RESUMO
Sterol O-acyltransferase 1 (SOAT1) is a key enzyme in lipid metabolism, which mediates cholesterol esterification metabolism and is closely associated with many cancers. However, the role of SOAT1 in lung cancer invasion remains unclear. We found that SOAT1 expression was positively correlated with lung cancer invasion. Downregulation of SOAT1 inhibited invasion, mitochondrial fragmentation, AKT phosphorylation, and phospho-Drp (Ser616) in lung cancer cells and promoted intracellular free cholesterol accumulation. Mechanistically, the AKT phosphorylation inhibitor MK-2206 alleviated both SOAT1 overexpression and high expression-induced mitochondrial fragmentation and lung cancer cell invasion. Furthermore, intracellular free cholesterol accumulation reduced AKT phosphorylation, SREBP1 mRNA expression, cell invasion, and mitochondrial fragmentation in lung cancer cells with high SOAT1 expression. In summary, our findings suggest that SOAT1 promotes lung cancer invasion by activating the PI3K/AKT signaling pathway by downregulating intracellular free cholesterol levels, thereby affecting the regulation of mitochondrial fragmentation.
Assuntos
Neoplasias Pulmonares , Proteínas Proto-Oncogênicas c-akt , Colesterol/metabolismo , Humanos , Pulmão/metabolismo , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases , Esterol O-AciltransferaseRESUMO
Lung cancer is the most common cause of cancer-related death in the world. Long non-coding RNAs (lncRNAs) are longer than 200 nucleotide transcripts, and are not translated into protein. The lncRNA linc00662 is overexpressed in lung cancer; however, its role in lung cancer is still unknown. In our study, by analyzing the TCGA data, we found that linc00662 was overexpressed in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). We knocked-down the expression of linc00662 using siRNA, and found that silencing linc00662 significantly inhibited the proliferation and colony formation of the lung cancer cell lines A549 and H460. We also found that knockdown of linc00662 increased the expression of the microRNA miR-145-5p and decreased the expression of the platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B2) gene. We further show that linc00662 binds with miR-145-5p, and that miR-145-5p binds to the 3'UTR of PAFAH1B2. miR-145-5p negatively regulates PAFAH1B2 both at the mRNA and the protein level. Loss of miR-145-5p abolished the inhibitory effects of silencing linc00662 on the proliferation and colony formation of A549 and H460 cells. These findings indicate that linc00662 functions as an oncogene by acting as a competing endogenous RNA (ceRNA) and sponges and regulates miR-145-5p in lung cancer, and thus may provide a potential target for treating lung cancer.
Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Proteínas Associadas aos Microtúbulos/metabolismo , RNA Longo não Codificante/genética , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Idoso , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
Numerous studies have indicated that microRNAs (miRNAs) play critical roles in the development and progression of cancer. However, how changes to the expression levels of miRNAs in response to dexmedetomidine affects the progression of lung cancer remains poorly understood. In this study, we treated the lung adenocarcinoma cell line-A549 with dexmedetomidine and then examined the changes to the expression levels of miRNAs. We found that one of the most significantly upregulated miRNAs was miR-493-5p, which has an important role in the growth and apoptosis of lung adenocarcinoma (LUAD) cells. In addition, bioinformatics searches and luciferase reporter assays revealed that miR-493-5p targets RASL11B, which has a high degree of similarity to RAS. Finally, database searches revealed that RASL11B is associated with survival of LUAD cells. In conclusion, dexmedetomidine causes changes to the expression levels of miRNAs in LUAD, including significant upregulation of miR-493-5p. MiR-493-5p targets RASL11B, thereby inhibiting cell growth and inducing apoptosis in LUAD.
