More than half of cancer patients are treated with IR at some point during their treatment
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shared by Nathan Goodyear on 09 Feb 21
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Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer... - 0 views
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EMT TME metastasis cancer stem cells cancer MMP2 Notch MMP-9 MMP-2 radioresistance Hedgehog CSC MMP9 Snail HIF-1alpha tumor microenvironment epithelial to mesenchymal transition TGF-beta radiation
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Nuclear DNA is the primary target of IR; it causes DNA damage (genotoxic stress) by direct DNA ionization
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EMT, stemness, and oncogenic metabolism are known to be associated with resistance to radiotherapy and chemotherapy
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Hanahan and Weinberg proposed ten hallmarks of cancer that alter cell physiology to enhance malignant growth: 1) sustained proliferation, 2) evasion of growth suppression, 3) cell death resistance, 4) replicative immortality, 5) evasion of immune destruction, 6) tumour-promoting inflammation, 7) activation of invasion and metastasis, 8) induction of angiogenesis, 9) genome instability, and 10) alteration of metabolism
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EMT is a developmental process that plays critical roles in embryogenesis, wound healing, and organ fibrosis
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transforming growth factor-β [TGF-β], epidermal growth factor [EGF]) and their associated signalling proteins (Wnt, Notch, Hedgehog, nuclear-factor kappa B [NF-κB], extracellular signal-regulated kinase [ERK], and phosphatidylinositol 3-kinase [PI3K]/Akt
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activate EMT-inducing transcription factors, including Snail/Slug, ZEB1/δEF1, ZEB2/SIP1, Twist1/2, and E12/E47
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IR has been shown to induce EMT to enhance the motility and invasiveness of several cancer cells, including those of breast, lung, and liver cancer, and glioma cells
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IR may increase metastasis in both the primary tumour site and in normal tissues under some circumstance
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sublethal doses of IR have been shown to enhance the migratory and invasive behaviours of glioma cells
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High levels of ROS trigger cell death by causing irreversible damage to cellular components such as proteins, nucleic acids, and lipids, whereas low levels of ROS have been shown to promote tumour progression—including tumour growth, invasion, and metastasis
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Treatment with the N-acetylcysteine (NAC), a general ROS scavenger, prevents IR-induced EMT, adhesive affinity, and invasion of breast cancer cells
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IR activates the p38 MAPK pathway, which contributes to the induction of Snail expression to promote EMT and invasion
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HIF-1 is a heterodimer composed of an oxygen-sensitive α subunit and a constitutively expressed β subunit.
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Under normoxia, HIF-1α is rapidly degraded, whereas hypoxia induces stabilisation and accumulation of HIF-1α
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levels of HIF-1α mRNA are enhanced by activation of the PI3K/Akt/mammalian target of rapamycin (mTOR)
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IR is known to increase stabilisation and nuclear accumulation of HIF-1α, since hypoxia is a major condition for HIF-1 activation
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IR causes the reoxygenation of hypoxic cancer cells to increase ROS production, which leads to the stabilisation and nuclear accumulation of HIF-1
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IR increases glucose availability under reoxygenated conditions that promote HIF-1α translation by activating the Akt/mTOR pathway
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The stabilised HIF-1α then translocates to the nucleus, dimerizes with HIF-1β, and increases gene expression— including the expression of essential EMT regulators such as Snail—to induce EMT, migration, and invasion
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PAI-1 signalling is also implicated in IR-induced Akt activation that increases Snail levels to induce EMT
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EGFR activation is known to be associated with IR-induced EMT, cell migration, and invasion by activating two downstream pathways: PI3K/Akt and Raf/MEK/ERK
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IR has been shown to induce Akt activation through several signalling pathways (EGFR, C-X-C chemokine receptor type 4 [CXCR4]/C-X-C motif chemokine 12 [CXCL12], plasminogen activator inhibitor 1 [PAI-1]) and upstream regulators (Bmi1, PTEN) that promote EMT and invasion
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CSCs possess a capacity for self-renewal, and they can persistently proliferate to initiate tumours upon serial transplantation, thus enabling them to maintain the whole tumour
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Conventional cancer treatments kill most cancer cells, but CSCs survive due to their resistance to therapy, eventually leading to tumour relapse and metastasis
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identification of CSCs, three types of markers are utilised: cell surface molecules, transcription factors, and signalling pathway molecules
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CSCs express distinct and specific surface markers; commonly used ones are CD24, CD34, CD38, CD44, CD90, CD133, and ALDH
