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1.
Anticancer Res ; 41(9): 4479-4482, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475072

RESUMO

BACKGROUND/AIM: This study determined whether computed tomography (CT) is an appropriate means by which to differentiate non-invasive and minimally invasive forms of pulmonary adenocarcinoma from the invasive variant. PATIENTS AND METHODS: A total of 64 patients (38 men and 26 women, aged 42-76, mean age 64), who underwent surgery for pulmonary adenocarcinoma and a chest CT no less than 1 month before surgery, were included in the study. Lesions exhibiting ground glass opacity or ground glass opacity with a solid component of 5 mm or smaller, were defined as minimally invasive or non-invasive adenocarcinomas. CT findings were correlated with histopathological examination. RESULTS: Distinguishing minimally invasive and non-invasive adenocarcinoma from invasive adenocarcinoma using CT was achieved with a sensitivity of 77.7%, a specificity of 97.8%, a positive predictive value of 93.3%, and a negative predictive value of 91.8%. CONCLUSION: CT can be useful in assessing the degree of invasiveness of pulmonary adenocarcinoma and is a potential tool for the individualization of treatment.


Assuntos
Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/cirurgia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Medicina de Precisão , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X
3.
Medicine (Baltimore) ; 100(32): e26474, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397869

RESUMO

ABSTRACT: This study is to identify potential biomarkers and therapeutic targets for lung adenocarcinoma (LUAD).GSE6044 and GSE118370 raw data from the Gene Expression Omnibus database were normalized with Robust Multichip Average. After merging these two datasets, the combat function of sva packages was used to eliminate batch effects. Then, limma packages were used to filtrate differentially expressed genes. We constructed protein-protein interaction relationships using STRING database and hub genes were identified based on connectivity degrees. The cBioportal database was used to explore the alterations of the hub genes. The promoter methylation of cyclin dependent kinase 1 (CDK1) and polo-like Kinase 1 (PLK1) and their association with tumor immune infiltration in patients with LUAD were investigated using DiseaseMeth version 2.0 and TIMER databases. The Cancer Genome Atlas-LUAD dataset was used to perform gene set enrichment analysis.We identified 10 hub genes, which were upregulated in LUAD, among which 8 were successfully verified in the Cancer Genome Atlas and Oncomine databases. Kaplan-Meier analysis indicated that the expressions of CDK1 and PLK1 in LUAD patients were associated with overall survival and disease-free survival. The methylation levels in the promoter regions of these 2 genes in LUAD patients were lower than those in normal lung tissues. Their expressions in LUAD were associated with tumor stages and relative abundance of tumor infiltrating immune cells, such as B cells, CD4+ T cells, and macrophages. Moreover, cell cycle, DNA replication, homologous recombination, mismatch repair, P53 signaling pathway, and small cell lung cancer signaling were significantly enriched in CDK1 and PLK1 high expression phenotype.CDK1 and PLK1 may be used as potential biomarkers and therapeutic targets for LUAD.


Assuntos
Adenocarcinoma de Pulmão/genética , Proteína Quinase CDC2/genética , Proteínas de Ciclo Celular/genética , Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Proteína Quinase CDC2/biossíntese , Proteínas de Ciclo Celular/biossíntese , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Prognóstico , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , RNA Neoplásico/genética , Transdução de Sinais
4.
Medicine (Baltimore) ; 100(32): e26911, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397927

