|
1
|
Rocha LGDN, Guimarães PAS, Carvalho MGR, Ruiz JC. Tumor Neoepitope-Based Vaccines: A Scoping Review on Current Predictive Computational Strategies. Vaccines (Basel) 2024; 12:836. [PMID: 39203962 PMCID: PMC11360805 DOI: 10.3390/vaccines12080836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 07/09/2024] [Accepted: 07/11/2024] [Indexed: 09/03/2024] Open
Abstract
Therapeutic cancer vaccines have been considered in recent decades as important immunotherapeutic strategies capable of leading to tumor regression. In the development of these vaccines, the identification of neoepitopes plays a critical role, and different computational methods have been proposed and employed to direct and accelerate this process. In this context, this review identified and systematically analyzed the most recent studies published in the literature on the computational prediction of epitopes for the development of therapeutic vaccines, outlining critical steps, along with the associated program's strengths and limitations. A scoping review was conducted following the PRISMA extension (PRISMA-ScR). Searches were performed in databases (Scopus, PubMed, Web of Science, Science Direct) using the keywords: neoepitope, epitope, vaccine, prediction, algorithm, cancer, and tumor. Forty-nine articles published from 2012 to 2024 were synthesized and analyzed. Most of the identified studies focus on the prediction of epitopes with an affinity for MHC I molecules in solid tumors, such as lung carcinoma. Predicting epitopes with class II MHC affinity has been relatively underexplored. Besides neoepitope prediction from high-throughput sequencing data, additional steps were identified, such as the prioritization of neoepitopes and validation. Mutect2 is the most used tool for variant calling, while NetMHCpan is favored for neoepitope prediction. Artificial/convolutional neural networks are the preferred methods for neoepitope prediction. For prioritizing immunogenic epitopes, the random forest algorithm is the most used for classification. The performance values related to the computational models for the prediction and prioritization of neoepitopes are high; however, a large part of the studies still use microbiome databases for training. The in vitro/in vivo validations of the predicted neoepitopes were verified in 55% of the analyzed studies. Clinical trials that led to successful tumor remission were identified, highlighting that this immunotherapeutic approach can benefit these patients. Integrating high-throughput sequencing, sophisticated bioinformatics tools, and rigorous validation methods through in vitro/in vivo assays as well as clinical trials, the tumor neoepitope-based vaccine approach holds promise for developing personalized therapeutic vaccines that target specific tumor cancers.
Collapse
Affiliation(s)
- Luiz Gustavo do Nascimento Rocha
- Biologia Computacional e Sistemas (BCS), Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, Brazil; (L.G.d.N.R.); (P.A.S.G.)
- Grupo Informática de Biossistemas e Genômica, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte 30190-002, Brazil
| | - Paul Anderson Souza Guimarães
- Biologia Computacional e Sistemas (BCS), Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, Brazil; (L.G.d.N.R.); (P.A.S.G.)
- Grupo Informática de Biossistemas e Genômica, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte 30190-002, Brazil
| | - Maria Gabriela Reis Carvalho
- Biologia Computacional e Sistemas (BCS), Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, Brazil; (L.G.d.N.R.); (P.A.S.G.)
- Grupo Informática de Biossistemas e Genômica, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte 30190-002, Brazil
| | - Jeronimo Conceição Ruiz
- Biologia Computacional e Sistemas (BCS), Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, Brazil; (L.G.d.N.R.); (P.A.S.G.)
- Grupo Informática de Biossistemas e Genômica, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte 30190-002, Brazil
| |
Collapse
|
|
2
|
Lazebnik T, Bunimovich-Mendrazitsky S. Predicting lung cancer's metastats' locations using bioclinical model. Front Med (Lausanne) 2024; 11:1388702. [PMID: 38846148 PMCID: PMC11153684 DOI: 10.3389/fmed.2024.1388702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 05/13/2024] [Indexed: 06/09/2024] Open
Abstract
Background Lung cancer is a global leading cause of cancer-related deaths, and metastasis profoundly influences treatment outcomes. The limitations of conventional imaging in detecting small metastases highlight the crucial need for advanced diagnostic approaches. Methods This study developed a bioclinical model using three-dimensional CT scans to predict the spatial spread of lung cancer metastasis. Utilizing a three-layer biological model, we identified regions with a high probability of metastasis colonization and validated the model on real-world data from 10 patients. Findings The validated bioclinical model demonstrated a promising 74% accuracy in predicting metastasis locations, showcasing the potential of integrating biophysical and machine learning models. These findings underscore the significance of a more comprehensive approach to lung cancer diagnosis and treatment. Interpretation This study's integration of biophysical and machine learning models contributes to advancing lung cancer diagnosis and treatment, providing nuanced insights for informed decision-making.
