Abstract:Abstract. Radiation-induced lung injury (RILI) is a common complication associated with thoracic radiotherapy. The aim of the present study was to investigate the effects of a single 15-Gy dose of right-thoracic lung irradiation on the expression levels of matrix metalloproteinases (MMPs) and other proteins in the alveolar epithelial type II (AE2) cells of Bama minipigs. All minipigs received either right-thoracic irradiation or sham irradiation under anesthesia, and were sacrificed at 4, 8, 12 or 24 weeks aft… Show more
“…MMPs degrade ECM that facilitates angiogenesis, tumour cell invasion, and metastasis [ 262 ]. IR also promotes MMP-2/9 activation in cancer cells to promote EMT, invasion, and metastasis [ 54 , 106 , 263 – 266 ]. IR enhances MMP-2 transcription and protein secretion by activating the EGFR/p38/Akt and EGFR/PI3K/Akt signalling pathways, which enhance the invasion of glioma cells [ 106 ].…”
Section: Introductionmentioning
confidence: 99%
“…IR also increases MMP-9 expression by activating the PI3K/Akt/NF-κB pathway, which enhances hepatocellular carcinoma cell invasion [ 263 ]. IR-induced MMP-2/MMP-9 expression not only degrades ECM proteins, but also cleaves latent TGF-β1 to activate the TME [ 266 ]. Fig.…”
Radiation therapy is one of the major tools of cancer treatment, and is widely used for a variety of malignant tumours. Radiotherapy causes DNA damage directly by ionization or indirectly via the generation of reactive oxygen species (ROS), thereby destroying cancer cells. However, ionizing radiation (IR) paradoxically promotes metastasis and invasion of cancer cells by inducing the epithelial-mesenchymal transition (EMT). Metastasis is a major obstacle to successful cancer therapy, and is closely linked to the rates of morbidity and mortality of many cancers. ROS have been shown to play important roles in mediating the biological effects of IR. ROS have been implicated in IR-induced EMT, via activation of several EMT transcription factors—including Snail, HIF-1, ZEB1, and STAT3—that are activated by signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, G-CSF, EGFR/PI3K/Akt, and MAPK. Cancer cells that undergo EMT have been shown to acquire stemness and undergo metabolic changes, although these points are debated. IR is known to induce cancer stem cell (CSC) properties, including dedifferentiation and self-renewal, and to promote oncogenic metabolism by activating these EMT-inducing pathways. Much accumulated evidence has shown that metabolic alterations in cancer cells are closely associated with the EMT and CSC phenotypes; specifically, the IR-induced oncogenic metabolism seems to be required for acquisition of the EMT and CSC phenotypes. IR can also elicit various changes in the tumour microenvironment (TME) that may affect invasion and metastasis. EMT, CSC, and oncogenic metabolism are involved in radioresistance; targeting them may improve the efficacy of radiotherapy, preventing tumour recurrence and metastasis. This study focuses on the molecular mechanisms of IR-induced EMT, CSCs, oncogenic metabolism, and alterations in the TME. We discuss how IR-induced EMT/CSC/oncogenic metabolism may promote resistance to radiotherapy; we also review efforts to develop therapeutic approaches to eliminate these IR-induced adverse effects.
“…MMPs degrade ECM that facilitates angiogenesis, tumour cell invasion, and metastasis [ 262 ]. IR also promotes MMP-2/9 activation in cancer cells to promote EMT, invasion, and metastasis [ 54 , 106 , 263 – 266 ]. IR enhances MMP-2 transcription and protein secretion by activating the EGFR/p38/Akt and EGFR/PI3K/Akt signalling pathways, which enhance the invasion of glioma cells [ 106 ].…”
Section: Introductionmentioning
confidence: 99%
“…IR also increases MMP-9 expression by activating the PI3K/Akt/NF-κB pathway, which enhances hepatocellular carcinoma cell invasion [ 263 ]. IR-induced MMP-2/MMP-9 expression not only degrades ECM proteins, but also cleaves latent TGF-β1 to activate the TME [ 266 ]. Fig.…”
Radiation therapy is one of the major tools of cancer treatment, and is widely used for a variety of malignant tumours. Radiotherapy causes DNA damage directly by ionization or indirectly via the generation of reactive oxygen species (ROS), thereby destroying cancer cells. However, ionizing radiation (IR) paradoxically promotes metastasis and invasion of cancer cells by inducing the epithelial-mesenchymal transition (EMT). Metastasis is a major obstacle to successful cancer therapy, and is closely linked to the rates of morbidity and mortality of many cancers. ROS have been shown to play important roles in mediating the biological effects of IR. ROS have been implicated in IR-induced EMT, via activation of several EMT transcription factors—including Snail, HIF-1, ZEB1, and STAT3—that are activated by signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, G-CSF, EGFR/PI3K/Akt, and MAPK. Cancer cells that undergo EMT have been shown to acquire stemness and undergo metabolic changes, although these points are debated. IR is known to induce cancer stem cell (CSC) properties, including dedifferentiation and self-renewal, and to promote oncogenic metabolism by activating these EMT-inducing pathways. Much accumulated evidence has shown that metabolic alterations in cancer cells are closely associated with the EMT and CSC phenotypes; specifically, the IR-induced oncogenic metabolism seems to be required for acquisition of the EMT and CSC phenotypes. IR can also elicit various changes in the tumour microenvironment (TME) that may affect invasion and metastasis. EMT, CSC, and oncogenic metabolism are involved in radioresistance; targeting them may improve the efficacy of radiotherapy, preventing tumour recurrence and metastasis. This study focuses on the molecular mechanisms of IR-induced EMT, CSCs, oncogenic metabolism, and alterations in the TME. We discuss how IR-induced EMT/CSC/oncogenic metabolism may promote resistance to radiotherapy; we also review efforts to develop therapeutic approaches to eliminate these IR-induced adverse effects.