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signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, platelet-derived growth factor receptor (PDGFR), and JAK/STAT
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EMT-inducing transcription factors, such as Snail, ZEB1, and Twist1, are known to confer CSC properties
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Signalling pathways involved in EMT, including those of TGF-β, Wnt, and Notch, have been shown to play important roles in inducing the CSC phenotype
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TGF-β1 not only increases EMT markers (Slug, Twist1, β-catenin, N-cadherin), but also upregulates CSC markers (Oct4, Sox2, Nanog, Klf4) in breast and lung cancer cells
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IR has been shown to induce the CSC phenotype in many cancers, including breast, lung, and prostate cancers, as well as melanoma
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Genotoxic stress due to IR or chemotherapy promotes a CSC-like phenotype by increasing ROS production
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In prostate cancer patients, radiotherapy increases the CD44+ cell population that exhibit CSC properties
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IR also induces the re-expression of stem cell regulators, such as Sox2, Oct4, Nanog, and Klf4, to promote stemness in cancer cells
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EMT-inducing transcription factors and signalling pathways, including Snail, STAT3, Notch signalling, the PI3K/Akt pathway, and the MAPK cascade, have been shown to play important roles in IR-induced CSC properties
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STAT3 directly binds to the Snail promoter and increases Snail transcription, which induces the EMT and CSC phenotypes, in cisplatin-selected resistant cells
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Other oncogenic metabolic pathways, including glutamine metabolism, the pentose phosphate pathway (PPP), and synthesis of fatty acids and cholesterol, are also enhanced in many cancers
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cancer cells depend on mitochondrial metabolism and increase mitochondrial production of ROS that cause pseudo-hypoxia
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CAFs have defective mitochondria that lead to the cells exhibiting the Warburg effect; the cells take up glucose, and then secrete lactate to 'feed' adjacent cancer cells
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Epithelial cancer cells express MCT1, while CAFs express MCT4. MCT4-positive, hypoxic CAFs secrete lactate by aerobic glycolysis, and MCT1-expressing epithelial cancer cells then uptake and use that lactate as a substrate for the tricarboxylic acid (TCA) cycle
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MCT4-positive cancer cells depend on glycolysis and then efflux lactate, while MCT1-positive cells uptake lactate and rely on OXPHOS
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metabolic heterogeneity induces a lactate shuttle between hypoxic/glycolytic cells and oxidative/aerobic tumour cells
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bulk tumour cells exhibit a glycolytic phenotype, with increased conversion of glucose to lactate (and enhanced lactate efflux through MCT4), CSC subsets depend on oxidative phosphorylation; most of the glucose entering the cells is converted to pyruvate to fuel the TCA cycle and the electron transport chain (ETC), thereby increasing mitochondrial ROS production
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the major fraction of glucose is directed into the pentose phosphate pathway, to produce redox power through the generation of NADPH and ROS scavengers
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regulatory molecules involved in EMT and CSCs, including Snail, Dlx-2, HIF-1, STAT3, TGF-β, Wnt, and Akt, are implicated in the metabolic reprogramming of cancer cells
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HIF-1 induces the expression of glycolytic enzymes, including the glucose transporter GLUT, hexokinase, lactate dehydrogenase (LDH), and MCT, resulting in the glycolytic switch
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HIF-1 represses the expression of pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), thereby inhibiting mitochondrial activity
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pyruvate kinase M2 (PKM2), LDH, and pyruvate carboxylase (PC), are implicated in the induction of the EMT and CSC phenotypes
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IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
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IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
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IR also elevates MCT1 expression that exports lactate into the extracellular environment, leading to acidification of the tumour microenvironment
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IR increases intracellular glucose, glucose 6-phosphate, fructose, and products of pyruvate (lactate and alanine), suggesting a role for IR in the upregulation of cytosolic aerobic glycolysis
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lactate stimulates cell migration and enhances secretion of hyaluronan from CAF that promote tumour metastasis
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promote tumour survival, growth, invasion, and metastasis; enhance the stiffness of the ECM; contribute to angiogenesis; and induce inflammation by releasing several growth factors and cytokines (TGF-β, VEGF, hepatocyte growth factor [HGF], PDGF, and stromal cell-derived factor 1 [SDF1]), as well as MMP
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tumours recruit the host tissue’s blood vessel network to perform four mechanisms: angiogenesis (formation of new vessels), vasculogenesis (de novo formation of blood vessels from endothelial precursor cells), co-option, and modification of existing vessels within tissues.
