE, International Consortium of Research Excellence of the Theodor-Billroth-Academy®, Germany, USA 3 Department of Surgery, Carl-Thiem-Klinikum, Cottbus, Germany 4 Risk-Based Decisions Inc., Sacramento, CA, USA

* Corresponding author: b-bruecher
gmx.de

Received: 21 March 2018Accepted: 16 December 2018

Abstract

Inflammation is the body"s reaction to lớn pathogenic (biological or chemical) stimuli và covers a burgeoning menu of compounds và pathways that act in concert to maintain the health of the organism. Eicosanoids & related fatty acid derivatives can be formed from arachidonic acid và other polyenoic fatty acids via the cyclooxygenase và lipoxygenase pathways generating a variety of pro- and anti-inflammatory mediators, such as prostaglandins, leukotrienes, lipoxins, resolvins and others. The cytochrome P450 pathway leads lớn the formation of hydroxy fatty acids, such as 20-hydroxyeicosatetraenoic acid, và epoxy eicosanoids. Free radical reactions induced by reactive oxygen and/or nitrogen free radical species lead khổng lồ oxygenated lipids such as isoprostanes or isolevuglandins which also exhibit pro-inflammatory activities. Eicosanoids & their metabolites play fundamental endocrine, autocrine and paracrine roles in both physiological & pathological signaling in various diseases. These molecules induce various unsaturated fatty acid dependent signaling pathways that influence crosstalk, alter cell–cell interactions, and result in a wide spectrum of cellular dysfunctions including those of the tissue microenvironment. Although the complete role of eicosanoids, including that of the recently elucidated anti-inflammatory specialized pro-resolving lipid mediators (SPMs), e.g. Lipoxins, resolvins, protectins và maresins, is not completely understood, the result of unremitting chronic inflammation is fostering early stages of carcinogenesis. Chronic inflammation facilitates the transition from a normal cell to a cancerous one. The disruption of homeostasis across a wide, but identifiable, swath of diverse molecular pathways creates a micromilieu which constitutes an early và necessary step in the 6-step sequence of carcinogenesis for the vast majority of cancers, termed “sporadic cancers”.

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Key words: 20-HETE / Cancer / Carcinogenesis / Cell transition / Chronic inflammation / Cyclooxygenase / Cox / EET / Eicosanoids / Epidemiology / Epigenetics / Fibrosis / Genomics / Leukotrienes / microRNA / Mutation / Pathogenesis / Precancerous niche / Proteomics / Reactive oxygen species / ROS / Somatic mutation


© B.L.D.M. Brücher và I.S. Jamall, Published by EDP Sciences 2019


*
This is an mở cửa Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Introduction

The term eicosanoids comes from the Ancient Greek term ‘εἴκοσι’ ‎(eíkosi) meaning twenty. A chain of 20 polyunsaturated fatty acids (PUFA) is found in every mammalian cell with đôi mươi carbon atoms & 4 double bonds in the cis-position also known as arachidonic acids (AA) & named all-cis-5,8,11,14-eicosatetraenoic acid <1>. C20H32O2, 20:4(ω-6) is the chemical formular for omega-6 (ω-6) PUFA in which 20:4 refers lớn its đôi mươi carbon atom chain with four double bonds & ω-6 refers to the position of the first double bond from the last, omega carbon atom. AA are found in animal và human tissue, in plants, và in food <1–6>. AA are esterified to lớn membrane phospholipids. We now recognize their importance “for normal cellular membrane fluidity, but also as a substrate for numerous enzymatic transformations that form biologically active lipid mediators, such as prostaglandins, leukotrienes, epoxyeicosatetraenoic acids, and endocannabinoids” <5>.

Although scientists investigated neutral fats, such as glycerins and phospholipids, as far back as in the 19th century <7–10 reviewed in 11–13>, significant progress began in the early days of X-ray crystallography <14 reviewed in 5>. Fish oil studies took place between 1899 và 1906 <15–17>, and the Japanese chemist, Mitsumaru Tsujimoto (1877–1940), described how the addition of bromine could result in products of PUFA which could then be crystalized <17>. The British physiologist, Sir Percival Hartley (1881–1957), was the first khổng lồ isolate & purify AA & understood that these fatty acids had four double bonds <18 reviewed in 5,19>. The German chemical engineer, Julius Isidor Lewkowitsch (1857–1913), moved lớn England in 1887 and in 1913 coined the term “arachidonic acid” for those fatty acids which had been described earlier by Sir Hartley <20>.

It was observed that the application of human seminal fluid induced uterine contractions <21 reviewed in 22>, which later was identified as due lớn lipophilic compounds <23>. Von Euler thought that such compounds were produced by the prostate and therefore named these as prostaglandins (PGs) <24>. There is an alternative reason for the name of PGs, which is the 5-membered prostane ring in its structure. It was Karl Sune Detlof Bergström (1916–2004) và Jan Sjövall who showed that PGs come from seminal vesicles and isolated PG E (PGE) và PG F2alpha (PGF2α) <25>. Two independent groups showed that PGs are derived from essential fatty acids <26,27>. Sir John Robert Vane (1927–2004) showed that PG synthesis could be inhibited by aspirin and aspirin-like drugs <28>. In 1982, Vane và Bergström received the Nobel Prize for the discoveries of PGs, và Samuelsson for the discoveries of leukotrienes.

Due lớn their complexity, the following discussion of eicosanoids contains their pathways of cyclooxygenases (Cox), lipoxygenase (ALOX), cytochrome P450 (CYP) and reactive oxygen species (ROS) and/or reactive nitrogen species (RNS), followed by unsaturated fatty acids & the recently discovered specialized anti-inflammatory lipid mediators (SPMs).

Eicosanoids

Eicosanoids contain signal-mediating molecules such as PGs, prostacyclines, thromboxanes (TXAs), leukotrienes (LTs), và related fatty acid derivatives which are integrated into the phospholipids of the cellular membranes formed from PUFA, especially the AA & other polyenioic fatty acids through four pathways <1,6> namely:

For some time, eicosanoids have been known lớn be associated with diarrhea <52> & inflammation <53>, and it was known that exogenous AA resulted in PGE synthesis <54>. Furthermore, that PGE was produced by mast cells <55,56>, polymorphonuclear leukocytes <57>, and macrophages <58>. Once the inflammatory effect of PGs were identified <59,60>, contradictory findings were reported which suggested that PGs act as a turn-on/off mediator relevant for homoestasis <61,62> and that PGs were not accumulated but instead were newly synthesized <56>.

