RESUMO
BACKGROUND: The presence of cancer stem-like cells within tumor microenvironment distinctly governs response to chemo-radiotherapy. The ALDH1 (Aldehyde dehydrogenase 1) has emerged as a cancer stem cell (CSC) marker in various tumors. The aim of the study was to examine the expression of ALDH1 in HNSCC patients undergoing radiotherapy to evaluate its correlation with clinicopathological parameter, treatment response and survival. METHODS: Expression of ALDH1 was evaluated by immunohistochemistry in 90 histopathologically confirmed HNSCC patients and 90 matched controls. The association between ALDH1 expression, clinicopathological parameters and treatment response was determined. RESULTS: The immunohistochemistry results showed that ALDH1 was consistently expressed in all the HNSCC specimens although at different intensities. On the other hand, control specimens did not show similar expression of ALDH1. ALDH1 expression demonstrated statistically significant association with tumor size (p<0.001), lymph node status (p<0.001), stage (p<0.001), grade (p<0.001) and treatment response (p<0.001). Multivariate ordinal logistic regression analysis indicated alcohol and ALDH1 as an independent predictor of responsiveness to radiotherapy in HNSCC patients. Multivariate Cox regression analysis indicated that lymph node status (p=0.020), grade (p=0.006) and recurrence (p=0.002) were potential independent predictors of overall survival. CONCLUSION: From previous studies, ALDH1 has been contemplated not only as a promising prognostic and diagnostic marker but also as a likely drug target. Our study gives new understanding regarding the association between ALDH1, cancer prognosis and radioresistance. Our findings suggest that ALDH1, lymph node status, grade and alcohol could be the viable targets for HNSCC and it also provides new prospects for radiotherapy sensitivity in HNSCC.
Assuntos
Família Aldeído Desidrogenase 1/efeitos da radiação , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias de Cabeça e Pescoço/radioterapia , Tolerância a Radiação/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/enzimologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Adulto , Biomarcadores Tumorais/efeitos da radiação , Estudos de Casos e Controles , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Imuno-Histoquímica , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/efeitos da radiação , Prognóstico , Modelos de Riscos Proporcionais , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Resultado do Tratamento , Microambiente Tumoral/efeitos da radiaçãoRESUMO
BACKGROUND HNSCC (head and neck squamous cell carcinoma) is a heterogeneous disease for which radiotherapy is a main treatment. As intrinsic radiosensitivity and immune status affect the initial and effective stage of the radiation-induced cancer immunity cycle, respectively, it is important to consider both of them when we select patients who can benefit from radiotherapy. MATERIAL AND METHODS Our study included all HNSCC patients with complete survival and radiotherapy information in TCGA database. Patients were divided into RS (radiosensitive), RR (radioresistant), immune, and non-immune groups according to their RSI (radiosensitivity index) and immune score calculated by the ESTIMATE algorithm. Survival analysis was performed to compare OS (overall survival) between patients receiving and not receiving radiotherapy. GO and KEGG pathway enrichment analysis was performed for functional analysis. Univariate Cox and ridge regression analysis were performed to construct a predictive gene signature based on the combined stratification. RESULTS Only patients in the RS-immune group could benefit from radiotherapy, and the survival analysis results remained consistent after we performed propensity score matching between patients receiving and not receiving radiotherapy. The differentially expressed genes between the RS-immune and non-RS-immune groups were mainly enriched in pathways related to immune process. The 3-gene signature we built exhibited predictive value in training and validation cohorts when treated as a binary or continuous variable. CONCLUSIONS The combined stratification of intrinsic radiosensitivity and immune status was superior to considering intrinsic radiosensitivity or immune status alone and could be used in preclinical evaluation to select patients or to decide whether radiotherapy sensitizers and immunotherapy should be used at the same time.