Collapse
Affiliation(s)
- Teddy Lazebnik
- Department of Cancer Biology, Cancer Institute, University College London, London, United Kingdom
- Department of Mathematics, Ariel University, Ariel, Israel
| | | |
Collapse
|
|
3
|
Lin SH, Lu JW, Hsieh WT, Chou YE, Su TC, Tsai TJ, Tsai YJ, Yang PJ, Yang SF. Evaluation of the clinical significance of long non-coding RNA MALAT1 genetic variants in human lung adenocarcinoma. Aging (Albany NY) 2024; 16:5740-5750. [PMID: 38517388 PMCID: PMC11006483 DOI: 10.18632/aging.205675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 03/04/2024] [Indexed: 03/23/2024]
Abstract
Lung adenocarcinoma (LUAD) is the most frequent histological subtype of lung cancer, which is the most common malignant tumor and the main cause of cancer-related mortality globally. Recent reports revealed that long non-coding RNA (lncRNA) of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a crucial role in tumorigenesis and metastasis development in lung cancer. However, the contribution of MALAT1 genetic variants to the development of LUAD is unclear, especially in epidermal growth factor receptor (EGFR) mutation status. In this study, 272 LADC patients with different EGFR status were recruited to dissect the allelic discrimination of the MALAT1 polymorphisms at rs3200401, rs619586, and rs1194338. The findings of the study showed that MALAT1 polymorphisms rs3200401, rs619586, and rs1194338 were not associated to LUAD susceptibility; however, rs3200401 polymorphisms was significantly correlated to EGFR wild-type status and tumor stages in LUAD patients in dominant model (p=0.016). Further analyses using the datasets from The Cancer Genome Atlas (TCGA) revealed that lower MALAT1 mRNA levels were associated with the advanced stage, and lymph node metastasis in LADC patients. In conclusion, our results showed that MALAT1 rs3200401 polymorphisms dramatically raised the probability of LUAD development.
Collapse
Affiliation(s)
- Shu-Hui Lin
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Jeng-Wei Lu
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
- The Finsen Laboratory, Rigshospitalet/National University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Wang-Ting Hsieh
- The Affiliated High School of Tunghai University, Taichung, Taiwan
- Department of Occupational Therapy, Asia University, Taichung, Taiwan
| | - Ying-Erh Chou
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Tzu-Cheng Su
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
| | - Tun-Jen Tsai
- The Affiliated High School of Tunghai University, Taichung, Taiwan
| | - Yun-Jung Tsai
- Translational Pathology Core Laboratory, Changhua Christian Hospital, Changhua, Taiwan
| | - Po-Jen Yang
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Family and Community Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| |
Collapse
|
|
4
|
Moran CA. Primary Pulmonary Carcinomas with Spindle and/or Giant Cell Features: A Review with Emphasis in Classification and Pitfalls in Diagnosis. Diagnostics (Basel) 2023; 13:2477. [PMID: 37568840 PMCID: PMC10417730 DOI: 10.3390/diagnostics13152477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 06/28/2023] [Accepted: 07/18/2023] [Indexed: 08/13/2023] Open
Abstract
Primary carcinomas of the lung are vastly represented by the conventional types of adenocarcinomas or squamous cell carcinomas. However, there are other types of non-small cell carcinomas that although uncommon represent a meaningful group that often pose a problem not only in diagnosis but also in classification. Spindle cell and/or giant cell carcinomas, although uncommon represent an important group of primary lung carcinomas. Important to highlight is that current criteria are rather ambiguous and likely not up to date, which renders the classification of these tumors somewhat more obscure. In addition, with the daily use of immunohistochemical stains, the classification of these tumors may also pose a different problem in the proper allocation of these tumors. Proper classification is highly important in the selection process that takes place using such material for molecular analysis. The current molecular characteristics of these tumors are limited and lack more in-depth studies and analyses that can provide specific targets for the treatment of patients with these tumors. The current review attempts to highlight the shortcomings in the current classification and definitions of these neoplasms as well as the more current view regarding these tumors when the use of immunohistochemical stains is employed.