RESUMO

RATIONALE: With the recent advancements in molecular biology research, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have emerged as excellent therapies for patients with EGFR-mutant cancers. However, these patients inevitably develop cross-acquired resistance to EGFR-TKIs. Transformation to small-cell lung cancer (SCLC) is considered a rare resistance mechanism against EGFR-TKI therapy. Here, we report a case of TKI resistance due to SCLC transformation and demonstrate its mechanisms and clinical features. PATIENT CONCERNS: A 54-year-old Chinese man with a history of smoking for 40 years complained of an intermittent cough in March 2019. DIAGNOSIS: Transbronchial lung biopsy was performed on the basal segment of the left lower lobe, which confirmed lung adenocarcinoma. In January 2020, repeat biopsy was performed, and the results of immunohistochemistry (IHC) staining showed TTF-1 (+), CK7 (+), napsin A (+), syn (+), and CD56 (+), with a Ki-67 (+) index 80% of small cell carcinomas. Infiltrating adenocarcinomas and small cell carcinomas were observed. INTERVENTIONS: Icotinib (125 mg thrice daily) was administered as a first-line treatment from June 2019. We subsequently administered a chemotherapy regimen consisting of etoposide (180 mg, days 1-3) plus cisplatin (45 mg, days 1-3) every 3 weeks for 1 cycle after recurrence. As the patient could not tolerate further chemotherapy, he continued taking icotinib orally and received whole-brain radiotherapy 10 times to a total dose of 30 Gy after brain metastases. OUTCOMES: The patient relapsed after successful treatment with icotinib for 9 months. A partial response was achieved after 4 cycles of chemotherapy, and despite the brief success of chemotherapy, our patient exhibited brain metastasis and metastases of the eleventh thoracic spine and the second lumbar vertebra with pathological fracture. The patient eventually died of aggressive cancer progression. LESSONS: Our case highlights the possibility of SCLC transformation from EGFR-mutant adenocarcinoma and the importance of repeat biopsy for drug resistance. Serum neuron-specific enolase levels may also be useful for detecting early SCLC transformation.


Assuntos
Adenocarcinoma de Pulmão/genética , DNA de Neoplasias/genética , Neoplasias Pulmonares/genética , Mutação , Carcinoma de Pequenas Células do Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Biópsia , Transformação Celular Neoplásica , Análise Mutacional de DNA , Receptores ErbB/genética , Receptores ErbB/metabolismo , Evolução Fatal , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/metabolismo , Tomografia Computadorizada por Raios X
5.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445287

RESUMO

Bovine herpesvirus 1 (BoHV-1) is a promising oncolytic virus with broad antitumor spectrum; however, its oncolytic effects on human lung adenocarcinoma in vivo have not been reported. In this study, we report that BoHV-1 can be used as an oncolytic virus for human lung adenocarcinoma, and elucidate the underlying mechanism of how BoHV-1 suppresses tumor cell proliferation and growth. First, we examined the oncolytic activities of BoHV-1 in human lung adenocarcinoma A549 cells. BoHV-1 infection reduced the protein levels of histone deacetylases (HDACs), including HDAC1-4 that are promising anti-tumor drug targets. Furthermore, the HDAC inhibitor Trichostatin A (TSA) promoted BoHV-1 infection and exacerbated DNA damage and cytopathology, suggesting a synergy between BoHV-1 and TSA. In the A549 tumor xenograft mouse model, we, for the first time, showed that BoHV-1 can infect tumor and suppressed tumor growth with a similar high efficacy as the treatment of TSA, and HDACs have potential effects on the virus replication. Taken together, our study demonstrates that BoHV-1 has oncolytic effects against human lung adenocarcinoma in vivo.


Assuntos
Adenocarcinoma de Pulmão/patologia , Herpesvirus Bovino 1/fisiologia , Neoplasias Pulmonares/patologia , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/terapia , Adenocarcinoma de Pulmão/virologia , Animais , Proliferação de Células/genética , Células Cultivadas , Cricetinae , Dano ao DNA , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Zhonghua Zhong Liu Za Zhi ; 43(7): 743-750, 2021 Jul 23.
Artigo em Chinês | MEDLINE | ID: mdl-34289567

RESUMO

The incidence and mortality of lung cancer ranked the first in China. China had 787, 000 new cases of lung cancer in 2015, and a majority of these patients with advanced lung cancer. With the development and popularization of high-resolution computed tomography, more and more early-stage lung adenocarcinomas are found in screening. The imaging finding of early-stage lung adenocarcinomas often manifests as part solid nodule (PSN) containing ground glass opacity (GGO). Although the imaging manifestation of the nodules can't accurately predict the pathologic type of nodules, the parts of solid nodule and GGO still have some pathologic indications, and the prognostic evaluation effect of the maximum diameter of PSN is superior to that of the whole nodule. With the development of the molecular radiography and molecular pathology, the relationship of imaging manifestation of the PSN and metastasis were focused on. Some PSNs with special nature are more active and rapidly progressed than the pure GGOs. While compared to the pure solid nodules, the aggressiveness of PSNs are insufficient, with lower metastatic rates of lymph node and better prognoses. Currently, international acknowledge recommends to take active intervention measure for PSNs which are highly suspected to be malignant. We focus on the diagnosis and treatment of PSNs, systemically depict their staging, follow-up, surgical treatment, gene detection and immunotherapy.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Nódulo Pulmonar Solitário , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , China , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Estadiamento de Neoplasias , Estudos Retrospectivos , Nódulo Pulmonar Solitário/diagnóstico por imagem , Tomografia Computadorizada por Raios X
9.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209868