One key checkpoint of AA metabolism is phospholipase A2 (PLA2); this enzyme was first isolated và purified from the venom of Vipera berus in 1971 <63>. Later the purification, sequencing & cloning of the first human non-pancreatic form obtained from synovial arthritic knee fluid (a point of inflammation) was identified <64,65>. A PLA2 superfamily has since been recognized <66>.

The substrate for Cox, ALOX & CYP to lớn generate eicosanoids are the AA. PLA2 in the cytosol is a key control checkpoint for inflammation and acts by hydrolyzing AA from membrane phospholipids <67>. The crystalline structure of human pancreatic PLA2 was determined <68> including its anti-bacterial and anti-viral functions <69,70>. PLA2s are expressed by macrophages, monocytes, T cells, mast cells, và neutrophils <71> và we know that the PLA2 in the cytoplasm responsible for the production of lipid mediators in human macrophages is cytosolic PLA2-alpha <72 reviewed in 66>. PLA2 knockdown in mice results in less PG synthesis, decreased inflammation, & decreased cancer development <73>. The anti-inflammatory effect of zinc is thought khổng lồ be mediated by inhibition of PLA2 <74>.

RAF proto-oncogene serine/mitogen-activated protein kinase kinase 1,2/threonine-protein kinase/extracellular signal-regulated kinase (Raf1/MEK1,2/Erk1,2) is activated by protein kinase C (PKC) activators such as phorbol esters but after stimulation of Erk2 phosphorylation, e.g., endotoxin. This pathway is only partially inhibited showing that there is a PKC independent pathway involved in E2k2 phosphorylation. The authors showed that using the selective inhibitor bis-indolylmaleimide (BIM) inhibited arachidonate metabolites from activated macrophages and that PKC-dependent Erk2-phosphorylation by the benzamide derivative JM34, which inhibits tumor necrosis factor alpha (TNFα) from macrophages, and is based on its inhibitory effect on PLA2 activation <75>.

Cyclooxygenase (Cox) pathway và pro- and anti-inflammatory Prostaglandins (PGs) (Fig. 1)

Increased cyclooxygenase 2 (Cox-2) in human colorectal adenomas and adenocarcinomas was first reported in 1994 <76> followed by the association of Cox-2 with chronic inflammation and colorectal cancer (CRC) <77–79>. The degree of malignancy in lung cancer is directly correlated with Cox-2 expression <80>. Co-localization of HBx with the inner mitochondrial cytochrome c oxidase protein COXIII in liver cancer cells upregulates Cox-2 with consecutive ROS-induced cell growth <81>.

It is known that PGs have multiple effects and are involved in inflammatory diseases such as rheumathoid arthritis, asthma, cardiovascular diseases, và cancer <22,82–89>.

There is an association of cyclic adenosine 3′,5′-monophosphate (cAMP) và PGs. CAMP was shown lớn be activated or abnormally regulated in neoplasia <90,91> but its impact in cancer is controversial as it was suggested cAMP has an inverse correlation with tumor growth <92> or is involved in hormone-induced tumor growth arrest <93>, compared to the interrelationship between cAMP and 3′,5′-cyclic guanosine monophosphate (cGMP) <94>.

Mouse-derived fibroblasts transformed by the oncogenic polyomavirus, simian virus (SV40), resulted in constant cAMP activity. On the other hand, SV40-transformed rat fibroblasts show decreased cAMP levels. Stimulating cAMP with PGs revealed that this phenomenon depends on prostaglandin E2 (PGE2). PGF2α & prostaglandin B1 (PGB1) were more effective as compared khổng lồ prostaglandin A2 (PGA2) <95>. These experiments are important in that they reveal that PGs have different effects & that the same experiment in different species may produce different results.

PGs can be produced by tumors <96,97> and it was shown that PGs activate cAMP <98>. It has long been suspected that PGs and cAMP are involved in cell growth and cancer development <99> but this seems to lớn be dependent on which specific PG is involved. PGF1alpha (PGF1a) and PGF2alpha (PGF2a) vị not increase cAMP but 2-acetylaminofluorene (AAF)-induced cancer is associated with increased prostaglandin E1 (PGE1) <100>.

The two Cox isoforms, cyclooxygenase 1 (Cox-1) và Cox-2 utilize AA liberated from membrane phospholipids và catalyze the conversion of AA khổng lồ prostanoids. A splice variant of Cox-1, is cyclooxygenase 3 (Cox-3; also called Cox-1b or Cox-1 variant) <101>. Inflammation-induced Cox-2 is regulated by cytokines through macrophage activation <102> while Cox-1 is expressed constitutively <103>. Cox-2 is repressed physiologically by 1α,25(OH)2-cholecalciferol (equivalent to lớn 1α,25(OH)2 vi-ta-min D3, 1,25(OH)2D3, calcitriol), which is the active khung of vitamin D <104> và by glucocorticosteroids <105>.

Cox-2 mRNA & protein suppression by calcitriol leads to an increase of the PG catabolyzing enzyme, 15-hydroxyprostaglandin dehydrogenase, which in turn decreases levels of PGs & inflammatory cytokines <106>. The bioxygenase activity of Cox catalyzes the addition of two oxygens lớn AA producing an unstable cyclic hydroperoxide, prostaglandin G2 (PGG2), which is then reduced by Cox peroxidase activity khổng lồ an endoperoxide, prostaglandin H2 (PGH2). PGH2 is converted by various routes khổng lồ prostaglandins (e.g. PGE2), prostacyclin, and thromboxane A2 (TXA2) <107,108 reviewed in 101>.

In K562 human leukemia cells, PGE2 activates Ca2+-permeable transient receptor potential cation 7 (TRPC7) channels which can trigger apoptosis <109>. NAD− & NADP− radicals triggered by Cox peroxidase activity generate superoxide (O2 · −) <107 reviewed in 101>. Exogenous PGE2 in human patellar tendon fibroblasts (HPTFs) induce cell death và autophagy in a dose-dependent manner and mechanical stretching stimulates PGE2 resulting in cell death. In contrast, the Cox inhibitors, indomethacin & celecoxib, block PGE2 & reduce stretching-induced autophagy <110>. Lipopolysaccharide (LPS), TNFα, interleukin-1-alpha (IL-1α), và nitric oxide (NO) donor (NONOate) increases acute & or chronic inflammation in both in vivo and in vitro in bovines with enhanced PGE2, PGF2α, leukotriene B4 (LTB4), & leukotriene C4 (LTC4) <111,112>. Cox-1 expressions is increased at the mRNA cấp độ with prostaglandin E synthase (PGES) và transforming growth factor beta 1 (TGF-β1) in small bowel cancers <113>.