Assuntos
Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/metabolismo , Dexmedetomidina/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Monoméricas de Ligação ao GTP/genética , Células Tumorais CultivadasRESUMO
Lung cancer is the leading cause of cancer-related death globally. Ubiquitin modification plays a crucial role in the regulation of gene expression, and is closely associated with cancer pathogenesis. The aim of our study was to clarify the role and mechanisms of action for HECT, C2 and WW domain containing E3 ubiquitin protein ligase 1 (HECW1) in non-small cell lung cancer (NSCLC). Herein, we demonstrate that the expression of HECW1 was significantly increased in NSCLC cell lines and tissues. Upregulation of HECW1 markedly enhanced the proliferation of NSCLC cells, whereas downregulation of HECW1 significantly inhibited proliferation. Moreover, the expression levels of HECW1 positively correlated with the migration and invasiveness of NSCLC cells. Upregulation or downregulation of HECW1 only affected the protein expression levels of SMAD family member 4 (Smad4), but had no effect on the mRNA expression levels. Furthermore, after treatment with MG-132, the relative protein level of Smad4 significantly increased in NSCLC cells. HECW1 promoted the proliferation, migration, and invasiveness of NSCLC cells by inducing the ubiquitination and degradation of Smad4, thus our data provide a novel target for NSCLC treatment.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteína Smad4/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/patologia , Proteínas do Tecido Nervoso/genética , Proteína Smad4/genética , Ubiquitina-Proteína Ligases/genética , UbiquitinaçãoRESUMO
Lung cancer is the most common cancer worldwide. Epigenetic modifications like DNA methylation play fundamental roles in the dynamic process of lung cancer. The objective of this study was to use methyl-CpG binding domain protein-enriched genome sequencing (MBD-Seq) to identify novel and high-confidence DNA methylation in lung tumor. We first compared the whole-genome DNA methylation of three lung cancer cell lines, including A549, H1299, and SK-MES-1, against BEAS-2B, a lung/bronchial normal epithelial cell line. We then used pyrosequencing and OneStep qMethyl kit methods to verify the results in the cell line specimens. MBD-Seq identified 279, 8046, and 22 887 differentially methylated regions (DMRs), respectively, with 120 common DMRs among three comparison groups. Three DMRs were consistent with the MBD-Seq results by both pyrosequencing and OneStep qMethyl validations. Furthermore, OneStep qMethyl kit was also performed for functional validation of these three potential DMRs in sputum DNA from clinical participants. We successfully identified one new DMR adjacent to ATG16L2. The novel DMR might have an important function in lung carcinogenesis. Further validation of the finding in clinical specimens of lung cancer patients and functional analysis of this novel DMR in the development of lung cancer through transcriptional silencing of ATG16L2 are warranted.
Assuntos
Proteínas Relacionadas à Autofagia/genética , Metilação de DNA , Técnicas Genéticas , Neoplasias Pulmonares/genética , Proteínas Relacionadas à Autofagia/química , Carcinogênese/genética , Linhagem Celular Tumoral , Epigênese Genética , Genoma Humano , Humanos , Domínios ProteicosRESUMO
Although the abundance of long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) in lung cancer has been well researched, the underlying mechanisms behind its effects were unknown. Here we investigated the molecular events regulating PVT1 in lung cancer. The pro-proliferative property of PVT1 was examined using a xenograft tumor model. Transwell chambers were used to analyze the impact of PVT1 expression on cell invasiveness and migration. In vivo metastasis was examined by tail-vein-injection in mice. Direct binding of miR-128 to PVT1 was investigated using a probe pulldown assay. The relative expression levels of miR-128 and PVT1 were quantified by real-time polymerase chain reaction and Western blotting. We show here that when PVT1 is amplified, there is a poor survival prognosis for patients with lung cancer. Elevated levels of PVT1 promoted lung cancer cell proliferation and metastasis, both in vitro and in vivo. Mechanistically, we found that PVT1 competes endogenously with miR-128 in the regulation of vascular endothelial growth factor C (VEGFC) expression, which is significantly associated with an unfavorable prognosis in lung cancer. We identified that copy number amplification significantly contributes to the high level of PVT1 transcripts in lung cancer, which promotes cell proliferation and metastatic behavior via modulating VEGFC expression by endogenous competition with miR-128.