Assuntos
Biomarcadores Tumorais , Neoplasias de Cabeça e Pescoço/radioterapia , Imunoterapia/métodos , Tolerância a Radiação , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/efeitos da radiação , HumanosRESUMO
Molecular alterations drive cancer initiation and evolution during development and in response to therapy. Radiotherapy is one of the most commonly employed cancer treatment modalities, but radiobiologic approaches for personalizing therapy based on tumor biology and individual risks remain to be defined. In recent years, analysis of circulating nucleic acids has emerged as a non-invasive approach to leverage tumor molecular abnormalities as biomarkers of prognosis and treatment response. Here, we evaluate the roles of circulating tumor DNA and related analyses as powerful tools for precision radiotherapy. We highlight emerging work advancing liquid biopsies beyond biomarker studies into translational research investigating tumor clonal evolution and acquired resistance.
Assuntos
Ácidos Nucleicos Livres/genética , Neoplasias/radioterapia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/efeitos da radiação , Ácidos Nucleicos Livres/efeitos da radiação , Ensaios Clínicos como Assunto , Humanos , Biópsia Líquida , Neoplasias/genética , Neoplasias/patologia , Medicina de Precisão , Prognóstico , Resultado do TratamentoRESUMO
Radiotherapy resistance is one of the main causes for treatment failure in colorectal cancer (CRC), and it is associated with the deregulation of certain microRNAs. In this study, we constructed the microRNA-mRNA network consisting of 2275 microRNAs and 7045 target genes, collected the known microRNAs related to CRC-radiosensitivity (CRCR) (n=18) as the seed nodes, and applied the algorithm of random walk with restart (RWR) to the network to identify novel CRCR-related microRNAs (n=263). In functional analysis, 263 novel microRNAs shared a high proportion of the same biological processes and pathways with the known microRNAs. In topological analysis of the sub-network of the 263 microRNAs and their targets, hsa-mir-506-3p and hsa-mir-140-5p were identified as network hub nodes. In plasma, radiosensitive patients had a higher expression level of hsa-mir-506-3p and hsa-mir-140-5p than radioresistant patients. In experimental validation, both hsa-mir-506-3p and hsa-mir-140-5p over-expression could obviously decrease the cell proliferation, survival rate and colonality in CRC cells after radiation. In conclusion, this study combined the novel network-based method with experimental validation, and identified two novel radiosensitive biomarkers of hsa-mir-506-3p and hsa-mir-140-5p in CRC.
Assuntos
Algoritmos , Biomarcadores Tumorais/efeitos da radiação , Neoplasias Colorretais/genética , MicroRNAs/efeitos da radiação , Humanos , Tolerância a RadiaçãoRESUMO
BACKGROUND: Dynamin-related protein 1 (DRP1) is a GTPase involved in mitochondrial fission, mitochondrial protein import, and drug sensitivity, suggesting an association with cancer progression. This study was conducted to evaluate the prognostic significance of DRP1 in glioblastoma multiforme (GBM). METHODS: DRP1 expression was measured by immunohistochemistry and Western blotting. Correlations between DRP1 expression and clinicopathological parameters were determined by statistical analysis. Differences in survival were compared using the log-rank test. DRP1 expression was detected in 87.2% (41/47) of the investigated patients with GBM. RESULTS: The patients with higher DRP1 levels had worse survival (p = 0.0398). In vitro, the silencing of DRP1 reduced cell proliferation, invasive potential, and radiation resistance. The addition of shikonin inhibited DRP1 expression and increased drug uptake. Moreover, shikonin reduced the nuclear entry of DNA repair-associated enzymes and increased radiation sensitivity, suggesting that reducing DRP1 expression could inhibit DNA repair and increase the radiation sensitivity of GBM cells. CONCLUSION: Our results indicate that DRP1 overexpression is a prospective radio-resistant phenotype in GBM. Therefore, DRP1 could be a potential target for improving the effectiveness of radiation therapy.
Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias Encefálicas/metabolismo , Dinaminas/biossíntese , Glioblastoma/metabolismo , Tolerância a Radiação/fisiologia , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/efeitos da radiação , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Estudos de Coortes , Dinaminas/genética , Dinaminas/efeitos da radiação , Feminino , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Despite the common application and considerable efforts to achieve precision radiotherapy (RT) in several types of cancer, RT has not yet entered the era of precision medicine; the ability to predict radiosensitivity and treatment responses in tumors and normal tissues is lacking. Therefore, development of genome-based methods for individual prognosis in radiation oncology is urgently required. Traditional DNA sequencing requires tissue samples collected during invasive operations; therefore, repeated tests are nearly impossible. Intra- and inter-tumoral heterogeneity may undermine the predictive power of a single assay from tumor samples. In contrast, analysis of circulating tumor DNA (ctDNA) allows for non-invasive and near real-time sampling of tumors. By investigating the genetic composition of tumors and monitoring dynamic changes during treatment, ctDNA analysis may potentially be clinically valuable in prediction of treatment responses prior to RT, surveillance of responses during RT, and evaluation of residual disease following RT. As a biomarker for RT response, ctDNA profiling may guide personalized treatments. In this review, we will discuss approaches of tissue DNA sequencing and ctDNA detection and summarize their clinical applications in both traditional RT and in combination with immunotherapy.
Assuntos
Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/sangue , Genômica , Neoplasias/radioterapia , Biomarcadores Tumorais/efeitos da radiação , Proliferação de Células/efeitos da radiação , DNA Tumoral Circulante/efeitos da radiação , Testes Diagnósticos de Rotina , Intervalo Livre de Doença , Feminino , Genoma Humano/efeitos da radiação , Humanos , Masculino , Neoplasia Residual/sangue , Neoplasia Residual/patologia , Neoplasia Residual/radioterapia , Neoplasias/sangue , Neoplasias/patologia , Medicina de Precisão , Prognóstico , Resultado do TratamentoAssuntos
Carcinoma de Células Escamosas/imunologia , Hospedeiro Imunocomprometido/efeitos da radiação , Mutação/efeitos da radiação , Neoplasias Cutâneas/imunologia , Raios Ultravioleta/efeitos adversos , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/efeitos da radiação , Carcinoma de Células Escamosas/genética , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/genética , Estados UnidosRESUMO
PURPOSE: We recently showed that prophylactic breast irradiation (PBI) reduces the risk of contralateral breast cancer in BRCA mutation carriers undergoing treatment for early breast cancer. It has been suggested that Background Parenchymal Enhancement (BPE) may be a biomarker for increased risk of breast cancer. METHODS: For participants in the trial we reviewed the MRI prior to enrollment and following radiation treatment and scored the contralateral breast for BPE and density. RESULTS: Significant reduction of BPE was more commonly noted following PBI (pâ¯=â¯0.011) compared to the control group. CONCLUSION: Reduction of BPE by PBI may contribute to its prophylactic effect.
Assuntos
Neoplasias da Mama/prevenção & controle , Aumento da Imagem/métodos , Imageamento por Ressonância Magnética/estatística & dados numéricos , Tecido Parenquimatoso/efeitos da radiação , Radioterapia/métodos , Adulto , Idoso , Proteína BRCA1 , Proteína BRCA2 , Biomarcadores Tumorais/efeitos da radiação , Mama/diagnóstico por imagem , Mama/efeitos da radiação , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença/prevenção & controle , Humanos , Pessoa de Meia-Idade , Mutação , Tecido Parenquimatoso/diagnóstico por imagemRESUMO
The optical imaging plays an increasing role in preclinical studies, particularly in cancer biology. The combined ultrasound and optical imaging, named photoacoustic imaging (PAI), is an emerging hybrid technique for real-time molecular imaging in preclinical research and recently expanding into clinical setting. PAI can be performed using endogenous contrast, particularly from oxygenated and deoxygenated hemoglobin and melanin, or exogenous contrast agents, sometimes targeted for specific biomarkers, providing comprehensive morphofunctional and molecular information on tumor microenvironment. Overall, PAI has revealed notable opportunities to improve knowledge on tumor pathophysiology and on the biological mechanisms underlying therapy. The aim of this review is to introduce the principles of PAI and to provide a brief overview of current PAI applications in preclinical research, highlighting also on recent advances in clinical translation for cancer diagnosis, staging, and therapy.