Lysophosphatidic acid (LPA) stimulates PGE2 production in stromal cells via the induction of prostaglandin-endoperoxide synthase 2 (PTGS2) và PGES mRNA expression in bovine endometrium <114> và through activating its G protein-coupled receptors (LPAR 1-6) directly influences aspects of endometriosis và reproductive tissue associated tumors <115>. PGE2 generated by Cox-2 in mice can protect beta-cells from apoptosis <116>.

Another Cox isoform, Cox-3, is under investigation & not completely elucidated. It was first disovered in 1989 & found primarily khổng lồ be expressed in the cerebral cortex & the heart <117>. We now know that Cox-3 is also found in the kidney & aorta <118>. Cox-3 is encoded by the same ren as Cox-1 with a difference of one intron and is under investigation <119>: Cox-3 derives from Cox-1 and is a smaller protein which is why it is also named partial Cox-1 (pCox-1), pCox-1 protein or Cox variant Cox-1V1. It is selectively inhibited by acetaminophen, phenacetin, antipyrine, & dipyrone, as well as by some non-steroidal anti-inflammatory drugs (NSAIDs) và useful in treating pain & fever. It shares all the catalytic features and important structural features of Cox-1 & −2 and its inhibition results in decreases of PGE2. Cox-3 may be involved in the regulation of body toàn thân temperature <120–122>. Cox-3 assays using an anti-Cox-3 polyclonal sera pCox-1a was shown khổng lồ have a little lower weight compared to Cox-3 (65kD) . NSAIDs inhibit PG synthesis and thereby function as anti-inflammatories và analgesics <124>.

Acetaminophen (Paracetamol®) was synthesized 1878 <125> & is included as a NSAID. It is interesting that it was reported not to lớn reduce inflammation or inhibit platelet aggregation & does not prolong bleeding time nor does it induce bleeding or ulceration <126> but it inhibits Cox-3 with a decrease in toàn thân temperature <122>. Cox-3 is highly expressed in cerebral endothelial cells & decreases PGE2 <127>. Cox-3 inhibition in rats increases PGE2, prostaglandin I2 (PGI2, prostacyclin), and TXA2 levels in rats in both inflammed and non-inflammed tissues suggesting that Cox-1 and Cox-2 are more specific and effective in terms of prostanoid synthesis of PGE2, PGI2, and TXA2 as compared to Cox-3. Furthermore, Cox-3 results in the augmentation of the vasodilatory activity of bradykinin by modifying Cox-1 & Cox-2 <128>.

Dipyrone (Metamizole®) inhibits Cox-3 more effectively than Cox-1 và Cox-2 and this effect is concentration dependent in that high levels (IC50 >1000 µM) inhibit all three isoforms, moderate levels (IC50: 350 µM) inhibt Cox-1 & Cox-3 & low levels (IC50: 52 µM) inhibit only Cox-3 <120 reviewed in 129,130>. It was suggested “that Cox inhibition achieved with dipyrone may be responsible for the augmentation of the smooth-muscle relaxing effects of the angiotensin-converting enzymes (ACEs) inhibitor losartan or lisinopril” while the combination of dipyrone with losartan inhibited phenylephrine (Phe), potassium chloride (KCl), & angiotensin II (Ang II) induced contractions compared lớn combined dipyrone with lisinopril inhibiting Phe and Ang II-induced contractions <130>.

All Cox enzymes (Cox-1, Cox-2 & Cox-3) have been found lớn be expressed in glioblastoma and normal brain tissues but Cox-3 expression was significant higher in cancerous versus normal tissues <131>. Inhibiting Cox-3 with acetaminophen decreased glioblastoma tumor kích cỡ by 71% in a rat model and by 43% using indomethacin. The exact molecular mechanisms still are unresolved. However, evidence such as epidemiology, molecular, genetic, polymorphisms, epigenetics, or proteomic Cox-3 research is warranted as information abouts its catalytic activity và signaling influence & crosstalk remains largely unknown.

Aspirin has long been known to be anti-inflammatory, anti-pyretic, và analgesic but this goes back khổng lồ the knowledge of the salicytes as the medicine of the early ages used in a powder from the bark of the willow tree lớn treat fevers and pain <132>. Aspirin was produced in 1853 by the French chemist, Charles Frédéric Gerhardt (1816–1856) <133> và the isolation of acetylsalicyclic acid (ASA) in pure form occurred in 1897 by Felix Hoffmann (1868–1946). The laboratory manager, Arthur Eichengrün (1867–1949), claimed that he had advised his co-worker Hoffmann to produce esters of salicyclic acid <134>, but Eichengrün was a German Jew & was arrested by the Nazis in 1943 và imprisoned in the Konzentrationslager Theresienstadt; after Eichengrün survived the KZ, he was confident enough to publish his claim in 1949 which was at first ignored. The British chemist, Walter Sneader, investigated the case during the 90s và came to the conclusion that attributing the discovery và first isolation of aspirin to the German chemist Felix Hoffmann (1868–1946) in 1897 had been wrong which was denied by Bayer <132,135–137>.

Aspirin affects the PG pathway by suppressing the production of PGs & TXAs through acetylation of a serine-rest of Cox-1 through prostaglandine-H2-synthasis-1 (PTGS1) and Cox-2 through PTGS2, discovered by British pharmacologist, Sir John Robert Vane (1927–2004) in 1971 <28>. For this he was awarded the Nobel Prize in 1982.

Salicylic acid (SA) has different effects in animal models và in the human body: (1) PG pathway, (2) formation of NO- radicals with decrease of leucocyte adhesion <138> (3) thrombocyte adhesion, (4) signaling through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway <139>, và (5) uncoupling of phosphorylation in mitochondria <140>.