Assuntos
Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/biossíntese , RNA Longo não Codificante/metabolismo , RNA Neoplásico/metabolismo , Fator C de Crescimento do Endotélio Vascular/biossíntese , Células A549 , Animais , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Proteínas de Neoplasias/genética , RNA Longo não Codificante/genética , RNA Neoplásico/genética , Fator C de Crescimento do Endotélio Vascular/genéticaRESUMO
INTRODUCTION: PELICAN (« Partager Éfficacement en Laboratoire les Informations des Comptes rendus ANatomopathologiques ¼) is a software which generates standardized reports and, in parallel, allows to automatically create a database that can be used for research purpose. This application has been used in our laboratory since 2014 for central nervous system tumors. The aim of this work was to extend it to another type of tumor, lung cancer. MATERIALS AND METHODS: The content of the pathology reports was previously defined using various standards (Société Française de Pathologie, Institut National du Cancer, WHO Classification 2015, ). A double codification was used with SNOMED and ADICAP codes. The PELICAN application is a Microsoft Excel file containing a software specifically developed for pathology laboratories, written in Visual Basic for Applications and respecting the CDA-R2 standard. RESULTS: After definition of the software specifications, a beta-version was installed in February 2018. After various updates, the 3.19 version was installed in July 2018. Almost all lung cancer surgical pathology reports are now generated with the PELICAN software; a total of 56 reports were validated at the time of writing this manuscript. The medical time for the generation of the report was globally the same or decreased for some pathologists. The secretarial time was greatly reduced. CONCLUSION: The PELICAN software is an easy to use tool that allows to generate standardized reports in pulmonary pathology and to feed a database that can be easily used for statistical purposes.
Assuntos
Sistemas de Gerenciamento de Base de Dados , Neoplasias Pulmonares/patologia , Prontuários Médicos/normas , Software , HumanosRESUMO
The identification of ALK and ROS1 rearrangements has become essential for the theranostic management of patients with non-small cell lung cancer, especially in stage IV or inoperable patients. These testings are now performed by immunohistochemistry on histological samples and confirmed by fluorescent in situ hybridization in case of positive or doubtful results. The diagnosis of lung cancer is often performed at an advanced or metastatic stage and cytological sample could be the only material containing malignant cells available at these stages. Therefore, the detection of ALK and ROS1 rearrangement by immunocytochemical analysis on cytological specimens is needed. We performed this test on 27 cytological samples of lung adenocarcinomas, and we compared our results with several other techniques: on the same sample or on biopsy in another laboratory, on the same sample by fluorescent in situ hybridization and/or immunochemistry. We found a very good concordance between all these techniques, thus validating our immunocytochemical method on cytological samples according to the ISO 15189 norm.
Assuntos
Adenocarcinoma/genética , Quinase do Linfoma Anaplásico/genética , Rearranjo Gênico , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/metabolismo , Feminino , Genes Neoplásicos/genética , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Biópsia Líquida , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismoRESUMO
Recombinant Helicobacter pylori neutrophil-activating protein fused with maltose-binding protein (rMBP-NAP), a potential TLR2 ligand, was reported to possess immunomodulatory effects on in situ tumors in our previous study. In the present work, we attempt to elucidate the effect of rMBP-NAP at the local immune modulation in B16-F10-induced metastatic lung cancer. Our results demonstrated that growth of B16-F10 melanoma metastases in the lung was significantly arrested after rMBP-NAP treatment, along with marked reduction in metastatic lung nodules and significant increase in survival. The treatment induced both local and systemic immune responses, which were associated with higher influx of CD4+/CD8+ T cells and drove toward Th1-like and cytotoxic immune environment. Moreover, rMBP-NAP also showed significant anti-angiogenic activity by reducing vascularization in lung tumor sections. rMBP-NAP could induce antitumor immunity through activating Th1 cells and producing pro-inflammatory cytokines, which are responsible for the effective cytotoxic immune response against cancer progression. Our findings indicate that rMBP-NAP might be a novel antitumor therapeutic strategy.
Assuntos
Proteínas de Bactérias/uso terapêutico , Progressão da Doença , Imunidade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Proteínas Ligantes de Maltose/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Animais , Proliferação de Células/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/imunologia , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Neovascularização Patológica/tratamento farmacológico , Proteínas Recombinantes de Fusão/farmacologia , Baço/patologia , Análise de Sobrevida , Células Th1/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
This study examined the metabolic response of lung cancer cells and normal lung fibroblasts to hypoxia and acidity. GLUT1 and HXKII mRNA/protein expression was up-regulated under hypoxia in the MRC5 fibroblasts and in the A549 and H1299 lung cancer cell lines, indicating intensified glucose absorption and glycolysis. Under hypoxia, the LDHA mRNA and LDH5 protein levels increased in the cancer cells but not in the fibroblasts. Acidity suppressed the above-mentioned hypoxia effect. PDH-kinase-1 (PDK1 mRNA and protein) and inactive phosphorylated-PDH protein levels were induced under hypoxia in the cancer cells, whereas these were reduced in the MRC5 lung fibroblasts. In human tissue sections, the prevalent expression patterns supported the contrasting metabolic behavior of cancer cells vs. tumor fibroblasts. The monocarboxylate/lactate transporter 1 (MCT1) was up-regulated in all the cell lines under hypoxic conditions, but it was suppressed under acidic conditions. The mitochondrial DNA (mtDNA) content per cell decreased significantly in the A549 cancer cell line under hypoxia, but it increased in the MRC5 fibroblasts. Taking into account these findings, we suggest that, under hypoxia, cancer cells intensify the anaerobic direction in glycolysis, while normal fibroblasts prefer to seek energy by intensifying the aerobic use of the available oxygen.