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immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
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immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
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The third phase, tumour escape, is mediated by antigen loss, immunosuppressive cells (TAM, MDSCs, and regulatory T cells), and immunosuppressive cytokines (TGF-β and IL-10).
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IR can elicit various changes in the TME, such as CAF activity-mediated ECM remodelling and fibrosis, cycling hypoxia, and an inflammatory response
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IR activates CAFs to promote the release of growth factors and ECM modulators, including TGF-β and MMP
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TGF-β directly influences tumour cells and CAFs, promotes tumour immune escape, and activates HIF-1 signalling
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MMPs degrade ECM that facilitates angiogenesis, tumour cell invasion, and metastasis
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IR promotes ROS production in cancer cells, which may induce the activation of oncogenes and the inactivation of tumour suppressors, which further promote oncogenic metabolism
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Although IR activates an antitumour immune response, this signalling is frequently suppressed by tumour escape mechanisms
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shared by Nathan Goodyear on 01 Jun 18
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Broad targeting of angiogenesis for cancer prevention and therapy - 0 views
www.ncbi.nlm.nih.gov/...PMC4737670
cancer curcumin VEGF EGCG green tea melatonin quercetin Resveratrol silymarin flavonoids HIF-1alpha
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vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), interleukin-8 (IL-8), placental growth factor (PlGF), transforming growth factor-beta (TGFbeta), platelet derived growth factor (PDGF), angiopoietins (Angs) and others (reviewed in [4])
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The switch may also involve down-regulation of endogenous inhibitors of angiogenesis such as endostatin, angiostatin or thrombospondin (reviewed in [5]) and has thus been regarded as the result of tipping the net balance between positive and negative regulators
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Environmental stress as a result of low oxygen and proper nutrient deprivation, such as glucose deprivation, are capable of inducing VEGF mRNA stabilization resulting in increased levels of the secreted ligand and angiogenic growth
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HIFalpha subunits accumulate in the cytoplasm where they bind HIFbeta to form a heterodimer that subsequently translocates to the nucleus to activate transcription of target genes, including genes important for various processes such as metabolism (glucose transporter (GLUT)-1, hexokinase (HK)-1), cell growth (cyclin (CCN)-D1 [23]) and also angiogenesis, such as erythropoietin, VEGF and PDGF [24] (summarized in Fig. 1)
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When oxygen levels are low (hypoxia; red arrow) PHDs cannot hydroxylate HIFalphas thereby allowing them to escape pVHL-mediated degradation. HIFalpha subunits accumulate and bind to their heterodimeric partner, HIFbeta, translocate into the nucleus and activate a cascade of hypoxic signaling first by the transcription of various target genes including microRNAs that are important for tumor promoting pathways
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c-Src is also capable of activating HIFs by indirectly inhibiting PHD activity via the NADPH oxidase/Rac pathway.
