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Disruption of signaling homeostasis induced crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer”. Simplified scheme of the Disruption of signaling homeostasis induced crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer” consisting of a six-step sequence: (1) a pathogenic stimulus followed by (2) chronic inflammation from which develops (3) fibrosis with associated remodeling of the cellular microenvironment; and from these changes a (4) precancerous niche (PCN), a product of fibrosis, with remodeling by persistent inflammation, develops which triggers the deployment of (5) a chronic stress escape strategy and when this fails resolve it by (6) normal cell to cancerous cell transition (NCCCT) by PCN-induced cell matrix stress occurs. This figure was published in paper 3 of this Special Issue [29]. Nomenclature: The nomenclature common abbreviations are bold, followed by the common trivial names (if available) and (if available) by the name in accordance to the International Union of Pure and Applied Chemistry (IUPAC): PCN: precancerous niche; CSES: chronic stress escape strategy; NCCCT: normal cell to cancerous cell transition; SphK: sphingosine kinase isoform; S1P: sphingosine-1-phosphate; IL-6: interleukin 6; IL-8: interleukin 8; TNFα: tumor necrosis factor alpha; IFNγ interferon gamma; ALOX: lipoxygenase, arachidonate lipoxygenase; ALOX12: 12-lipoxygenase, 12-LOX, 12S-LOX, arachidonate 12-lipoxygenase 12S type; ALOX5: 5-lipoxygenase, 5-LOX, arachidonate 5-lipoxygenase; 12-HETE: 12-hydroxyeicosatetraenoic acid; LTA4: leukotriene A4, 4-[(2S,3S)-3-[(1E,3E,5Z,8Z)-tetradeca-1,3,5,8-tetraenyl]oxiran-2-yl]butanoic acid; LTB4: leukotriene B4, (5S,6Z,8E,10E,12R,14Z)-5,12-dihydroxyicosa-6,8,10,14-tetraenoic acid; LTC4: leukotriene C4, (5S,6R,7E,9E,11Z,14Z)-6-[(2R)-2-[[(4S)-4-amino-4-carboxybutanoyl]amino]-3-(carboxymethylamino)-3-oxopropyl]sulfanyl-5-hydroxyicosa-7,9,11,14-tetraenoic acid; LTD4: leukotriene D4, (5S,6R,7E,9E,11Z,14Z)-6-[(2R)-2-amino-3-(carboxymethylamino)-3-oxopropyl]sulfanyl-5-hydroxyicosa-7,9,11,14-tetraenoic acid; LTE4: leukotriene E4, (5S,6R,7E,9E,11Z,14Z)-6-[(2R)-2-amino-2-carboxyethyl]sulfanyl-5-hydroxyicosa-7,9,11,14-tetraenoic acid; 5-oxo-ETE: (6E,8Z,11Z,14Z)-5-oxoicosa-6,8,11,14-tetraenoic acid; Cox: cyclooxygenase; Cox-1: cyclooxygenase 1; Cox-2: cyclooxygenase 2; Cox-3: isoform of Cox-2 (therefore in brakes); PGG2: prostaglandin G2, (Z)-7-[(1S,4R,5R,6R)-5-[(E,3S)-3-hydroperoxyoct-1-enyl]-2,3-dioxabicyclo[2.2.1]heptan-6-yl]hept-5-enoic acid; PGH2: prostaglandin H2, (Z)-7-[(1S,4R,5R,6R)-5-[(E,3S)-3-hydroxyoct-1-enyl]-2,3-dioxabicyclo[2.2.1]heptan-6-yl]hept-5-enoic acid; PGFF2α: prostaglandine F2 alpha, (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopentyl]hept-5-enoic acid; PGD2: prostaglandin D2, (Z)-7-[(1R,2R,5S)-5-hydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]-3-oxocyclopentyl]hept-5-enoic acid; PGE2: prostaglandin E2, (Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxocyclopentyl]hept-5-enoic acid; MDA: malondialdehyde, propanedial; TXA2: thromboxane A2, (Z)-7-[(1S,2S,3R,5S)-3-[(E,3S)-3-hydroxyoct-1-enyl]-4,6-dioxabicyclo[3.1.1]heptan-2-yl]hept-5-enoic acid; CYP*: cytochrome P450 isoforms; 20-OH-PGE2: 20-hydroxy prostaglandin E2; 20-HETE: 20-hydroxyeicosatetraenoic acid, (5Z,8Z,11Z,14Z)-20-hydroxyicosa-5,8,11,14-tetraenoic acid; SOX: [sex-determining region Y (Sry) box-containing] transcription factor family; IL-β1: interleukin beta 1; IL-33: interleukin 33; ROS: reactive oxygen species; CXC CC: chemokine receptors; αSMAD: alpha-smooth muscle actin; miR21: micro RNA-21; p300: protein 300 (p300-CBP coactivator family); SP1: specificity protein 1; AP1: activator protein 1; E2F4/5: cytoplasmic complex of Smad3, retinoblastoma-like protein 1 (P107, RBL1), E2F4/5 and D-prostanoid (DP1); p107: retinoblastoma-like protein 1, RBL1; TGFβ: transforming growth factor beta; Pro-MMP-9: pro-matrix metalloproteinase 9; Pro-MMP-1: pro-matrix metalloproteinase 1; Pro-MMP-7: pro matrix metalloproteinase 7; SNAIL: zinc finger protein SNAI1; MMP-1: matrix metalloproteinase 1; MMP-7: matrix metalloproteinase 7; MMP-2: matrix metalloproteinase 2; E-Cadherin: CAM 120/80 or epithelial cadherin, cadherin-1, epithelial cadherin; CXCL1: chemokine (C-X-C motif) ligand 1; Osm: oncostatin-M; PI3K: phosphatidylinositide 3-kinase; FOXO3a: forkhead box protein O3a; p120: catenin delta-1, protein 120; Rho: Ras homolog gene family, member A; Rac1: Ras-related C3 botulinum toxin substrate 1; cdc42: cell division control protein 42 homolog; BIM: Bcl-2 interacting mediator of cell death; PUMA: BH3-only protein; CXCR4: C-X-C motif of chemokine receptor 4; cdk2: cyclin-dependent kinase 2; LOXL3: lysyl oxidase homolog 3; mTORc1: rapamycin complex 1; PAI1: Plasminogen activator inhibitor-1.

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