RESUMO

Pancracine, a montanine-type Amaryllidaceae alkaloid (AA), is one of the most potent compounds among natural isoquinolines. In previous studies, pancracine exhibited cytotoxic activity against diverse human cancer cell lines in vitro. However, further insight into the molecular mechanisms that underlie the cytotoxic effect of pancracine have not been reported and remain unknown. To fill this void, the cell proliferation and viability of cancer cells was explored using the Trypan Blue assay or by using the xCELLigence system. The impact on the cell cycle was determined by flow cytometry. Apoptosis was evaluated by Annexin V/PI and by quantifying the activity of caspases (-3/7, -8, and -9). Proteins triggering growth arrest or apoptosis were detected by Western blotting. Pancracine has strong antiproliferative activity on A549 cells, lasting up to 96 h, and antiproliferative and cytotoxic effects on MOLT-4 cells. The apoptosis-inducing activity of pancracine in MOLT-4 cells was evidenced by the significantly higher activity of caspases. This was transmitted through the upregulation of p53 phosphorylated on Ser392, p38 MAPK phosphorylated on Thr180/Tyr182, and upregulation of p27. The pancracine treatment negatively altered the proliferation of A549 cells as a consequence of an increase in G1-phase accumulation, associated with the downregulation of Rb phosphorylated on Ser807/811 and with the concomitant upregulation of p27 and downregulation of Akt phosphorylated on Thr308. This was the first study to glean a deeper mechanistic understanding of pancracine activity in vitro. Perturbation of the cell cycle and induction of apoptotic cell death were considered key mechanisms of pancracine action.


Assuntos
Adenocarcinoma de Pulmão/patologia , Proliferação de Células/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Leucemia/patologia , Neoplasias Pulmonares/patologia , Células A549 , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Amaryllidaceae/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Células Hep G2 , Compostos Heterocíclicos de 4 ou mais Anéis/isolamento & purificação , Humanos , Células MCF-7
10.
Am J Pathol ; 191(9): 1638-1650, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34119472

RESUMO

Cullin (CUL) 4A and 4B ubiquitin ligases are often highly accumulated in human malignant neoplasms and are believed to possess oncogenic properties. However, the underlying mechanisms by which CUL4A and CUL4B promote pulmonary tumorigenesis remain largely elusive. This study reports that CUL4A and CUL4B are highly expressed in patients with non-small cell lung cancer (NSCLC), and their high expression is associated with disease progression, chemotherapy resistance, and poor survival in adenocarcinomas. Depletion of CUL4A (CUL4Ak/d) or CUL4B (CUL4Bk/d) leads to cell cycle arrest at G1 and loss of proliferation and viability of NSCLC cells in culture and in a lung cancer xenograft model, suggesting that CUL4A and 4B are oncoproteins required for tumor maintenance of certain NSCLCs. Mechanistically, increased accumulation of the cell cycle-dependent kinase inhibitor p21/Cip1/WAF1 was observed in lung cancer cells on CUL4 silencing. Knockdown of p21 rescued the G1 arrest of CUL4Ak/d or CUL4Bk/d NSCLC cells, and allowed proliferation to resume. These findings reveal that p21 is the primary downstream effector of lung adenocarcinoma dependence on CUL4, highlight the notion that not all substrates respond equally to abrogation of the CUL4 ubiquitin ligase in NSCLCs, and imply that CUL4Ahigh/CUL4Bhigh may serve as a prognostic marker and therapeutic target for patients with NSCLC.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Proteínas Culina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Neoplasias Pulmonares/metabolismo , Adenocarcinoma de Pulmão/patologia , Animais , Biomarcadores/metabolismo , Proliferação de Células , Sobrevivência Celular , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Xenoenxertos , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Prognóstico , Transdução de Sinais/fisiologia , Ubiquitina/metabolismo
11.
Cancer Treat Rev ; 99: 102237, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34182217