Assuntos
Ácidos/farmacologia , Fibroblastos/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Hexoquinase/metabolismo , Hipóxia/fisiopatologia , Neoplasias Pulmonares/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Simportadores/metabolismo , Western Blotting , Células Cultivadas , Fibroblastos/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 1/genética , Hexoquinase/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Transportadores de Ácidos Monocarboxílicos/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Simportadores/genéticaRESUMO
BACKGROUND: At the request of French public authorities, the Institute of Radiological Protection and Nuclear Safety has assessed the radiological situation of a house built on uranium ore residues in Haute-Vienne and the health risks induced from exposure to radon for all occupants. Classified as a lung carcinogen by the World Health Organization, radon is a proven cause of lung cancer in case of regular inhalation over a long period, and the risk increases with cumulative exposure. METHODS: Radon exposure was reconstructed for various standard profiles of house occupancy. A risk model derived from a European epidemiological study was used to calculate the lifetime probability of death from lung cancer according to these standard profiles. RESULTS: Risk assessment of the occupants of the house highlighted the following main findings. For a resident school child having been exposed to radon from birth to the age of 7, the lifetime relative risk (LRR) was estimated at 5. For last adult and young adult residents having lived more than 10years in the house, the probability of death from lung cancer was in the same order of magnitude as that of a regular cigarette smoker, with a LRR from 10 to 13 and a lifetime probability of death from lung cancer between 3 and 4%. If these individuals smoked regularly, in addition to being exposed to radon, this probability would be between 6 and 32% (supposing an additive or multiplicative interaction). CONCLUSION: For former occupants (non-smokers) having been exposed 10years during childhood, the LRR was two-fold lower. For children having been in day care in the house, the increased probability of death from lung cancer was low, with a LRR lower than 2. Supposing, as in adults, that the risk decreases beyond 30years after the end of radon exposure, the increase was almost zero for former occupants exposed during childhood and during day care, with a LRR close to 1.
Assuntos
Exposição Ambiental/análise , Habitação , Radônio/toxicidade , Urânio/toxicidade , Exposição Ambiental/estatística & dados numéricos , Habitação/estatística & dados numéricos , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etiologia , Neoplasias Induzidas por Radiação/epidemiologia , Doenças Profissionais/epidemiologia , Doenças Profissionais/etiologia , Exposição Ocupacional/estatística & dados numéricos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Urânio/químicaRESUMO
Nowadays, the analysis of theranostic molecular markers is central in the management of lung cancer. As those tumors are diagnosed in two third of the cases at an advanced stage, molecular screening is frequently performed on "small samples". The screening strategy starts by an accurate histopathological characterization, including on biopsies or cytological specimens. WHO 2015 provided a new classification for small biopsy and cytology, defining categories such as non-small cell carcinoma (NSCC), favor adenocarcinoma (TTF1 positive), or favor squamous cell carcinoma (p40 positive). Only the NSCC tumors, non-squamous, are eligible to molecular testing. A strategy aiming at tissue sparing for the small biopsies has to be organized. Tests corresponding to available drugs are prioritized. Blank slides will be prepared for immunohistochemistry and in situ hybridization based tests such as ALK. DNA will then be extracted for the other tests, EGFR mutation screening first associated or not to KRAS. Then, the emerging biomarkers (HER2, ROS1, RET, BRAF ) as well as potentially other markers in case of clinical trials, can been tested. The spread of next generation sequencing technologies, with a very sensitive all-in-one approach will allow the identification of minority clones. Eventually, the development of liquid biopsies will provide the opportunity to monitor the apparition of resistance clones during treatment. This non-invasive approach allows patients with a contraindication to perform biopsy or with non-relevant biopsies to access to molecular screening.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias Pulmonares/diagnóstico , Técnicas de Diagnóstico Molecular , Proteínas de Neoplasias/análise , Algoritmos , Biomarcadores Tumorais/genética , Biópsia , Contraindicações , Análise Mutacional de DNA , Humanos , Imuno-Histoquímica/métodos , Hibridização In Situ , Neoplasias Pulmonares/química , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Neoplasias/genética , Translocação GenéticaRESUMO