Because of the inflammation-carcinogenesis association, aspirin data show an anticancer effect on overall cancer reduction <141–145>. Aspirin is effective in CRC <146–150> and may explain why it has an effect as a neoadjuvant khổng lồ radiochemotherapy in rectal cancer <151>. Aspirin was shown to lớn be effective in the precancerous adenomatosis polyposis coli or APC <152> & in terms of adenoma prior khổng lồ CRC <153>. Effective aspirin use against cancers had been shown in ovarian <154,155>, stomach <156–158>, pancreas <159,160>, hepatocellular carcinoma (HCC) <161>, breast <162,163>, prostate <164–166>, melanoma <167> & mesothelioma <168>. Furthermore, aspirin seems lớn be effective in inflammatory diseases such as Alzheimer"s <169> as well as in obesity, as morbid obesity increased cancer risk was reduced in those patients taking aspirin <170>.

However, the mechanistic signaling pathways of aspirin are still under investigation <171>. Aspirin is absorbed in high-pH environments (pH of proximal colon 5–8.0) <172,173>.

A meta-analysis of 5648 patients from 29 studies revealed that an overexpression of Cox-2 correlated with recurrence and survival in CRC. The analysis was judged to lớn have contradictory findings in terms of survival và recurrence and, therefore, it was not recommended until recently to use Cox-2 as a prognostic biomarker for CRC patients <149>. For completeness, some authors advise caution with regard to bleeding complications <159>.

Additional insights on the role of Cox pathways in cancer come from the following findings: (1) when TGF-β1 was applied khổng lồ human lung cancer A549 cells, it induced a downregulation of Cox-2 which resulted in a decrease of PGE2; (2) the researchers administered PGE2 or PGE2 receptor agonists, và found that it suppressed TGF-β1-induced actin remodeling <174> và PGE-2 inhibited the transition of a normal cell lớn a cancerous cell <175>. On the other hand, the continuous activation of macrophages led lớn interleukin 6 (IL-6)-induced increases in Cox-2 expression & serum PGE2 levels (Cox-2/PGE2 pathway), thus facilitating cell transition và metastasis in lung cancer <176>. The fact that increased levels of TNFα & IL-6 in patients in various stages of chronic kidney disease reflects an ongoing chronic inflammatory state <177> & highlights the importance of maintaining Cox homeostasis. This observation may explain why a continuous activation of T-cells with triggering of neutrophils, macrophages, và their cytokine release may be of greater consequence than previously thought. Excellent reviews about the different opinions on Cox isoenzymes, in vivo PGs, PGE2, PGI2, prostaglandin D2 (PGD2) and PGF2α, & the diversity of receptor subtypes (EP1-EP4) are available <178,179>.

Lipoxygenase (ALOX) pathway (Fig. 2)

The ALOX enzymes are another important class within AA metabolism. The abbreviation LOX here should not be mistaken for the 2nd available abbreviation of lysyl oxidase which constitutes a completely different enzyme. The various LOXs convert “arachidonic, linoleic, & other polyunsaturated fatty acids into biologically active metabolites that influence cell signaling, structure, and metabolism” <180 reviewed in 181>. The following LOXs are known such as arachidonate 5-lipoxygenase (5-LOX, ALOX5), 12-lipoxygenase (12-LOX, ALOX12, 12S-LOX), 15-LOXa, and 15-LOXb, respectively <79>.

Various hydroxyeicosatetraeonic acid (HETE) metabolites are formed via the lipoxygenase pathway, such as 5-hydroxyeicosatetraenoic acid (5-HETE), the reaction intermediate 5-hydroperoxy eicosatetraenoic acid (5-HpETE), 5-oxo-eicosatetraenoic acid (5-oxo-ETE), 8-hydroxyeicosatetraenoic acid (8-HETE), 12-hydroxyeicosatetraenoic acid (12-HETE), 15-hydroxyeicosatetraenoic acid (15-HETE) as well as the LTs, such as LTB4, LTC4, leukotriene D4 (LTD4) và leukotriene E4 (LTE4) <182>. The prostate, lung, colorectal, & ovarian cancer (PLCO) screening trial was a nested case-control study (157 cases/156 matched controls) that analyzed the pre-diagnostic serum levels of 31 AA/linoleic acid/alpha-linoleic acid metabolites with risk of developing ovarian cancer and found the following results to be positively associated with ovarian cancer: the identification risk-related fatty acid metabolites such as 8-HETE, 12,13-Dihydroxyoctadec-9-enoic acid (12,13-DHOME), 13-hydroxyoctadecadienoic acid (13-HODE) & 9-hydroxyoctadecadienoic acid (9-HODE) <154>.

Leukotrienes

Under the influence of mast cells, the expression of ALOX in immune cells such as leukocytes, eosinophils, basophils, neutrophils, macrophages, and platelets is activated resulting into the release of leukotrienes (LTs) from these cell types <183>. LTs are brokers of the inflammatory immune response and are found in body toàn thân fluids. Cysteinyl LTs (CysLTs) that involve the amino acid cysteine in their structure include LTC4, LTD4, LTE4 and LTF4, LTB4, LTG4 & leukotriene 5 (LTB5) <184>. LTB5 is the LTB4 equivalent formed from eicosapentaenoc acid and its chemotactic activity is several orders of magnitude lower than that of LTB4 <185>.

The LT receptor slow reacting substance (SRS) of anaphylaxis antagonist FPL-55712 was found lớn be much more effective in inhibiting LTE4 & LTF4 compared khổng lồ LTC4 & LTD4 <186> which raises the question if there are different bioactivities và if the concentrations in biological samples as well as bioactivity might be poorly understood.

As part of the immune response, LTs chemically attract T-cells <187,188>. Consequently, LTs have been linked lớn conditions associated with an inflammatory response such as asthma and allergy <189,190>, neurological diseases including dementia <191>, stroke, và ischemic events <192,193>, multiple sclerosis <194,195> and cancer <196–198>.

The association of various leukotrienes & cancers such as lung, esophageal và prostate cancer had been reported in detail . However, the cysteinyl leukotrienes LTC4, LTD4 và LTE4 induce various effects, such as cell recruitment, muscle contraction và vessel dilatation & permeability, & 5-LO signaling can induce increased LTs synthesis especially by leukocyte recruitment. The released exosomes with LTB4 can even create a gradient with additional para- và autocrine neutrophile stimulation and chemoattractivity.

The disruption of homeostatic mechanisms by LTs alters the tumor microenvironment & facilitates the progression of cancer <182> but it is important to cảnh báo that immune cells can play dual roles both producing immunosuppressive & inflammatory regulatory mediators <199>. Especially the interaction of the immune systems with its various cell types needs to be further elucidated as Cox-2 inhibition can result into LTB4 increase . The homeostasis of Cox-2 versus 5-LO seems khổng lồ be of importance if cell proliferation is effectively or ineffectively inhibited. For this, the various ALOX enzymes are likely to be important.