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hypoxia inducible factors (HIFs), heterodimeric transcription factors composed from alpha and beta subunits, which can be rapidly stabilized to fluidly adapt to and overcome the effects of a hypoxic environment
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Curcumin inhibits the expression of epidermal growth factor receptor (EGFR), VEGFR-1, VEGFR-2 and VEGFR-3, and the kinase activity of Src and FAK, which are responsible for the induction of angiogenic genes as well as endothelial cell polarity and migration
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Curcumin also reduces the MMP-2 and MMP-9 expression, along with the suppression of growth and invasion potential of tumor cells in culture and xenograft experiments
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The expression of angiogenic biomarkers COX-2 and serum levels of VEGF were significantly reduced in the curcumin-treated group
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[155] and impeding angiogenesis by suppressing VEGF expression through down-regulation of HIF-1alpha
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resveratrol was reported to inhibit cell proliferation of human ovarian cancer cells and human osteosarcoma cells by attenuating HIF-1alpha
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The underlying molecular mechanisms include: blocking VEGF- and FGF-receptor-mediated MAPK activation, inhibiting Akt- and MAPK-driven HIF-1alpha basal expression and its induction by IGF-1, stimulating the proteasomal degradation of HIF-1alpha, inhibiting phosphatidyl inositol (PI)-3K/Akt and Ras/mitogen/extracellular signal-regulated kinase (MEK)/ERK pathways, and activation of forkhead box (FOX)O transcription factors
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Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effe... - 0 views
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HIF-1 activation is highly associated with cancer cell growth and survival, tumor development, tumor angiogenesis, and poor clinical prognosis
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The adaptation of cancer cells to hypoxia is mediated via hypoxia-inducible Factor 1 (HIF-1),1 a key transcription factor that up-regulates a series of genes involved in glycolytic energy metabolism, angiogenesis, cell survival, and erythropoiesis. Included among these genes are vascular endothelial growth factor (VEGF), erythropoietin (EPO), glucose transporters (GLUT), and several glycolytic enzymes (12, 13).
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shared by Nathan Goodyear on 13 Nov 14
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The ROS-induced cytotoxicity of ascorbate is attenuated by hypoxia and HIF-1alpha in th... - 0 views
onlinelibrary.wiley.com/...full
vitamin C IV IV vitamin C hypoxia HIF-1alpha HBO hyperbaric oxygen hyperbaric cancer
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shared by Nathan Goodyear on 01 Apr 21
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Modulation of hypoxia-inducible factor-1 alpha in cultured primary cells by intracellul... - 0 views
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VEGF cancer GLUT Hypoxia-inducible Factor 1 vitamin C HIF-1alpha HIF-1
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Hypoxia Decreases Insulin Signaling Pathways in Adipocytes | Diabetes - 0 views
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Acute hypobaric-hypoxia challenge an... [Aviat Space Environ Med. 2012] - PubMed - NCBI - 0 views
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shared by Nathan Goodyear on 01 Apr 21
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Effects of Transferrin Receptor Blockade on Cancer Cell Proliferation and Hypoxia-Induc... - 0 views
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HIF-1alpha cancer HIF-1 vitamin C Hypoxia-inducible Factor 1 hypoxia
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shared by Nathan Goodyear on 01 Apr 21
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Vitamin C Administration by Intravenous Infusion Increases Tumor Ascorbate Content in P... - 0 views
www.ncbi.nlm.nih.gov/...PMC7830882
VEGF IV vitamin C vitamin C colon cancer hypoxia HIF-1alpha cancer HIF-1 GLUT
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Pharmacokinetic and anti-cancer properties of high dose ascorbate in solid tumours of a... - 0 views
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Very nice mouse study. They reduced hypoxia signialing, HIF-1alpha, via daily vitamin C administration. Also a very interesting point, that the vitamin C had a much longer half life within the tumor than normal tissue-up to 48 hours compared to 30 minutes in normal. So, that begs the question, what does higher dose do? In this study they also saw a reduction in angiogenesis and tumor growth.