Molecular screening has become a standard of care for patients with advanced cancers and impacts on how to treat a patient. Advances in genomic technologies with the development of high throughput sequencing methods will certainly improve the possibilities to access a more accurate molecular diagnosis and to go beyond the identification of validated targets as a large number of genes can be screened for actionable changes. Moreover, accurate high throughput testing may help tumor classification in terms of prognosis and drug sensitivity. Finally, it will be possible to assess tumor heterogeneity and changes in molecular profiles during follow-up using ultra-deep sequencing technologies and circulating tumor DNA characterization. The accumulation of somatic ADN alterations is considered as the main contributing factor in carcinogenesis. The alterations can occur at different levels: mutation, copy number variations or gene translocations resulting in altered expression of the corresponding genes or impaired protein functions. Genes involved are mainly tumor suppressors, oncogenes or ADN repair genes whose modifications in tumors will impinge cell fate and proliferation from tumor initiation to metastasis. The entire genome of various tumor types, have now been sequenced. In lung cancer, the average number of mutations is very high with more than 8.9 mutations/Mb (Network TCGAR, 2014) that is to say more than 10,000 mutations/genome. These alterations need to be classified, indeed, some are true drivers that directly impact proliferation and some are passenger mutations linked to genetic instability. The development of targeted therapies relies on the identification of oncogenic drivers. The identification of genotype-phenotype associations as in the case of EGFR-TKI (Epidermal growth factor receptor-tyrosine kinase inhibitor) and EGFR mutations in lung cancer led to the restriction of drugs to patients for which tumor genotype predicts efficacy. Tumor-molecular directed therapy based on validated targets (EGFR, ALK) is in the clinics, rapidly, with the developments of multi-targets or multi-drug assays there will be a need for tumor-molecular-profile directed therapy. Today, there are practical challenges to a successful implementation of NGS technologies for clinical applications. Broadly, some are linked to the tumor (heterogeneity), to the tissue (availability, storage, fixative), to the design of specific assays or set of genes, to the interpretation of non-driver mutations and to a possible access to drugs once a target is identified. Technical challenges are solved, NGS (at least targeted-NGS) plateforms have been validated by INCa labeled laboratories, in this context, we will address different questions: How, for whom, what kind of profiling and what can we expect?
Assuntos
Biomarcadores Tumorais/análise , DNA de Neoplasias/análise , Neoplasias Pulmonares/diagnóstico , Técnicas de Diagnóstico Molecular , Análise de Sequência de DNA/métodos , Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA , Exoma , Genes Neoplásicos , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/genética , Terapia de Alvo Molecular , MutaçãoRESUMO
The diagnosis of large cell carcinoma can only be made on a sampled resected tumor and should not be applied to biopsies or cytology. In the 2015 WHO classification, the definition of large cell carcinoma is restricted to carcinomas both lacking morphological signs of glandular, squamous or neuroendocrine differentiation and exhibiting a null or unclear phenotype (TTF1-/p40 ou p63 ou CK5/6+ focally). These carcinomas have an adenocarcinoma molecular profile because they harbor a significant number of KRAS and BRAF mutations, a profile that is more similar to adenocarcinoma than squamous cell carcinoma. They also have a worse prognosis than the other types of non-small cell lung carcinoma. Many large cell carcinomas previously classified on morphological data alone are now reclassified in the adenocarcinoma and squamous cell carcinoma types, including immunohistochemical features. The other large cell carcinoma subtypes from the 2004 WHO classification, i.e. large cell neuroendocrine carcinoma and basaloid carcinoma, are grouped respectively with the other neuroendocrine tumors and squamous cell carcinomas. Clear cell and rhabdoid features are now considered as cytological variants that can occur in any histopathological subtype and not as distinct subtypes. Lymphoepithelioma-like carcinoma is moved to the group of other and unclassified carcinomas as NUT carcinoma.