RESUMO

Adenocarcinoma has become the most prevalent lung cancer sub-type and its frequency is increasing. The earliest stages in the development of lung adenocarcinomas are visible using modern computed tomography (CT) as ground glass nodules. These pre-invasive nodules can progress over time to become invasive lung adenocarcinomas. Lesions in this developmental pathway are termed 'adenocarcinoma spectrum' lesions. With the introduction of lung cancer screening programs there has been an increase in the detection of these lesions raising questions about natural history, surveillance and treatment. Here we review how the radiological appearance of an adenocarcinoma spectrum lesion relates to its underlying pathology and explore the natural history and factors driving lesion progression. We examine the molecular changes that occur at each stage of adenocarcinoma spectrum lesion development, including the effects of the driver mutations, EGFR and KRAS, that are key to invasive adenocarcinoma pathology. A better understanding of the development of pre-invasive disease will create treatment targets. Our understanding of how tumours interact with the immune system has led to the development of new therapeutic strategies. We review the role of the immune system in the development of adenocarcinoma spectrum lesions. With a clear preinvasive phase there is an opportunity to treat early adenocarcinoma spectrum lesions before an invasive lung cancer develops. We review current management including surveillance, surgical resection and oncological therapy as well as exploring potential future treatment avenues.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/terapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/patologia , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Invasividade Neoplásica , Tomografia Computadorizada por Raios X
12.
Int J Cancer ; 149(8): 1593-1604, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34152598

RESUMO

Lung adenocarcinoma (LUAD) is the most common types among lung cancers generally arising from terminal airway and understanding of multistep carcinogenesis is crucial to develop novel therapeutic strategy for LUAD. Here we used human induced pluripotent stem cells (hiPSCs) to establish iHER2-hiPSCs in which doxycycline induced the expression of the oncoprotein human epidermal growth factor receptor 2 (HER2)/ERBB2. Lung progenitors that differentiated from iHER2-hiPSCs, which expressed NKX2-1/TTF-1 known as a lung lineage maker, were cocultured with human fetal fibroblast and formed human lung organoids (HLOs) comprising alveolar type 2-like cells. HLOs that overexpressed HER2 transformed to tumor-like structures similar to atypical adenomatous hyperplasia, which is known for lung precancerous lesion and upregulated the activities of oncogenic signaling cascades such as RAS/RAF/MAPK and PI3K/AKT/mTOR. The degree of morphological irregularity and proliferation capacity were significantly higher in HLOs from iHER2-hiPSCs. Moreover, the transcriptome profile of the HLOs shifted from a normal lung tissue-like state to one characteristic of clinical LUAD with HER2 amplification. Our results suggest that hiPSC-derived HLOs may serve as a model to recapitulate the early tumorigenesis of LUAD and would provide new insights into the molecular basis of tumor initiation and progression.


Assuntos
Adenocarcinoma de Pulmão/patologia , Carcinogênese , Regulação Neoplásica da Expressão Gênica , Células-Tronco Pluripotentes Induzidas/patologia , Neoplasias Pulmonares/patologia , Organoides/patologia , Receptor ErbB-2/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Organoides/metabolismo , Receptor ErbB-2/genética , Transcriptoma , Células Tumorais Cultivadas
13.
Cancer Sci ; 112(9): 3411-3418, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34143937

RESUMO

There could be two carcinogenetic pathways for lung adenocarcinoma (LADC): the nonsmokers' pathway and the smokers' pathway. This review article describes the two pathways with special reference to potential relationships between histological subtypes, malignant grades, and driver mutations. The lung is composed of two different tissue units, the terminal respiratory unit (TRU) and the central airway compartment (CAC). In the nonsmokers' pathway, LADCs develop from the TRU, and their histological appearances change from lepidic to micropapillary during the progression process. In the smokers' pathway, LADCs develop from either the TRU or the CAC, and their histological appearances vary among cases in the middle of the progression process, but they are likely converged to acinar/solid at the end. On a molecular genetic level, the nonsmokers' pathway is mostly driven by EGFR mutations, whereas in the smokers' pathway, approximately one-quarter of LADCs have KRAS mutations, but the other three-quarters have no known driver mutations. p53 mutations are an important factor triggering the progression of both pathways, with unique molecular alterations associated with each, such as MUC21 expression and chromosome 12p13-21 amplification in the nonsmokers' pathway, and HNF4α expression and TTF1 mutations in the smokers' pathway. However, investigation into the relationship between histological progression and genetic alterations is in its infancy. Tight cooperation between traditional histopathological examinations and recent molecular genetics can provide valuable insight to better understand the nature of LADCs.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Progressão da Doença , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , não Fumantes , Fumantes , Fumar , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Receptores ErbB/genética , Feminino , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética
14.
Cancer Sci ; 112(9): 3810-3821, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34145929