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Increased Tumor Ascorbate is Associated with Extended Disease-Free Survival and Decreas... - 0 views
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hypoxia HIF-1 IV vitamin C VEGF Hypoxia-inducible Factor 1 vitamin C HIF-1alpha cancer
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Enough said: "There was an inverse relationship between tumor ascorbate content and HIF-1 pathway activation and tumor size. Higher tumor ascorbate content was associated with significantly improved disease-free survival in the first 6 years after surgery with additional disease-free days. This was independent of tumor grade and stage. Survival advantage was associated with the amount of ascorbate in the tumor, but not with the amount in adjacent normal tissue. Our results demonstrate that higher tumor ascorbate content is associated with decreased HIF-1 activation."
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The Potential Role of Hypoxia Inducible Factor 1α in Tumor Progression after ... - 0 views
Hepcidin: A Critical Regulator of Iron Metabolism during Hypoxia - 0 views
Hypoxia signaling pathways in cancer metabolism: the importance of co-selecting interco... - 0 views
cancerandmetabolism.biomedcentral.com/...2049-3002-2-3
Hypoxia-inducible Factor 1 iron metabolism cancer metabolism cancer Iron Fe oncogenic metabolism hypoxia
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Hypoxia and metabolic adaptation of cancer cells | Oncogenesis - 0 views
www.nature.com/...oncsis201550
cancer metabolism oncogenic metabolism hypoxia Hypoxia-inducible Factor 1 cancer
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shared by Nathan Goodyear on 12 Nov 14
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BMC Cancer | Full text | A lactate shuttle system between tumour and stromal cells is a... - 0 views
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cancer prostate cancer CAFs cancer associated fibroblasts mono-carboxylate transporters
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Under hypoxic conditions, tumour cells primarily use glycolysis for energy, producing lactate, which is expelled to the tumour microenvironment, allowing tumours to continue their glycolytic activity
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Sonveaux et al. showed that lactate, which is generally considered a waste product, is preferred over glucose by oxidative tumour cells as their primary energy source
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MCT4 is a low-affinity transporter, which is abundant in highly glycolytic muscle cells and is one of the many target genes of hypoxia-inducible factor 1 alpha (HIF-1α)
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Other targets of HIF-1α include glucose transporter-1 (GLUT-1), the main transporter involved in glucose uptake [9,10]; lactate dehydrogenase V (LDHV), which is responsible for the conversion of pyruvate into lactate; pyruvate dehydrogenase kinase isozyme 1 (PDK1), which is responsible for the phosphorylation and consequent inactivation of pyruvate dehydrogenase (PDH); and carbonic anhydrase IX (CAIX), a hypoxia-related protein involved in pH regulation [11]. Alpha-methylacyl-CoA racemase (AMACR), pristanoyl-CoA oxidase (ACOX-3) and D-bifunctional protein (DBP), are also important fatty acid oxidation-related proteins in prostate cancer
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the essential role played by the cross-talk between stroma and epithelium in carcinogenesis and prostate cancer progression has been increasingly recognised
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strong membranous expression of MCT1 was consistently observed in cancer cells, suggesting a role for MCT1 in the transport of lactate into tumour cells from the acidic extracellular matrix, suggesting that lactate might be used as a fuel by oxidative cancer cells.
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Our hypothesis is in agreement with those of Fiaschi et al.[17], who describe the metabolic reprogramming of CAFs towards the Warburg phenotype as a result of contact with prostate cancer cells
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Using in vitro studies, they showed lactate production and efflux by de novo expressed MCT4 in CAFs and also demonstrated that, upon contact with CAFs, prostate cancer cells were reprogrammed towards aerobic metabolism, with an increase in lactate uptake via the lactate transporter MCT1.