“…large number of pro-inflammatory and fibrotic cytokines induced by thoracic radiotherapy can also cause acute and delayed injury to the lung tissue. [3][4][5] It is known that molecules, such as tumor necrosis factor-(TNF-), transforming growth factor-1, interleukin-1 (IL-1), interleukin-6 (IL-6), and interferon-, and changes in their gene expression are involved in the initiation and development of RP. [6][7][8][9] Serum amylase A (SAA), an acute phase response protein, has been reported to be Prec.…”
Section: 2 Amentioning
confidence: 99%
“…RP is commonly considered to be a complex inflammatory process involving a series of cytokines and adhesion molecules mediated by lung parenchymal cells and circulating immune cells . A large number of pro‐inflammatory and fibrotic cytokines induced by thoracic radiotherapy can also cause acute and delayed injury to the lung tissue …”
Objective: Serum amyloid A (SAA) is a non-specific acute phase reaction protein that shows much higher levels in patients with cancer than in healthy individuals. The present study was designed to investigate the correlation of SAA level with overall survival (OS) and radiation pneumonitis (RP) in non-small cell lung cancer patients receiving thoracic radiotherapy.
Methods:Patients with locally advanced non-small cell lung cancer receiving thoracic radiotherapy or concurrent chemoradiotherapy were eligible for the study. Plasma samples were collected before radiotherapy (baseline), 2 and 4 weeks during radiotherapy, and at 3 months after the end of radiotherapy. The incidence of RP was recorded 1 year after radiotherapy. OS was defined as the interval between the date of treatment initiation and the date of death or last follow up if the patients were still alive. SPSS 18.0 and GraphPad Prism 5.0 software were used for statistical analyses, and P ≤ 0.05 was considered significant.
Results:In total, data from 114 patients were used for the final analyses. The median baseline SAA level was 101.4 g/mL; patients with lower baseline SAA levels had a longer OS than those with a higher SAA level (25.8 vs 14.3 months, 2 = 5.519, P = 0.019). In multivariate analysis, sex, radiation dose, and baseline SAA level were independent prognostic factors. The SAA level after radiotherapy was significantly lower than that at baseline (142.6 vs 420.1 g/mL, t = 3.50, P = 0.001).The average SAA level in patients with grade 2 or higher and less than grade 2 RP after radiotherapy was 476.7 g/mL and 113.0 g/mL, respectively, t = 2.72, P = 0.009.
Conclusions:SAA level might be a predictive biomarker for RP and OS in patients with locally advanced non-small cell lung cancer receiving thoracic radiotherapy.
“…[ 11 , 12 ] It is reported that MMP-2 activity is associated with the collagen deposition and the formation of subretinal deposit. [ 13 , 14 ] It has been identified that the expression level of MMP-2 is upregulated in choroidal neovascularization in animal model. [ 15 ] The study performed by Hussain et al [ 16 ] suggested that the total level of pro-MMP-2 was raised in AMD.…”
The purpose of this study was to investigate the correlation of single nucleotide polymorphisms (SNPs) in Matrix metalloproteinase -2 (MMP-2) gene and the risk of age-related macular degeneration (AMD) in Chinese Han population.A total of 126 AMD patients and 141 healthy controls participated in this study. Genotypes of MMP-2 gene polymorphisms were identified by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). χ2test was used to detect the differences of genotypes and alleles frequencies between case and control groups. Relative risk of AMD was evaluated by odds ratios (ORs) with 95% confidence intervals (CIs).Distribution of variant allele carriers (computed tomography + TT genotypes) of MMP-2 gene rs243865 SNP was significantly different between case and control groups, and might act as protective factors for the onset of AMD (P = .044, OR = 0.583, 95% CI = 0.344–0.987). Nevertheless, the T allele might reduce the AMD risk (P = .030, OR = 0.611, 95% CI = 0.390–0.956). However, no significant association existed between rs243865 and AMD risk in the subgroup analysis based on age. GA + AA genotypes of rs243866 SNP may associate with a decreased risk of AMD in the age≤65 years subgroup (P = .028, OR = 0.399, 95% CI = 0.174–0.915).MMP-2 gene rs243865 and rs243866 SNPs associated with the risk of AMD. Further studies should be performed to confirm the results.
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