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Various LOX enzymes

Until now, our knowledge about the detailed biological functions of LOXs isoforms is limited <37>, và known arachidonate LOXs contain arachidonate 5-lipoxygenase (5-LOX, ALOX5, 15-LO-1, 15-LOX-1), 12-LOX, arachidonate 12-lipoxygenase type II (ALOX12B, 12R-LOX), arachidonate 15-lipoxygenase (ALOX15), & ALOX15 type II (ALOX15B) <200>.

5-LOX is upregulated in cancers of the lung <201>, esophagus <202>, colon <203>, pancreas <204–206> prostate <207,208>, breast <209>, brain và promyelitic leukemic HL-60 cells <210>, & in osteosarcoma <211> & mesothelioma <212>. 5-LOX is also found to be downregulated in colon adenoma of familial adenomatous polyposis (FAP) patients versus non-cancer colorectal mucosa <213>. 5-LOX derived from mast cells promote in the APC (Δ468) murine mã sản phẩm of colon polyposis triggers polyposis <214>. The inhibition of 5-LOX in a mouse breast cancer model revealed the opposite: abrogation of neutrophil pro-metastatic activity resulted in reduced metastasis <215>. We assume that these contradictory data may be a result of differences in expressed metabolites such as e.g. 5-HpETE & 5-HETE.

Increased expression of Cox-2 & ALOX5 are reported in lung cancer & knocking-out 5-LOX resulted into progression <216>. In this regard 5-LOX blockade resulted in an increase of apoptosis <200>. 5-LOX was shown khổng lồ be higher expressed in HCC versus normal liver tissues and inhibiting 5-LOX induces apoptosis & blocks cancer progression <217>. A 22-fold elevated expression of 15-lipoxygenase-2 in ovarian cancer compared lớn normal ovarian tissue was observed and 15-lipoxygenase-2 was augmented <218>. Increased 5-LOX metabolites enhanced TNFα và heparin-binding epidermal growth factor-like growth factor (HB-EGF) through upregulation of matrixmetalloproteinase 7 (MMP-7) which was associated with increased tumor-associated macrophages infiltration <219>. 5-LOX was also increased in brain cancer <210>, thyroid cancer together with promotion of metalloproteinase 9 (MMP-9) <220>.

Procarcinogenic LOXs include 5-, 8-lipoxygenase (8-LOX), and 12-LOX while 15-lipoxygenase-1 (15-LOX-1) & possibly 15-lipoxygenase-2 (15-LOX-2) which was previously thought khổng lồ be anticarcinogenic <221>. 15-LOX-1 is decreased in esophageal cancer but applying the Cox-2 inhibitor SC-236 lớn gastric cancer cells induced apoptosis without affecting Cox-1, Cox-2, 5-LOX and 12-LOX. Thus, the upregulation of 15-LOX-1 may be developed as a therapeutic target in the future <222>. NSAIDs can induce apoptosis in colon cancer cells through 15-LOX-1 upregulation in the absence of Cox-2 <181,221>. TGF-β1 induces SMAD4/4 with consequent increase of the 5-LOX promoter activity followed with upregulated 5-LOX expression <223> building yet another bridge khổng lồ chronic inflammation during carcinogenesis via the lipooxygeanse signaling pathways.

Chronic cystitis showed slight increases of 5-LOX and 12-LOX versus marked increase in bladder cancer tissues và inhibition of lipoxygenase resulted into “chromatin condensation, cellular shrinkage, small membrane bound bodies (apoptotic bodies) and cytoplasmic condensation” <224>. This effect was also shown in bladder cancer cells in vitro <225>. In canine osteosarcoma cells 5-LOX was upregulated in about 65% in the cytoplasm, cell culture và xenograft model and application of the canine 5-lipoxygenase inhibitor tepoxalin diminished xenograft tumor growth together with cell proliferation in mice <226>.

Applying the thromboxane synthetase và 5-lipoxygenase inhibitor ketoconazole versus placebo into melanoma cell incubated mice showed significantly reduced incidence of metastasis và tumor mass with better survival in the ketoconazole-treated mice compared to lớn placebo <227>. Recently CarbORev-5901 as a new carborane-based inhibitor of the 5-LOX was reported khổng lồ be more stable và effective in melanoma & colon cancer cell lines was reported <228>, but investigations in various cancers so far missing. It seems that 5-LOX is also constitutively highly expressed in patients with idiopathic pulmonary fibrosis <229>.

It was suggested that Cox-2 is responsible for the regulation of the lipid metabolism <230>. This goes in line with the findings that inhibiting 5-LOX và Cox-2 blocks colon cancer proliferation, migration, as well as invasion in vitro <231>. This may explain why NSAID intake might result in some một nửa reduction of the relative CRC risk <232,233> as the combined Cox-1 & Cox-2 activity is increased in CRC <234>. The non-enteroendocrine “tuft cells” which are referred khổng lồ chemosensory cells showed mainly Cox-1 overexpression while Cox-2 was primarily found in absorptive cells and are “rather constitute a distinct entity with transcription factor requirements for differentiation that differ from those of enterocytes, enteroendocrine, Paneth, and goblet cells” . Tuft cells first were reported in 1956 in rat trachea and mouse gastrointestinal tract <236,237 reviewed in 235>.

Inhibiting 5-LOX and the 5-lipoxygenase-activating protein (FLAP) by the tobacco carcinogen, 4-methylnitrosamino-1-(3-pyridyl)-1-butanone suppresses carcinogenesis <238> and modulating LOX by clearly defining pro- & anti-carcinogenic effects depend on which metabolite is used & may be an option in anticancer treatment <181>. Receptors for LTB4 are upregulated in gastric cancer but 5-LOX does not appear to lớn be involved in gastric <239> or in colon carcinogenesis in rodents <240> which may explain why 5-LOX is not widely observed in carcinogenesis or it may well be that 5-LOX itself may have its own homeostasis maintenance pathway. Furthermore, anti-Helicobacter therapy by Tanshinone IIA from Salvia miltiorrhiza Bge resulted in lower chronic inflammation & 5-LOX <241>. 15-LOX suppresses colitis associated colon cancer by inhibiting IL-6/signal transducers và activators of transcription (STAT3) signaling <242>. Therefore antagonizing 5-LOX and/or promoting 15-LOX is thought being effective as a future anti-cancer therapy. However, recent experiments with 15-LOX1 knockout mice suggested that this enzyme exhibits a pro-inflammatory role in the dextrane sodium sulfate induced mouse colitis model. In fact, these knockout mice were strongly protected from inflammatory symptoms <243>.