Assuntos
Neoplasias/diagnóstico , Técnicas Fotoacústicas/métodos , Nanomedicina Teranóstica/tendências , Absorção de Radiação , Animais , Biomarcadores Tumorais/efeitos da radiação , Sistemas Computacionais , Meios de Contraste/efeitos da radiação , Detecção Precoce de Câncer/métodos , Desenho de Equipamento , Hemoglobinas/efeitos da radiação , Humanos , Verde de Indocianina/efeitos da radiação , Lasers , Substâncias Macromoleculares/efeitos da radiação , Melaninas/efeitos da radiação , Nanopartículas Metálicas/efeitos da radiação , Nanotubos de Carbono/efeitos da radiação , Neoplasias/metabolismo , Neoplasias/terapia , Neoplasias Experimentais/química , Neoplasias Experimentais/diagnóstico por imagem , Técnicas Fotoacústicas/instrumentação , Pontos Quânticos/efeitos da radiação , Espalhamento de Radiação , Nanomedicina Teranóstica/métodos , TransdutoresRESUMO
Preoperative radiotherapy (RT) plays an important role in the management of locally advanced rectal cancer (RC). Tumor regression after RT shows marked variability, and robust molecular methods are needed to help predict likely response. The aim of this study was to review the current published literature and use Gene Ontology (GO) analysis to define key molecular biomarkers governing radiation response in RC. A systematic review of electronic bibliographic databases (Medline, Embase) was performed for original articles published between 2000 and 2015. Biomarkers were then classified according to biological function and incorporated into a hierarchical GO tree. Both significant and nonsignificant results were included in the analysis. Significance was binarized on the basis of univariate and multivariate statistics. Significance scores were calculated for each biological domain (or node), and a direct acyclic graph was generated for intuitive mapping of biological pathways and markers involved in RC radiation response. Seventy-two individual biomarkers across 74 studies were identified. On highest-order classification, molecular biomarkers falling within the domains of response to stress, cellular metabolism, and pathways inhibiting apoptosis were found to be the most influential in predicting radiosensitivity. Homogenizing biomarker data from original articles using controlled GO terminology demonstrated that cellular mechanisms of response to RT in RC-in particular the metabolic response to RT-may hold promise in developing radiotherapeutic biomarkers to help predict, and in the future modulate, radiation response.
Assuntos
Biomarcadores Tumorais/análise , Terapia Neoadjuvante/métodos , Tolerância a Radiação , Neoplasias Retais/terapia , Biomarcadores Tumorais/efeitos da radiação , Intervalo Livre de Doença , Humanos , Protectomia , Prognóstico , Radioterapia Adjuvante/métodos , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Resultado do TratamentoRESUMO
BACKGROUND/AIM: Head and neck cancers are a heterogenous group of epithelial tumors represented mainly by squamous cell carcinomas (HNSCC), which are the sixth most common type of cancer worldwide. Surgery together with radiotherapy (RT) is among the basic treatment modalities for most HNSCC patients. Various biomarkers aiming to predict patients' response to RT are currently investigated. The reason behind this effort is, on one hand, to distinguish radioresistant patients that show weak benefit from RT and, on the other hand, reduce the ionizing radiation dose in less aggressive radiosensitive HNSCC with possibly less acute or late toxicity. MATERIALS AND METHODS: A total of 94 HNSCC patients treated by definitive intensity-modulated radiotherapy were included in our retrospective study. We used a global expression analysis of microRNAs (miRNAs) in 43 tumor samples and validated a series of selected miRNAs in an independent set of 51 tumors. RESULTS: We identified miR-15b-5p to be differentially expressed between patients with short and long time of locoregional control (LRC). Kaplan-Meier analysis confirmed that HNSCC patients with higher expression of miR-15b-5p reach a significantly longer locoregional relapse-free survival compared to patients expressing low levels. Finally, multivariable Cox regression analysis revealed that miR-15b-5p is an independent predictive biomarker of LRC in HNSCC patients (HR=0.25; 95% CI=0.05-0.78; p<0.016). CONCLUSION: miR-15b-5p represents a potentially helpful biomarker for individualized treatment decisions concerning the management of HNSCC patients.