RESUMO

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in patients with non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, due to acquired resistance to EGFR-TKIs, even patients on third-generation osimertinib have a poor prognosis. Resistance mechanisms are still not fully understood. Here, we demonstrate that the increased expression of MUSASHI-2 (MSI2), an RNA-binding protein, is a novel mechanism for resistance to EGFR-TKIs. We found that after a long-term exposure to gefitinib, the first-generation EGFR-TKI lung cancer cells harboring the EGFR-TKI-sensitive mutations became resistant to both gefitinib and osimertinib. Although other mutations in EGFR were not found, expression levels of Nanog, a stemness core protein, and activities of aldehyde dehydrogenase (ALDH) were increased, suggesting that cancer stem-like properties were increased. Transcriptome analysis revealed that MSI2 was among the stemness-related genes highly upregulated in EGFR-TKI-resistant cells. Knockdown of MSI2 reduced cancer stem-like properties, including the expression levels of Nanog, a core stemness factor. We demonstrated that knockdown of MSI2 restored sensitivity to osimertinib or gefitinib in EGFR-TKI-resistant cells to levels similar to those of parental cells in vitro. An RNA immunoprecipitation (RIP) assay revealed that antibodies against MSI2 were bound to Nanog mRNA, suggesting that MSI2 increases Nanog expression by binding to Nanog mRNA. Moreover, overexpression of MSI2 or Nanog conferred resistance to osimertinib or gefitinib in parental cells. Finally, MSI2 knockdown greatly increased the sensitivity to osimertinib in vivo. Collectively, our findings provide proof of principle that targeting the MSI2-Nanog axis in combination with EGFR-TKIs would effectively prevent the emergence of acquired resistance.


Assuntos
Acrilamidas/farmacologia , Adenocarcinoma de Pulmão/metabolismo , Compostos de Anilina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Gefitinibe/farmacologia , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas de Ligação a RNA/metabolismo , Regulação para Cima , Células A549 , Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/patologia , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Gefitinibe/uso terapêutico , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/patologia , Mutação , Proteína Homeobox Nanog/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas de Ligação a RNA/genética , Transcriptoma , Transfecção
15.
Cancer Sci ; 112(9): 3796-3809, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34145937

RESUMO

Tissue-clearing technology is an emerging imaging technique currently utilized not only in neuroscience research but also in cancer research. In our previous reports, tissue-clearing methods were used for the detection of metastatic tumors. Here, we showed that the cell cycles of primary and metastatic tumors were visualized by tissue-clearing methods using a reporter system. First, we established cancer cell lines stably expressing fluorescent ubiquitination-based cell cycle indicator (Fucci) reporter with widely used cancer cell lines A549 and 4T1. Fluorescence patterns of the Fucci reporter were investigated in various tumor inoculation models in mice. Interestingly, fluorescence patterns of the Fucci reporter of tumor colonies were different between various organs, and even among colonies in the same organs. The effects of antitumor drugs were also evaluated using these Fucci reporter cells. Of the three antitumor drugs studied, 5-fluorouracil treatment on 4T1-Fucci cells resulted in characteristic fluorescent patterns by the induction of G2 /M arrest both in vitro and in vivo. Thus, the combination of a tissue-clearing method with the Fucci reporter is useful for analyzing the mechanisms of cancer metastasis and drug resistance.