Assuntos
Carcinoma de Células Grandes/classificação , Neoplasias Pulmonares/classificação , Adenocarcinoma/química , Adenocarcinoma/classificação , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Biomarcadores Tumorais , Carcinoma de Células Grandes/química , Carcinoma de Células Grandes/diagnóstico , Carcinoma de Células Grandes/patologia , Diferenciação Celular , Proteínas de Ligação a DNA/análise , Genes ras , Humanos , Imunofenotipagem , Queratinas/análise , Neoplasias Pulmonares/química , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Prognóstico , Proteínas Proto-Oncogênicas B-raf/análise , Fatores de Transcrição/análise , Proteínas Supressoras de Tumor/análiseRESUMO
Lung cancer is the first cancer-related cause of death worldwide. This is in partially due to therapeutic resistance, which occurs in around 70% of patients, especially those receiving platinum salts, the gold-standard chemotherapy. The massive deregulation of alternative transcript splicing processes observed in many cancers has led to the development of a new class of pharmacological agents aimed at inhibiting the activity of the splicing machinery (spliceosome). The molecular mechanisms by which these inhibitors act remain largely unknown, as do the benefits of using them in combination with other therapies. In this context, our work is focused on an inhibitor of the SRPK1 kinase, a major regulator of the spliceosome.
Assuntos
Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Spliceossomos/genética , Spliceossomos/metabolismo , Splicing de RNA , Processamento Alternativo , Proteínas Serina-Treonina Quinases/genéticaRESUMO
The contribution of artificial intelligence (AI) to medical imaging is currently the object of widespread experimentation. The development of deep learning (DL) methods, particularly convolution neural networks (CNNs), has led to performance gains often superior to those achieved by conventional methods such as machine learning. Radiomics is an approach aimed at extracting quantitative data not accessible to the human eye from images expressing a disease. The data subsequently feed machine learning models and produce diagnostic or prognostic probabilities. As for the multiple applications of AI methods in thoracic imaging, they are undergoing evaluation. Chest radiography is a practically ideal field for the development of DL algorithms able to automatically interpret X-rays. Current algorithms can detect up to 14 different abnormalities present either in isolation or in combination. Chest CT is another area offering numerous AI applications. Various algorithms have been specifically formed and validated for the detection and characterization of pulmonary nodules and pulmonary embolism, as well as segmentation and quantitative analysis of the extent of diffuse lung diseases (emphysema, infectious pneumonias, interstitial lung disease). In addition, the analysis of medical images can be associated with clinical, biological, and functional data (multi-omics analysis), the objective being to construct predictive approaches regarding disease prognosis and response to treatment.
Assuntos
Nódulos Pulmonares Múltiplos , Pneumonia , Humanos , Inteligência Artificial , Algoritmos , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: This study aimed to assess the shifting patterns of the mediastinum, including the target volume and the isocenter point during the postoperative radiotherapy (PORT) process of non-small cell lung cancer (NSCLC), and to observe the occurrence of radiation injury. Additionally, we investigated the significance of mid-term assessment during the implementation of the PORT process. MATERIAL AND METHODS: We established coordinate axes based on bone anatomy and measured the mediastinum's three-dimensional direction and the shift of the isocenter point's shift in the PORT process. Statistical analysis was performed using Wilcoxon, Kruskal-Wallis, and the Chi-square test. P<0.05 was considered statistically significant. RESULTS: In this study, the analysis of patients revealed that the shift of anterior and posterior mediastinum (X), left and right mediastinum (Y), upper and lower mediastinum (Z), anterior and posterior isocenter point (Xi), and the left and right isocenter points (Yi) in the PORT process were 0.04-0.53, 0.00-0.84, 0.00-1.27, 0.01-0.86, and 0.00-0.66cm, respectively. The shift distance of the mediastinum was Z>Y>X, and the shift distance of the isocenter point was Xi>Yi. According to the ROC curve, the cut-off values were 0.263, 0.352, 0.405, 0.238, and 0.258, respectively, which were more significant than the cut-off values in 25 cases (25%), 30 cases (30%), 30 cases (30%), 17 cases (17%), and 15 cases (15%). In addition, there was a significant difference in the shift of the mediastinum and the isocenter point (all P=0.00). Kruskal-Wallis test showed no statistically