Cytochrome P450 pathway (CYP) & hydroxy fatty acids (20-HETE) (Fig. 3)

The CYP signaling pathway in AA metabolism involves the ω-hydroxylases và epoxygenases: “ω-hydroxylases convert AA into hydroxyeicosatetraenoic acids (HETEs) and epoxygenases which converts it lớn epoxyeicosatrienoic acids (EETs)” <79>.

20-hydroxyeicosatetraenoic acid (20-HETE)

Another underappreciated hàng hóa of PUFA metabolism rin the context of eicosanoids is the (CYP) metabolite, 20-HETE <244>, which has been in cardiovascular diseases <245> và cancers <246,247>. Downregulation of 20-HETE decreases proliferation in renal cancer cells <248>, & enzymes that catalyze the formation of 20-HETE, such as cytochrome P450 4A/F (CYP4A/F) are found in higher concentrations in ovarian cancer than in normal tissues <249>. Cytochrome P450 2J2 (CYP2J2) is highly expressed in hematologic malignant diseases & promotes tumor cell growth <250>. Future research on the metabolism of 20-HETE & its biosynthesizing cytochromes might demonstrate specifically how 20-HETE contributes to carcinogenesis. 20-HETE increases ACE mRNA, protein through NF-κB <251>.

Epoxyeicosatrienoic acids (EETs)

Another group of products of eicosanoid metabolism are the cytochrome P-450 metabolites, the EETs <252>. Cytochrome P450 2C (CYP2C) và cytochrome P450 2J (CYP2J) are CYPs epoxygenases that metabolize AA to lớn biologically active EETs (5,6-EET, 8,9-EET, 11,12-EET, & 14,15-EET), which in turn, are further “metabolized to lớn less active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH)” <253>.

The idea of using EETs in anticancer therapy emerged in the late 1980s <254,255>. An elevated CYP2J2 expression has been reported in esophageal, liver, breast, lung, & colorectal organs <250,256 reviewed in 253>. Markers such as these eicosanoids could serve as targets in cancer therapy <257>. The potential for such a use was demonstrated by the inhibition of sEH, which decreased NF-κB, TGF-β1/Smad3, & inflammatory signaling pathways, together with activating peroxisome proliferator-activated receptor (PPAR) isoforms with consequent treating effectively renal interstitial fibrogenesis in obstructive nephropathy in mice <258>.

Cytochrome P450 3A4 (CYP3A4) expression promotes STAT3-mediated breast cancer cell growth via 14,15-EET <259>. EET analogs và sEH inhibitors are thought to lớn have application in multiple diseases <260>, such as Parkinson"s <261>, renal interstitial fibrosis in obstructive nephropathy <258>, marrow or cord blood transplantation <262>, inflammatory bowel disease-associated cancer <263>, & other cancers <264,265>.

Elastase (ELA) is known to be induced by bacteria và regulates fibrosis và PG output; ELA-inhibition is assumed khổng lồ reduce “mare endometrial fibrosis by stimulating the production of anti-fibrotic PGE2 and inhibiting pro-fibrotic PGF2 α” <266>. In the rabbit, 5,6-EET stimulates endogenous PGE2 synthesis <267>.

11,12-EET triggers hematopoietic stem & progenitor cells (HSPCs) in zebra fish via the activator protein 1 (AP-1) & runt-related transcription factor 1 (RUNX1) transcription, independent of any hemogenic endothelium need for phosphatidylinositide 3-kinase (PI3K) pathway activation <262>. Dual inhibition with RAF-1 & sEH with trans-4-4-<3-(4-chloro-3-trifluoromethyl-phenyl)-ureido>-cyclohexyloxy-pyridine-2-carboxylic acid methylamide (t-CUPM) was reported to lớn be of potential use in preventing chronic pancreatitis và in ameliorating pancreatic cancer <268>. Greater 14,15-epoxyeicosatrienoic acid levels were reported in breast cancer tissue than in noncancerous tissue <265>.

EETs are rapidly metabolized, short-lived signaling molecules produced by various cell types và investigated & reported as potential targets for treating inflammation and cancer <269>. Lipid hydroperoxides (LOOHs), with vitamin C as a regulator, seem to be necessary for EET formation <270>. On the other hand, EETs have been seen as a double-edged sword in cardiovascular diseases & cancer concerning the use of anti-EET drugs <253>. The anti-inflammatory effects of soluble sEH inhibitors appear khổng lồ be independent of leukocyte recruitment <271>.

The CYP allele CYP3A7*1C is associated with adverse outcomes in chronic lymphocytic leukemia (CLL), breast cancer, & lung cancer <272>. CYP3A4, found mainly in liver & intestine, binds lớn N1-hexyl-N5-benzyl-biguanide (HBB) inhibiting the CYP3A4 AA epoxygenase activity that suppress intra-tumoral mechanistic target of rapamycin (mTOR) <273>. CYP2J2 metabolizes AA lớn anti-flammatory, −fibrotic & −oxidant 5,6-, 8,9-, 11,12-, và 14,15-EETs <274–279> resulting in a decrease of IL-1β, IL-8, TNF-α, sP- and sE-selectin together with decreased NF-κB p65 activation and degradation of IκBα which may be mediated though peroxisome proliferator-activated receptor gamma (PPARγ) activation <280,281>.

Furthermore, the epoxygenase-dependent metabolite, 11,12-EET, inhibits epithelial mãng cầu channels (ENaC) in the rat renal cortical region <282> (renal tubular epithelial cells) which is dependent on Cox activity and cell polarity <283>.

Another bridge khổng lồ chronic inflammation was recently shown. SEH plays a significant role in neurological diseases such as Parkinson or dementia <284> but also triggers obesity induced chronic colonic inflammation <285>. The importance of the research of LOXs may be recognized as most recently endogeneous nitro-fatty acids (NFAs) were identified as potential future new well tolerated chemotherapeutic drug candidates <286>.