Assuntos
Adenocarcinoma de Pulmão/patologia , Neoplasias da Mama/patologia , Ciclo Celular , Medições Luminescentes/métodos , Neoplasias Pulmonares/patologia , Células A549 , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Feminino , Fluoruracila/administração & dosagem , Genes Reporter , Vetores Genéticos/genética , Humanos , Proteínas Luminescentes/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia de Fluorescência/métodos , Transfecção , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Cancer Sci ; 112(8): 3278-3292, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34091997

RESUMO

It is widely accepted that redox reprogramming participates in malignant transformation of lung adenocarcinoma (LUAD). However, the source of excessive reactive oxygen species (ROS) and the downstream signaling regulatory mechanism are complicated and unintelligible. In the current study, we newly identified the aquaporin 3 (AQP3) as a LUAD oncogenic factor with capacity to transport exogenous hydrogen peroxide (H2 O2 ) and increase intracellular ROS levels. Subsequently, we demonstrated that AQP3 was necessary for the facilitated diffusion of exogenous H2 O2 in LUAD cells and that the AQP3-dependent transport of H2 O2 accelerated cell growth and inhibited rapamycin-induced autophagy. Mechanistically, AQP3-mediated H2 O2 uptake increased intracellular ROS levels to inactivate PTEN and activate the AKT/mTOR pathway to subsequently inhibit autophagy and promote proliferation in LUAD cells. Finally, we suggested that AQP3 depletion retarded subcutaneous tumorigenesis in vivo and simultaneously decreased ROS levels and promoted autophagy. These findings underscore the importance of AQP3-induced oxidative stress in malignant transformation and suggest a therapeutic target for LUAD.


Assuntos
Adenocarcinoma de Pulmão/patologia , Aquaporina 3/genética , Aquaporina 3/metabolismo , Peróxido de Hidrogênio/metabolismo , Neoplasias Pulmonares/patologia , PTEN Fosfo-Hidrolase/metabolismo , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Animais , Autofagia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Transplante de Neoplasias , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Sirolimo/farmacologia
17.
Medicine (Baltimore) ; 100(26): e26449, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34190169

RESUMO

RATIONALE: Anaplastic lymphoma kinase (ALK) inhibitors have been approved for patients with ALK-rearrangement lung cancer. The effect is superior to the standard first-line therapy of pemetrexed plus platinum-based chemotherapy. However, ALK inhibitors are associated with rare and sometimes fatal adverse events. Organizing pneumonitis (OP) is a rare and serious adverse event usually caused by ceritinib, and it is easily misdiagnosed as infectious pneumonia, metastasis, or cancer progression. PATIENT CONCERNS: A 56-year-old female presented with chest tightness and dyspnea for more than 10 days. She was previously healthy with no significant medical history. Workup including chest computed tomography (CT), pathological examination of a biopsy specimen, and next-generation sequencing was consistent with a diagnosis of IVA ALK-rearrangement lung adenocarcinoma. She was treated with pemetrexed plus platinum-based chemotherapy and crizotinib concurrently, followed by maintenance therapy with crizotinib alone and she had an almost complete response. However, about 26 months after beginning treatment she developed multiple brain metastases. Crizotinib was discontinued and she was begun on ceritinib. After about 3 months the brain metastases had almost complete response. After 5 months of ceritinib, however, multiple patchy lesions appeared in the bilateral upper lungs. DIAGNOSES: Treatment with antibiotics had no effect and blood and sputum cultures are negative. A CT-guided biopsy of the upper lung was performed, and pathological hematoxylin-eosin staining and immunohistochemical studies were consistent with OP. INTERVENTIONS: Ceritinib was discontinued, she was begun on prednisone 0.5 mg/kg orally every day, and regular follow-up is necessary. OUTCOMES: CT of the chest 2 and 4 weeks after beginning prednisone showed the lung lesions to be gradually resolving, and she was continued on prednisone for 2 months and gradually reduced the dose of prednisone every 2 weeks. No related adverse events were occurred in patient. LESSONS: OP must be differentiated from infectious pneumonia, metastasis, or cancer progression. The mechanism of OP is still unknown and needs further research. Biopsy plays a role in making a diagnosis of OP. In our patient, discontinuing ceritinib and treating her with prednisone resulted in a good outcome.