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pharmacological inhibition of MCT1-mediated lactate uptake dramatically affected PCa cell survival and tumour outgrowth
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In this model, “energy transfer” or “metabolic coupling” between the tumour stroma and epithelial cancer cells fuels tumour growth and metastasis via oxidative mitochondrial metabolism in anabolic cancer cells
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the concomitant expression of MCT1 in tumour cells and MCT4 in fibroblasts in the same tissue is clinically significant, and associated with poor prognosis.
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shared by Nathan Goodyear on 12 Nov 14
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Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxid... - 0 views
www.ncbi.nlm.nih.gov/...PMC3180189
cancer reverse warburg effect warburg effect NF-kapppB HIF-1alpha Cav-1 H2O2
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reducing oxidative stress with powerful antioxidants, is an important strategy for cancer prevention, as it would suppress one of the key early initiating steps where DNA damage and tumor-stroma metabolic-coupling begins. This would prevent cancer cells from acting as metabolic “parasites
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Oxidative stress in cancer-associated fibroblasts triggers autophagy and mitophagy, resulting in compartmentalized cellular catabolism, loss of mitochondrial function, and the onset of aerobic glycolysis, in the tumor stroma. As such, cancer-associated fibroblasts produce high-energy nutrients (such as lactate and ketones) that fuel mitochondrial biogenesis and oxidative metabolism in cancer cells. We have termed this new energy-transfer mechanism the “reverse Warburg effect.
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Then, oxidative stress, in cancer-associated fibroblasts, triggers the activation of two main transcription factors, NFκB and HIF-1α, leading to the onset of inflammation, autophagy, mitophagy and aerobic glycolysis in the tumor microenvironment
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oxidative stress and ROS, produced in cancer-associated fibroblasts, has a “bystander effect” on adjacent cancer cells, leading to DNA damage, genomic instability and aneuploidy, which appears to be driving tumor-stroma co-evolution
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tumor cells produce and secrete hydrogen peroxide, thereby “fertilizing” the tumor microenvironment and driving the “reverse Warburg effect.”
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This type of stromal metabolism then produces high-energy nutrients (lactate, ketones and glutamine), as well as recycled chemical building blocks (nucleotides, amino acids, fatty acids), to literally “feed” cancer cells
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loss of stromal caveolin (Cav-1) is sufficient to drive mitochondrial dysfunction with increased glucose uptake in fibroblasts, mimicking the glycolytic phenotype of cancer-associated fibroblasts.
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Then, cancer-associated fibroblasts show quantitative reductions in mitochondrial activity and compensatory increases in glucose uptake, as well as high ROS production
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These findings may explain the prognostic value of a loss of stromal Cav-1 as a marker of a “lethal” tumor microenvironment
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Interruption of this process, by addition of catalase (an enzyme that detoxifies hydrogen peroxide) to the tissue culture media, blocks ROS activity in cancer cells and leads to apoptotic cell death in cancer cells
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our results may also explain the “field effect” in cancer biology,5 as hydrogen peroxide secreted by cancer cells, and the propagation of ROS production, from cancer cells to fibroblasts, would create an increasing “mutagenic field” of ROS production, due to the resulting DNA damage
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aerobic glycolysis takes place in cancer-associated fibroblasts, rather than in tumor cells, as previously suspected.
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In this new paradigm, cancer cells induce oxidative stress in neighboring cancer-associated fibroblasts
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cancer cells secrete hydrogen peroxide, which induces ROS production in cancer-associated fibroblasts
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Then, oxidative stress in cancer-associated fibroblast leads to decreases in functional mitochondrial activity, and a corresponding increase in glucose uptake, to fuel aerobic glycolysis
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fibroblasts and cancer cells in co-culture become metabolically coupled, resulting in the development of a “symbiotic” or “parasitic” relationship.
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cancer-associated fibroblasts undergo aerobic glycolysis (producing lactate), while cancer cells use oxidative mitochondrial metabolism.