significant difference between mediastinal shift and resection site in X, Y, and Z directions (P=0.355, P=0.239, P=0.256), surgical method (P=0.241, P=0.110, P=0.064). There was no significant difference in the incidence of RE and RP in PORT patients (P>0.05). No III-IV RP occurred. However, the incidence of ≥ grade III RE in the modified plan cases after M-S was significantly lower than in the original PORT patients, 0% and 7%, respectively (P=0.000). CONCLUSION: In conclusion, this study provides evidence that mediastinal shift is a potential complication during the PORT process for patients with N2 stage or R1-2 resection following radical resection of NSCLC. This shift affects about 20-30% of patients, manifesting as actual radiation damage to normal tissue and reducing the local control rate. Therefore, mid-term repositioning of the PORT and revision of the target volume and radiation therapy plan can aid in maintaining QA and QC during the treatment of NSCLC patients and may result in improved patient outcomes.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/patologia , Controle de Qualidade , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
Among non-small cell lung carcinomas, adenocarcinomas are historically the first histological sub-group for which necessary and sufficient mutations driving to cancer can be targeted by tyrosine kinase inhibitors in patients with locally advanced or metastatic forms. In 2013, targeted therapies with a marketing authorization in thoracic oncology are indicated in patients whose tumor has an EGFR-positive or ALK-positive status. Biomarkers KRAS, BRAF, HER2, PI3K, and MET can account for resistance mechanisms to these treatments and are themselves subject to development of new therapeutic inhibitors. Because the systematic detection (or in the process of being) of these biomarkers has become in the last three years an essential task for pathologists and biologists working in hospital platforms of molecular genetics of cancer supported by INCa, this article aims to describe the physiological and pathophysiological role of the main predictive biomarkers of response to targeted therapies indicated in lung adenocarcinomas.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias Torácicas/diagnóstico , Neoplasias Torácicas/tratamento farmacológico , Adenocarcinoma/diagnóstico , Adenocarcinoma/tratamento farmacológico , Quinase do Linfoma Anaplásico , Receptores ErbB/análise , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Fosfatidilinositol 3-Quinases/análise , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas c-met/análise , Receptores Proteína Tirosina Quinases/análise , Proteínas ras/análiseRESUMO
Although tyrosine kinase inhibitors (TKI) have revolutionized the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer (ALKr-NSCLC), radiotherapy (RT) still plays an essential role for treatment of both intracranial and extracranial metastases, particularly for patients experienced a TKI-failure. We reported the case of a 38-year-old woman with metastatic ALKr-NSCLC who received whole-brain radiotherapy (RT) for multiple brain metastases (BMs), initially. After RT, alectinib was initiated and the patient had a good clinico-radiological response in both intracranial and extracranial regions. However, intracranial progression was developed and, stereotactic radiosurgery (SRS) was applied to the four progressed BMs. Two months after SRS, all BMs disappeared. While patient was using alectinib, a recurrent lung lesion, a hilar lymph node and bone metastasis were detected. Stereotactic body radiotherapy (SBRT) was applied to all metastatic sites and, alectinib was continued again. Three months after SBRT, a complete response was obtained. She has been alive with the initial systemic therapy agent for more than 4years without evidence of neither disease nor toxicity. SRS/SBRT may eradicate the TKI-resistant tumoral clones and it may prevent switching the systemic therapy, even if there is a failure.
Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Radiocirurgia , Adulto , Feminino , Humanos , Encéfalo/patologia , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Estudos RetrospectivosRESUMO
Ultracentral (UC) lung lesions are generally defined by the presence of the tumour or the Planning Target Volume (PTV) abutting proximal bronchial tree (PBT) or the esophagus. Initial reports rose awareness regarding the potential toxicity of stereotactic body radiotherapy (SBRT) when delivered to UC lesions. Major concerns include necrosis, stenosis, and bleeding of the PBT. Technological improvements now enable the delivery of more accurate treatments, possibly redefining the historical "no-fly zone". In this review, studies focusing on the treatment of UC lesions with SBRT are presented. The narrow therapeutic window requires a multidisciplinary approach.