Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation - 0 views
www.ncbi.nlm.nih.gov/...PMC5282724
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
shared by Nathan Goodyear on 09 Feb 21
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More than half of cancer patients are treated with IR at some point during their treatment
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fractionation schedule is the delivery of 1.8–2.0 Gy per day, five days per week
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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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IR also indirectly induces DNA damage by stimulating reactive oxygen species (ROS) production
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IR is known to induce EMT in vitro
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p53 is activated in response to IR-induced DNA damage
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IR paradoxically also promotes tumour recurrence and metastasis
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DNA double-strand breaks (DSBs)
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cancer cells undergoing EMT acquire invasive and metastatic properties
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changes in the tumour microenvironment (TME)
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IR seems to induce EMT and CSC phenotypes by regulating cellular metabolism
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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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IR is known to induce stemness and metabolic alterations in cancer cells
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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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Loss of E-cadherin is considered a hallmark of EMT
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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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ROS are known to play an important role in IR-induced EMT
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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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hypoxia-inducible factor-1 (HIF-1) is involved in IR-induced EMT
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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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Snail has been shown to play a crucial role in IR-induced EMT, migration, and invasion
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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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NF-κB signalling that promotes cell migration
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ROS promote EMT to allow cancer cells to avoid hostile environments
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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 induces vascular damage that causes hypoxia
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ROS is implicated in IR-induced 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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TGF-β signalling has been shown to play a crucial role in IR-induced EMT
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AP-1 transcription factor is involved in IR-induced TGF-β1 expression
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Wnt/β-catenin signalling is also implicated in IR-induced EMT
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Notch signalling is known to be involved in IR-induced EMT
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IR also increases Notch-1 expression [99]. Notch-1 is known to induce EMT by upregulating Snail
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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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ROS and RNS are also implicated in IR-induced EGFR activation
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IR has also been shown to activate Hedgehog (Hh) signalling to induce EMT
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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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Transcription factors, including Oct4, Sox2, Nanog, c-Myc, and Klf4,
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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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microRNAs (miRNAs), including let-7, miR-22, miR-34a, miR-128, the miR-200 family, and miR-451
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Non-CSCs can be reprogrammed to become CSCs by epigenetic and genetic changes
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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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some CSC subpopulations arise independently of EMT
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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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IR has been shown to induce reprogramming of differentiated cancer cells into CSCs
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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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metabolic reprogramming
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HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism
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metabolic reprogramming
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tumour cells exhibit high mitochondrial metabolism as well as aerobic glycolysis
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occurring within the same tumour
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CSCs can be highly glycolytic-dependent or oxidative phosphorylation (OXPHOS)-dependen
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mitochondrial function is crucial for maintaining CSC functionality
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cancer cells depend on mitochondrial metabolism and increase mitochondrial production of ROS that cause pseudo-hypoxia
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HIF-1 then enhances glycolysis
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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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lactate transporter, monocarboxylate transporter (MCT)
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nutrient microenvironment
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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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HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism
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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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STAT3 has been implicated in EMT-induced metabolic changes as well
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TGF-β and Wnt play important roles in the metabolic alteration of cancer cells
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Akt is also implicated in the glycolytic switch and in promoting cancer cell invasiveness
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EMT, invasion, metastasis, and stemness
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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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decreased activity of PKM2 is known to promote an overall shift in metabolism to aerobic glycolysis
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LDH catalyses the bidirectional conversion of lactate to pyruvate
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High levels of LDHA are positively correlated with the expression of EMT and CSC markers
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IR has been shown to induce metabolic changes in cancer cells
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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 can activate latent TGF-
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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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intrinsic immunogenicity or induce tolerance
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cancer immunoediting’
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three phases: 1) elimination, 2) equilibrium, and 3) escape.
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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 also promotes MMP-2/9 activation in cancer cells to promote EMT, invasion, and metastasis
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IR-induced Snail increases MMP-2 expression to promote EMT
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Radiotherapy has the paradoxical side-effect of increasing tumour aggressiveness
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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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Metabolic alterations
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oncogenic metabolism
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elicit various changes in the TME
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Although IR activates an antitumour immune response, this signalling is frequently suppressed by tumour escape mechanisms