Assuntos
Adenocarcinoma de Pulmão , Quinase do Linfoma Anaplásico , Pneumonia em Organização Criptogênica , Neoplasias Pulmonares , Prednisona/administração & dosagem , Pirimidinas , Sulfonas , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/fisiopatologia , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/genética , Antineoplásicos/uso terapêutico , Biópsia/métodos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Crizotinibe/uso terapêutico , Pneumonia em Organização Criptogênica/induzido quimicamente , Pneumonia em Organização Criptogênica/patologia , Pneumonia em Organização Criptogênica/terapia , Substituição de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , Pessoa de Meia-Idade , Pemetrexede/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Sulfonas/administração & dosagem , Sulfonas/efeitos adversos , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
18.
Lung Cancer ; 158: 91-96, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34139640

RESUMO

OBJECTIVE: Lung cancer can spread in numerous ways, one of which has been suggested to be spread through air spaces (STAS). The tumor immune microenvironment appears to play a significant role in this spread. Particularly, tumor-associated macrophages (TAMs) can create a favorable microenvironment for tumor progression. In this study, we analyzed data from 709 patients with stage 0-IIIA lung adenocarcinoma, resected between 1999 and 2016, and investigated whether immune cell infiltration was associated with the occurrence of STAS and clinical outcome of the disease. MATERIALS AND METHODS: Tissue microarrays were constructed, and immunohistochemical analysis was performed for CD3, CD4, CD8, CD45RO, CD25, CD20, and CD68. The three tumor areas with the highest density of immune cells were photographed, and the immune cells were quantified. Associations between variables were analyzed using chi-square tests and Mann-Whitney U tests. Recurrence-free probability and overall survival were analyzed using log-rank tests and Cox proportional hazards models. RESULTS: After analyzing the associations between STAS and each type of immune cell infiltration, high density of CD68 + TAMs was identified as an independent predictor of a high STAS rate (p =  0.014) and was found to be associated with a high risk of recurrence, using univariate analysis (p =  0.008). After adjusting for CD68+ TAMs, pathological stage, and lymphovascular invasion, STAS remained significantly associated with a high risk of recurrence (HR = 3.50, p < 0.001). CONCLUSION: We demonstrated that a high density of CD68 + TAMs is an independent predictor of an increased STAS rate. Additionally, STAS is correlated with aggressive tumor behavior characteristics.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/patologia , Humanos , Neoplasias Pulmonares/patologia , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Microambiente Tumoral , Macrófagos Associados a Tumor
20.
Am J Clin Oncol ; 44(7): 350-355, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34008498

RESUMO

INTRODUCTION: The role of specific immune cell types within the tumor immune microenvironment in non-small cell lung cancer survival is unclear. The potential of these immune cells to become predictive biomarkers of prognosis, and to define subpopulations who will benefit of additional treatment is urgently needed. METHODS: Stage I to IIIA non-small cell lung cancer patients who underwent surgical resection were queried from the Cancer Genome Atlas; RNAseq data as well as clinical information was extracted. Sample-specific scores for different immune cells were computed via xCell. The association between each cell type and survival was assessed with Cox regression, both unadjusted and adjusted for sex, stage, smoking status, and tumor purity. Models were stratified by lung adenocarcinoma and lung squamous cell carcinoma. RESULTS: There were 383 lung adenocarcinoma and 328 lung squamous cell carcinoma samples, and 161 (42%) and 124 (38%) deaths respectively. There was no association between any immune cell infiltrations and survival in the combined unadjusted Cox regression model. After adjustment, the presence of CD8+ cytotoxic T cells (adjusted hazard ratio [HRajd]: 0.84; 95% confidence interval [CI]: 0.71-0.99; P=0.03), CD4+ helper T cells (HRajd: 0.79; 95% CI: 0.66-0.95; P=0.01) and CD20+ B cells (HRajd: 0.80; 95% CI: 0.66-0.97; P=0.02) were significant predictors of decreased risk of death. CONCLUSIONS: This study shows that the adjustment for clinical characteristics is key when evaluating tumor immune infiltration and its association with cancer outcomes. Adjustment for confounding factors modified the prognostic significance of specific immune cell populations in early-stage surgically resected NSCLC cases; clinical attributes may have high relevance on immune infiltration composition.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Microambiente Tumoral/imunologia , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/cirurgia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Feminino , Humanos , Células Matadoras Naturais/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/cirurgia , Linfócitos do Interstício Tumoral/patologia , Masculino , Prognóstico , Fumar
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