Reactive oxygen and nitrogen species induced formation of EETs & oxygenated lipids

The không lấy phí radical story <287,288> started by the Swedish student John Rhodin in 1954 who reported in his doctorate microbodies <289>, which afterwards were “mistakenly suggested ….that they were precursors to lớn mitochondria” <290 reviewed in 291–293>. In 1966, these microbodies were described as peroxysomes by the British born Belgian biochemist Christian de Duve (1917–2013) <294>. At that time De Duve already had discovered new organelles & had termed lysosomes and endosomes; he also discovered important processes, such as autophagy, endocytosis and exocytosis <293>.

McCord & Fridovich created an inactive metal-free apoenzyme và adding copper resulted into some 80% recovery from dismutase activity; they reported superoxide dismutase (SOD) catalyzing “the dismutation or disproportionation of superoxide không lấy phí radical anions” of the superoxide (O2−) radical into both molecular oxygen (O2) and hydrogen peroxide (H2O2): O2− + O2− + 2H+ → O2 + H2O2 <295,296>. Saito et al. Investigated SOD in erythrocytes without finding a difference between young và elderly subjects <297>. Peroxisomes from fungi và plants contain antibiotics <298>, toxins <299>, & signaling molecules <300 reviewed in 292>, & liver peroxiosomes are involved in beta-oxidation of rare fatty acids <301–304>.

Today, three SOD families are known in regard to the metal cofactor và protein: (1) copper-zinc-SOD (Cu-Zn-SOD) in eukaryotes (animals/humans, plants, fungus) found in cytosol, peroxisomes, or chloroplast, (2) iron-SOD (Fe-SOD) or manganese-SOD (Mn-SOD) which are found in peroxisomes and mitochondria in prokaryotes (archaea and bacteria) và plants (Fe-SOD) or in humans (Mn-SOD) & (3) nickel-SOD (Ni-SOD) in prokaryotes <305>. There are not just intra- & intersubunit motions within the different subdomains of SOD known but there also seems to lớn be an intersubunit information exchange <306>.

Reactive oxygen (ROS) & reactive nitrogen species (RNS)

Reactive oxygen species (ROS) “are a family of molecules that are continuously generated, transformed và consumed in all living organisms as a consequence of aerobic life” <101,307,308> meaning ROS are naturally a metabolism hàng hóa relevant for homeostasis, physiology as well as for so-called oxidative stress, a term coined by Sies in 1985 <309 reviewed in 310,311>. ROS include nonradical derivatives of singulet oxygen (1O2), H2O2 and ozone (O3), & oxygen radicals such as hydroxyl radical (OH), & superoxide (O2 · −). When ROS & RNS react with unsaturated lipids, lipid hydroperoxides are formated, which can damage biomembranes and or inactivate proteins. The major source of ROS in most mammalian cells is the respiratory chain of the mitochondria and about 1–2% of the daliy oxygen consumption is converted to ROS (incomplete reduction of oxygen during cellular respiration). 1–2% does not really seems a lot but considering the fact thast a normal humen being consumes about 450 l of oxygen per day, a large number of ROS are normally produced. Luckily, most of these potentially damaging chemicals are readily detoxified by the anti-oxidative defense system. In addition, other ROS & RNS sources are the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) & xanthine oxidase (XO). Accumulation of ROS is prevented by SOD, which rapidly convert in the cytosol cytosolic và in the mitochondrial intermembrane space superoxide dismutase 1 (SOD1). Superoxide dismutase 2 (SOD2) is located in the mitochondrial matrix & contributes to detoxifying superoxide produced during cellular respiration <312–314>. As pointed out, “accumulation of superoxide is more associated with oxidative bít tất tay than redox signaling” <315>.

Reactive nitrogen species (RNS) are antimicrobial molecules; they are mainly generated by phagocytic cells & involve nitric oxide (NO), with its derivative peroxynitrite (ONOO−), nitrogen dioxide (NO2−), dinitrogen trioxide (N2O3), nitrous acid (HNO2), & others <316,317>. Both, ROS and RNS can modulate regulatory proteins và are linked to lớn each other in plants and animals/humans inducing consequent signaling <316,318>.

ROS is also involved in autophagy & the major source regulating ROS is superoxide (O2−) <319>. Mitochondrial ROS metabolism is needed for normal kRAS associated cancer cell proliferation <320>. AA metabolites such as 5-LOX & Cox can induce ROS through Nox stimulation <321 reviewed in 322>.

ROS have various physiological và pathophysiological damaging properties next lớn evolution và are an essential consecutive part of signaling for various physiologies as cellular adhesion, signaling và migration, apoptosis, lipid metabolism, stem cell differentiation, immune response, và sport, and during aerobic and anaerobic respiration as well as pathologies, such as e.g. Acute và chronic inflammation, atherosclerosis, renal diseases, arthritis, cardiovascular & neurodegenerative diseases, ageing, cancer . ROS levels are increased by ultraviolet (UV) radiation, cigarette smoking, và alcohol consumption. They are also elevated in infections and after an ischemia-reperfusion (I/R) injury. It has been suggested that the homeostasis of ROS production versus the capacity khổng lồ detoxify rapidly is what determines the degree of oxidative áp lực at any given time in a tissue or organ <101>. In synovial fibroblasts, ROS promote the phosphorylation of mitogen-activated protein kinases (MAPKs) and NF-κB through the activation of transforming growth factor beta-activated kinase 1 (TAK1), và lead to an increased expression of Cox-2 và PGE2 <325>. Further, even PGs induce Cox-2 expression <326>.

Abnormal ROS levels can result in MAPK and PI3K signaling with STAT3 activation và phosphorylation of SNAIL with E-Cadherin suppression & a loss of cell polarity <327>. A chronic increase in ROS by macrophages increases levels of C-X-C chemokine receptor type 4 (CXCR4) và trigger the transition of a normal cell lớn a cancer cell <328>. It seems that under physiological conditions, a Cox- and −ROS homeostasis exists. Both Cox-1 & Cox-2 are expressed in normal human gastric mucosa and in gastric ulcers; they are increased by an H. Pylori infection, but Cox-1 alone can increase gastric PGE2 production <329>. H. Pylori-infected gastric epithelium co-express gastrin, its receptors, cholecystokinin B receptor (CCK(B)-R), Cox-2, & prostaglandin <330>. The continuous stimulation of Cox-2 & NF-κB signaling results in a persistent increase of inflammatory cytokines such as TNFα & IL-6, as well as ROS and nitrogen-free radical species <331>. Skin samples from patients with chronologically aged and photoaged skin showed greater Cox-2 expression in keratinocytes & fibroblasts compared lớn that observed in younger individuals <332>.