Assuntos
MicroRNAs/genética , Recidiva Local de Neoplasia/radioterapia , Radioterapia de Intensidade Modulada , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Biomarcadores Tumorais/efeitos da radiação , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Resultado do TratamentoRESUMO
AIM: To evaluate the prediction ability of neutrophils and develop a nomogram on radiosensitivity in thoracic cancer patients. METHODS: We retrospectively reviewed 398 lung and esophageal cancers patients who received external-beam radiotherapy or concurrent chemoradiotherapy as first-line therapy. RESULTS: Logistic regression model showed that patients with low levels of neutrophil counts and/or TGF-ß1 exhibited better radiation sensitivity. Furthermore, a nomogram was created to predict radiotherapy sensitivity. The combination of neutrophil count and TGF-ß1 level was an independent prognostic factor for lung and esophageal cancers patients. CONCLUSION: The study developed a nomogram based on the levels of circulating neutrophils and TGF-ß1. The prediction value in radiosensitivity and protumorigenic effect of neutrophils might owe to N2 tumor-associated neutrophils.
Assuntos
Neoplasias Esofágicas/radioterapia , Neoplasias Pulmonares/radioterapia , Neutrófilos/metabolismo , Tolerância a Radiação , Fator de Crescimento Transformador beta1/metabolismo , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/efeitos da radiação , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/patologia , Feminino , Humanos , Contagem de Leucócitos , Modelos Logísticos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos da radiação , Nomogramas , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Context: Radioactive iodine (RAI) has been epidemiologically associated with the development of hematologic malignancies. Clonal hematopoiesis (CH) is a precursor clonal state that confers increased risk of leukemia and occurs at an elevated rate in patients with thyroid cancer relative to other solid tumors. Objective: We explore if the high prevalence of CH may be a result of RAI exposure and whether CH may be a surrogate in the association between RAI and leukemia. Design: CH, CH-potential driver (CH-PD), and overall survival were evaluated in 279 patients with advanced thyroid carcinoma. Results: The prevalence of CH in patients with thyroid cancer was 37%, and that of CH-PD was 5.2%. Age was the strongest predictor of CH and CH-PD. For every year increase in age, there was a 5% and 13% increase in the odds of CH and CH-PD, respectively. RAI dose was significantly associated with CH and CH-PD, even after adjustment for age, external beam radiation therapy, and chemotherapy. For every 10 mCi increase in the dose of RAI administered, there was a 2% and 4% increase in the odds of CH and CH-PD, respectively. Patients with CH-PD previously exposed to RAI had a significantly poorer survival, even when stratified by age (heart rate = 3.75, 95% CI = 1.23 to 11.5, P = 0.02). Conclusions: RAI was associated with a high prevalence of CH, and CH is a precursor state of hematologic malignancies. The implications of this study may favor identification of CH in patients where the risks might outweigh the benefits of receiving RAI therapy for thyroid cancer.