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We have previously shown that oxidative stress in cancer-associated fibroblasts drives a loss of stromal Cav-1, due to its destruction via autophagy/lysosomal degradation
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a loss of stromal Cav-1 is sufficient to induce further oxidative stress, DNA damage and autophagy, essentially mimicking pseudo-hypoxia and driving mitochondrial dysfunction
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loss of stromal Cav-1 is a powerful biomarker for identifying breast cancer patients with early tumor recurrence, lymph-node metastasis, drug-resistance and poor clinical outcome
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this type of metabolism (aerobic glycolysis and autophagy in the tumor stroma) is characteristic of a lethal tumor micro-environment, as it fuels anabolic growth in cancer cells, via the production of high-energy nutrients (such as lactate, ketones and glutamine) and other chemical building blocks
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one such enzymatically-active protein anti-oxidant that may be of therapeutic use is catalase, as it detoxifies hydrogen peroxide to water
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numerous studies show that “catalase therapy” in pre-clinical animal models is indeed sufficient to almost completely block tumor recurrence and metastasis
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by eliminating oxidative stress in cancer cells and the tumor microenvironment,55 we may be able to effectively cut off the tumor's fuel supply, by blocking stromal autophagy and aerobic glycolysis
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breast cancer patients show systemic evidence of increased oxidative stress and a decreased anti-oxidant defense, which increases with aging and tumor progression.68–70 Chemotherapy and radiation therapy then promote further oxidative stress.69 Unfortunately, “sub-lethal” doses of oxidative stress during cancer therapy may contribute to tumor recurrence and metastasis, via the activation of myofibroblasts.
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a loss of stromal Cav-1 is associated with the increased expression of gene profiles associated with normal aging, oxidative stress, DNA damage, HIF1/hypoxia, NFκB/inflammation, glycolysis and mitochondrial dysfunction
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cancer-associated fibroblasts show the largest increases in glucose uptake, while cancer cells show corresponding decreases in glucose uptake, under identical co-culture conditions
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Thus, increased PET glucose avidity may actually be a surrogate marker for a loss of stromal Cav-1 in human tumors, allowing the rapid detection of a lethal tumor microenvironment.
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In the brain, astrocytes are glycolytic and undergo aerobic glycolysis. Thus, astrocytes take up and metabolically process glucose to lactate.7
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Then, lactate is secreted via a mono-carboxylate transporter, namely MCT4. As a consequence, neurons use lactate as their preferred energy substrate
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both astrocytes and cancer-associated fibroblasts express MCT4 (which extrudes lactate) and MCT4 is upregulated by oxidative stress in stromal fibroblasts.34
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In accordance with the idea that cancer-associated fibroblasts take up the bulk of glucose, PET glucose avidity is also now routinely used to measure the extent of fibrosis in a number of human diseases, including interstitial pulmonary fibrosis, postsurgical scars, keloids, arthritis and a variety of collagen-vascular diseases.
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PET glucose avidity and elevated serum inflammatory markers both correlate with poor prognosis in breast cancers.
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PET signal over-estimates the actual anatomical size of the tumor, consistent with the idea that PET glucose avidity is really measuring fibrosis and inflammation in the tumor microenvironment.
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human breast and lung cancer patients can be positively identified by examining their exhaled breath for the presence of hydrogen peroxide.
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tumor cell production of hydrogen peroxide drives NFκB-activation in adjacent normal cells in culture6 and during metastasis,103 directly implicating the use of antioxidants, NFκB-inhibitors and anti-inflammatory agents, in the treatment of aggressive human cancers.
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shared by Nathan Goodyear on 16 Nov 18
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Bicarbonate and dichloroacetate: Evaluating pH altering therapies in a mouse model for ... - 0 views
www.ncbi.nlm.nih.gov/...PMC3125283
DCA dichloracetic acid dichloroacetate cancer "pH and cancer" acid alkaline
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