Since a multi-billion market grew promising the health effects of antioxidants and creating a global dietary supplements industry that is expected to lớn grow in the U.S. Alone to lớn some $220 billion by 2022 <333>. The detailed understanding of the ROS complexity may not be as easy as earning money through the sale of antioxidants.

Applying the cytochrome c peroxidase assay lớn measure the rates of không tính phí H2O2 with a cytosolic steady-state concentration và a rate of 90 nmol/l/min/wet weight of liver revealed that “some (40–80%) of the H202 generated in the peroxisomes is destroyed inside the organelle, & that the remaining 20–60% diffuses to lớn the surrounding medium” <334>. Half-life times (T1/2) of ROS are short contain in between 335 reviewed in 336>: the very reactive OH radical has a T1/2 of approximately 10−9 s <337> compared to O2− and H2O2 in between 10−6 s và 10−5 s <338> respectively . There is hope using low màn chơi magnetic field lớn modulate cellular produced H2O2 <336>.

Unsaturated fatty acids (PUFAs)

Unsaturated fatty acids are associated with the Cox và LOX pathways. PUFAs are essential & have to ingested by external sources (food). They are associated with inflammation and cancer; the main two PUFAs families are metabolized through 6Δ desaturase, elongase, 5Δ desaturase, & 4Δ desaturase; those deriving from α-linolenic acid (ALA) result into eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) và are named family of omega-3 (n-3) PUFAs (ω-3 PUFAs) & are less inflammatory. In contrast, those deriving from linoleic acid (LA) result in gamma-linolenic acid (GLA), di-homo-gamma-linolenic acid (DGLA), AA, docosatetraenoic and docosapentaenoic acid and are part of the family of omega-6 (n-6) PUFAs (ω-6 PUFAs). The last (most far away from the carboxylic group) carbon-carbon double bond is found in the ω-6 position. ω-6 PUFAs are more pro-inflammatory while ω-3 PUFAs with the carbon-carbon double bond in the ω-3 position have more anti-inflammatory effects <340–344>. The third fatty acids family involves the non-essential monounsaturated fatt acid omega-9 (n-9), ω-9 MUFAs with the carbon-carbon double bond in the ω-9 position <345,346>. ω-9 MUFAs induce fatty acid oxidation và are associated with a greater anti-inflammatory effect in a sepsis model <347>, but showed direct associations with mortality within the Cardiovascular Health Study <348>. Furthermore, “high ω-9:ω-6 ratio và low ω-6:ω-3 ratio significantly reduced inflammatory response in rats submitted to dental extraction” <349>.

ω-3 PUFAs are anti-inflammatory. Their metabolism via the Cox / lipooxygenase pathway induce the formation of prostaglandin D3 (PGD3), prostaglandin F3alpha (PGF3α), prostaglandin I3 (PGI3), thromboxane A3 (TXA3), và LTs such as leukotriene A5 (LTA5), leukotriene B5 (LTB5), leukotriene C5 (LTC5) and and leukotriene D5 (LTD5). ω-6 PUFAs induce more pro-inflammatory effects triggering the biosynthesis of the 2-series of prostaglandins which comprises prostaglandin E2 (PGE2), prostaglandin F2alpha (PGF2α), PGD2, TXA2, and LTs LTB4, LTC4, LTD4 and LTE4.

The association of PUFAs with AA metabolism & Cox metabolism and inflammatory/anti-inflammatory effects & cancer/anti-cancer effects provides in vitro và in vivo evidence, that ω-6 PUFAs stimulate cancers of the oral cavity <350>, gastric <351,352>, colon <353–355>, liver <356,357>, prostate <358,359>, breast <360–364>, endometrium <365>, pancreas <366,367>, bladder <368>, urethial <369>, lung <370>, và melanoma cell growth <371–374> compared to lớn ω-3 PUFAs suppressing it. This is in accordance with our understanding of precancerous lesions <375–379>.

As PUFAs are directly associated with various signaling pathways và crosstalk in chronic inflammation, obesity, và the microbiome, these topics are reviewed separately within this Special Issue.

Due khổng lồ the above studies, the involvement of PGE2, and LTB4 involvement through Cox-1, Cox-2 và 5-LOX are thought lớn have a pro-carcinogenesis effects via inflammation <341,366,380>. Cox-2, PGE2 and EP2 và EP4 receptors stimulating pancreatic cancer cell growth while ω-3 PUFAs e.g. ω-3 PUFAs downregulates MMP-9 <381> and PGE2 by competitive effect in the AA metabolism <382>, & has anti-inflammatory effects <383>. Granulocyte-macrophage CSF colony stimulating factor (CSF) (gm-CSF) induce PLA2 activity with PLA2 protein and consequent trigger rat alveolar macrophages (but not peritoneal macrophages or peripheral blood monocytes) lớn generate LTB4 as well as the 5-lipoxygenase products LTC, và 5-HETE <384 reviewed in 385>.

Specialized pro-resolving lipid mediators (SPMs) (Figs. 2–4)

A new class of lipid mediators derived from AA and other polyenoic fatty acids are the family of specialized pro-resolving mediators (SPM). These signaling molecules are biosynthesized from AA and other frequently occurring polyenoic fatty acids (DHA, EPA) and function as counterregulators of pro-inflammatory stimuli inducing the resolution of inflammation <386–397>. This class of mediators involves lipoxins (LXs), resolvins (RVs), protectins (PDs) & maresins (MaRs); SPMs have distinct cellular và sometimes transcellular pathways of biosynthesis and they have been suggested khổng lồ be quick at the resolution of inflammation. LXs derive from ω-6 PUFAs và Rvs, PDs and MaRs from ω-3 PUFAs <387–391,393,395,396,398–400 reviewed in 397–405>.

Although not entirely clear at the present, the newly discovered anti-inflammatory và pro-resolving eicosanoids, such as lipoxins, resolvins, maresins và protectins could be one reason why multiple inflammatory changes in the tumor microenvironment directly results in a remodeled ECM. Furthermore, it could explain why the disruption of the homeostasis between anti- & pro-inflammatory mediators is needed, although there are additional pieces of missing information such as the period of time how long the disruption has khổng lồ occur with regard to lớn various pathogenic stimuli until a normal to lớn cancer cell transition can occur.