Assuntos
Carcinoma/radioterapia , Hematopoese/efeitos da radiação , Radioisótopos do Iodo/efeitos adversos , Lesões Pré-Cancerosas/epidemiologia , Neoplasias da Glândula Tireoide/radioterapia , Fatores Etários , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/efeitos da radiação , Carcinoma/mortalidade , Análise Mutacional de DNA , Feminino , Seguimentos , Células-Tronco Hematopoéticas/patologia , Células-Tronco Hematopoéticas/efeitos da radiação , Humanos , Radioisótopos do Iodo/administração & dosagem , Leucemia/genética , Leucemia/patologia , Leucemia/prevenção & controle , Masculino , Pessoa de Meia-Idade , Mutação/efeitos da radiação , Neoplasias Induzidas por Radiação/genética , Neoplasias Induzidas por Radiação/patologia , Neoplasias Induzidas por Radiação/prevenção & controle , Lesões Pré-Cancerosas/etiologia , Lesões Pré-Cancerosas/patologia , Prevalência , Estudos Prospectivos , Análise de Sobrevida , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/mortalidadeRESUMO
OBJECTIVES: To examine the relationship between erectile function status and prostate-specific antigen bounce after prostate brachytherapy for localized prostate cancer. METHODS: We identified 154 patients who were followed up for at least 24 months after brachytherapy. Erectile function status was assessed prospectively before brachytherapy (baseline), and 3, 6, 12, 18, 24 and 36 months postoperatively using the International Index of Erectile Function-15 questionnaire. Prostate-specific antigen bounce was defined as an increase of at least 0.4 ng/mL from a previous prostate-specific antigen level with a subsequent decline equal to, or less than, the initial nadir without treatment. A logistic regression analysis was used to identify a significant set of independent predictors of prostate-specific antigen bounce after brachytherapy. RESULTS: Prostate-specific antigen bounce was observed in 38 (24.7%) men. The prostate-specific antigen bounce group had a higher erectile function domain score, higher orgasmic function domain score, and higher total International Index of Erectile Function-15 score before (at baseline) and after brachytherapy (3, 6, 12, 18, 24 and 36 months after brachytherapy) than their counterparts (P < 0.05). Of the 77 patients who completed the International Index of Erectile Function-15 questionnaire 18 months after brachytherapy (the median time of prostate-specific antigen bounce), sexual desire and intercourse satisfaction domain scores, and total International Index of Erectile Function scores 18 months after brachytherapy correlated with the occurrence of prostate-specific antigen bounce. A multivariate analysis identified the intercourse satisfaction domain score 18 months after brachytherapy as an independent indicator for the occurrence of prostate-specific antigen bounce (P = 0.008). CONCLUSIONS: International Index of Erectile Function-15 score seems to be correlated with the prostate-specific antigen bounce in prostate cancer patients undergoing brachytherapy, and an occurrence of prostate-specific antigen bounce seems to be more likely in those who are more sexually active.
Assuntos
Biomarcadores Tumorais/efeitos da radiação , Braquiterapia/métodos , Recidiva Local de Neoplasia/diagnóstico , Ereção Peniana , Antígeno Prostático Específico/efeitos da radiação , Neoplasias da Próstata/radioterapia , Idoso , Biomarcadores Tumorais/sangue , Seguimentos , Humanos , Radioisótopos do Iodo/uso terapêutico , Japão , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Antígeno Prostático Específico/sangue , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Although ultraviolet (UV) rays cause premature aging of human skin, which is called photoaging, its detailed mechanisms are not known. Stratifin (SFN), a member of the 14-3-3 protein family, is secreted by keratinocytes on human skin, and has an effect on gene expression in other cells. In this study, the association of SFN with the mechanism of photoaging was investigated. The effect of UVB irradiation on SFN expression in epidermal keratinocytes was examined by in vitro and in vivo studies. In addition, the effects of SFN on epidermal keratinocytes and dermal fibroblasts were examined. SFN mRNA expression and protein levels increased significantly in UVB-irradiated keratinocytes. SFN significantly decreased filaggrin and serine palmitoyltransferase mRNA expression in epidermal keratinocytes and hyaluronan synthase 2 mRNA expression in dermal fibroblasts. In addition, it was reconfirmed that SFN induces the downregulation of collagen content through changes of COL-1, MMP-1 and MMP-2 mRNA expressions. Furthermore, the expression level of SFN mRNA was significantly higher in sun-exposed compared with that in sun-shielded skin. These results suggest that SFN affects the water-holding capacity, barrier function and dermal matrix components in photoaging skin. An increase of SFN triggered by UVB irradiation may be one of the causes of alterations observed in photoaging skin.
Assuntos
Proteínas 14-3-3/metabolismo , Proteínas 14-3-3/efeitos da radiação , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/efeitos da radiação , Exorribonucleases/metabolismo , Exorribonucleases/efeitos da radiação , Envelhecimento da Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Proteínas 14-3-3/genética , Biomarcadores Tumorais/genética , Linhagem Celular , Colágeno Tipo I/genética , Epiderme/metabolismo , Epiderme/efeitos da radiação , Exorribonucleases/genética , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Proteínas Filagrinas , Expressão Gênica/efeitos da radiação , Glucuronosiltransferase/genética , Humanos , Hialuronan Sintases , Técnicas In Vitro , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 2 da Matriz/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Envelhecimento da Pele/fisiologiaRESUMO
Human glioblastomas may be hierarchically organized. Within this hierarchy, glioblastoma-initiating cells have been proposed to be more resistant to radiochemotherapy and responsible for recurrence. Here, established stem cell markers and stem cell attributed characteristics such as self-renewal capacity and tumorigenicity have been profiled in primary glioblastoma cultures to predict radiosensitivity. Furthermore, the sensitivity to radiotherapy of different subpopulations within a single primary glioblastoma culture was analyzed by a flow cytometric approach using Nestin, SRY (sex-determining region Y)-box 2 (SOX2) and glial fibrillary acidic protein. The protein expression of Nestin and SOX2 as well as the mRNA levels of Musashi1, L1 cell adhesion molecule, CD133, Nestin, and pleiomorphic adenoma gene-like 2 inversely correlated with radioresistance in regard to the clonogenic potential. Only CD44 protein expression correlated positively with radioresistance. In terms of proliferation, Nestin protein expression and Musashi1, pleiomorphic adenoma gene-like 2, and CD133 mRNA levels are inversely correlated with radioresistance. Higher expression of stem cell markers does not correlate with resistance to radiochemotherapy in the cancer genome atlas glioblastoma collective. SOX2 expressing subpopulations exist within single primary glioblastoma cultures. These subpopulations predominantly form the proliferative pool of the primary cultures and are sensitive to irradiation. Thus, profiling of established stem cell markers revealed a surprising result. Except CD44, the tested stem cell markers showed an inverse correlation between expression and radioresistance. Markers used to define glioma-initiating cells (GIC) are generally not defining a more resistant, but rather a more sensitive group of glioma cells. An exemption is CD44 expression. Also proliferation of the GIC culture itself was not systematically associated with radiosensitivity or - resistance, but a SOX-2 positive, proliferative subgroup within a GIC culture is showing the highest radiosensitivity.
Assuntos
Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/efeitos da radiação , Glioblastoma/radioterapia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos da radiação , Animais , Feminino , Previsões , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Nus , Radioterapia/métodos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
The purpose of the present study was to elucidate whether premature senescence contributes to the outcome of radiotherapy (RT) and to validate senescence biomarkers in vitro and in vivo. Cultured human cancer cell lines and xenografted mice were exposed to single (SR; 2, 6 or 12 Gy) or fractionated radiation (FR; 3 x 2 Gy or 6 x 2 Gy), and premature senescence was assessed using senescence-associated ß-galactosidase (SA-ß-Gal) activity, hypophosphorylation of pRb and p21 accumulation. A variety of senescence-associated biomarkers including cathepsin D (CD), the eukaryotic translation elongation factors eEF1A1, eEF1B2, decoy receptor 2 and Dec1 were further validated in vivo or in vitro. We demonstrated the beneficial tumor suppressive role of ionizing radiation (IR)-induced premature senescence in vitro and in vivo. FR inhibited tumor growth via induction of premature senescence as effectively as an equivalent SR dose (≥6 Gy). In addition, CD and eEF1 were valuable biomarkers of cellular senescence in either SR- or RF-exposed carcinoma cells or xenograft mice. Our results suggest that 2 Gy of a conventional RT regime could achieve a better clinical outcome if premature senescence could be increased through an improved understanding of its molecular action mechanism.
Assuntos
Biomarcadores Tumorais/efeitos da radiação , Carcinoma/radioterapia , Senescência Celular/efeitos da radiação , Fracionamento da Dose de Radiação , Animais , Carcinoma/mortalidade , Carcinoma/patologia , Catepsina D/metabolismo , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Fator 1 de Elongação de Peptídeos/metabolismo , Fosforilação , Proteína do Retinoblastoma/metabolismo , Transplante Heterólogo , Resultado do Tratamento , Receptores Chamariz do Fator de Necrose Tumoral/metabolismo , Proteínas Supressoras de Tumor/metabolismo , beta-Galactosidase/metabolismoRESUMO
MicroRNAs (miRNAs) are small non-protein coding RNA that play an important role in gene regulation. These RNA molecules function as post-transcriptional regulators. miRNAs bind to complementary sequences on target messenger RNA transcripts, usually resulting in translational repression or target mRNA degradation and gene silencing. miRNA are abundantly present in all human cells, target approximately 60% of all genes, and are able to repress hundreds of targets each. Since their discovery in 1993 miRNA are emerging as important modulators in cellular pathways such as growth and proliferation, apoptosis, carcinogenesis, timing of cell-fate decision, and metabolic pathways. A large number of studies have examined the general and specific effects of miRNAs perturbation in radiation-exposed cells. These studies include expression profiling of miRNA, functional analysis, the role of specific miRNAs in tumor radiosensitivity, and targeting miRNA for improved cancer radiotherapy. Other studies have explored the involvement of miRNA in radiobiological phenomenon like bystander effect. Emerging evidence is establishing that miRNA are involved in regulating radiation-induced cellular processes, can be exploited to improve cancer radiation therapy, and could serve as biomarkers of human radiation exposure.
Assuntos
Carcinogênese/efeitos da radiação , MicroRNAs/genética , MicroRNAs/efeitos da radiação , Neoplasias/genética , Apoptose/efeitos da radiação , Biomarcadores Tumorais/efeitos da radiação , Carcinogênese/genética , Proliferação de Células/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , MicroRNAs/uso terapêutico , Neoplasias/radioterapiaRESUMO
The objective of this review is to present an argument for performing joint analyses between functional imaging with global gene expression studies. The reason for making this link is that tumor microenvironmental influences on functional imaging can be uncovered. Such knowledge can lead to (1) more informed decisions regarding how to use functional imaging to guide therapy and (2) discovery of new therapeutic targets. As such, this approach could lead to identification of patients who need aggressive treatment tailored toward the phenotype of their tumor vs those who could be spared treatment that carries risk for more normal tissue complications. Only a handful of papers have been published on this topic thus far, but all show substantial promise.
Assuntos
Diagnóstico por Imagem , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/radioterapia , Microambiente Tumoral , Animais , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/efeitos da radiação , Regulação Neoplásica da Expressão Gênica , Humanos , FenótipoRESUMO
A growing body of evidence attributes properties of chemo- and/or radiation-resistance to cancer stem cells (CSCs). Moreover, non-targeted delayed effects such as genomic instability, transmitted through many generations, can be observed in the progeny of surviving irradiated cells. As a consequence, we propose that radiation-resistance properties associated to CSCs could confer a key role to this subpopulation in the transmission of genomic instability. To test this hypothesis, we searched the CSC markers associated to radiation-resistance in breast cancer cell lines and studied the role of the resistant cells in the transmission of genomic instability. First, we show that irradiation induces a 2-4 weeks period of intense cell death leading to the emergence of chromosomal unstable cells during more than 35 population doublings. Then, among seven breast CSC markers, we identify CD24(-/low) labelling as a marker of radiation-resistance. We demonstrate that CD24(+) progeny of irradiated cells exclusively descends from CD24(-/low) cells. Finally, we show that delayed chromosomal instability is only expressed by CD24(+) cells, but is transmitted by stable surviving CD24(-/low) cells. So, for the first time a CSC marker, CD24, is associated with the transmission of genomic instability. This work may assign a new deleterious role to breast CSCs in aggressive recurrence after radiotherapy, as the transmitted genomic instability potentially leads tumour cells to acquire more aggressive characteristics.