Collapse
Affiliation(s)
- Cesar A Moran
- MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA
| |
Collapse
|
|
5
|
Zhang S, Liu D, Ning X, Zhang X, Lu Y, Zhang Y, Li A, Gao Z, Wang Z, Zhao X, Chen S, Cai Z. A Signature Constructed Based on the Integrin Family Predicts Prognosis and Correlates with the Tumor Microenvironment of Patients with Lung Adenocarcinoma. J Environ Pathol Toxicol Oncol 2023; 42:59-77. [PMID: 36749090 DOI: 10.1615/jenvironpatholtoxicoloncol.2022046232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
As an important element in regulating the tumor microenvironment (TME), integrin plays a key role in tumor progression. This study aimed to establish prognostic signatures to predict the overall survival and identify the immune landscape of patients with lung adenocarcinoma based on integrins. The Cancer Genome Atlas-Lung Adenocarcinoma (TCGA-LUAD) and Gene Expression Omnibus datasets were used to obtain information on mRNA levels and clinical factors (GSE72094). The least absolute shrinkage and selection operator (LASSO) model was used to create a prediction model that included six integrin genes. The nomogram, risk score, and time-dependent receiver operating characteristic analysis all revealed that the signatures had a good prognostic value. The gene signatures may be linked to carcinogenesis and TME, according to a gene set enrichment analysis. The immunological and stromal scores were computed using the ESTIMATE algorithm, and the data revealed, the low-risk group had a higher score. We discovered that the B lymphocytes, plasma, CD4+ T, dendritic, and mast cells were much higher in the group with low-risk using the CiberSort. Inflammatory processes and several HLA family genes were upregulated in the low-risk group. The low-risk group with a better prognosis is more sensitive to immune checkpoint inhibitor medication, according to immunophenoscore (IPS) research. We found that the patients in the high-risk group were more susceptible to chemotherapy than other group patients, according to the prophetic algorithm. The gene signatures could accurately predict the prognosis, identify the immune status of patients with lung adenocarcinoma, and provide guidance for therapy.
Collapse
Affiliation(s)
- Shusen Zhang
- Department of Pulmonary and Critical Care Medicine, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, Hebei, China; The First Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China; Hebei Province Xingtai People's Hospital Postdoctoral Workstation, Xingtai, Hebei, China; Postdoctoral Mobile Station, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Dengxiang Liu
- Department of Oncology, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, Hebei, China
| | - Xuecong Ning
- Department of Pulmonary and Critical Care Medicine, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, Hebei, China
| | - Xiaochong Zhang
- Department of Oncology, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, Hebei, China
| | - Yuanyuan Lu
- Department of Anesthesiology, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, Hebei, China
| | - Yang Zhang
- Department of Pulmonary and Critical Care Medicine, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, Hebei, China
| | - Aimin Li
- Department of Pulmonary and Critical Care Medicine, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, Hebei, China
| | - Zhiguo Gao
- Department of Pulmonary and Critical Care Medicine, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, Hebei, China
| | - Zhihua Wang
- Department of Pulmonary and Critical Care Medicine, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, Hebei, China
| | - Xiaoling Zhao
- Department of Oncology, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, Hebei, China
| | - Shubo Chen
- Hebei Province Xingtai People's Hospital Postdoctoral Workstation, Xingtai, Hebei, China; Department of Oncology, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, Hebei, China
| | - Zhigang Cai
- The First Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China; Department of Oncology, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, Hebei, China
| |
Collapse
|
|
6
|
TREM2 as a Potential Immune-Related Biomarker of Prognosis in Patients with Skin Cutaneous Melanoma Microenvironment. DISEASE MARKERS 2023; 2023:8101837. [PMID: 36741909 PMCID: PMC9897921 DOI: 10.1155/2023/8101837] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 10/14/2022] [Accepted: 11/24/2022] [Indexed: 01/30/2023]
Abstract
Background The skin cutaneous melanoma (SKCM) is a devastating form of skin cancer triggered by genetic and environmental factors, and the incidence of SKCM has rapidly increased in recent years. Immune infiltration of the tumor microenvironment is positively associated with overall survival in many tumors. Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily and a crucial signaling hub for multiple pathological pathways that mediate immunity. Although numerous evidences suggest a crucial role for TREM2 in tumorigenesis of some tumors, no systematic SKCM analysis of TREM2 is available. Mehods. The relationship between TREM2 expression and diagnostic and prognostic value of SKCM patients via using The Cancer Genome Atlas (TCGA) data. The expression level of TREM2 and clinical characteristic correlation in SKCM patients were assessed by the Wilcoxon rank sum test. The cox regression methods, Kaplan-Meier (KM), and log-rank test were used to assess the impact of TREM2 expression on the overall survival (OS). Furthermore, the Gene Set Enrichment Analysis (GSEA) and TIMER were performed to evaluate the enrichment pathways and potential functions and quantify the immune cell infiltration level for TREM2 expression. Results The TREM2 in SKCM sample expression levels was significantly higher than in normal tissues. Moreover, this expression level of TREM2 was also associated with the BMI of SKCM patients. KM overall survival analysis and OS curve displayed that a high-level TREM2 expression was significantly correlated with a better SKCM prognosis of patients as compared with a low level of TREM2 expression. The GSEA analysis also revealed that TREM2 was associated with immune functions, such as neutrophil activation. Conclusion TREM2 played a crucial role in SKCM, which might be a prognostic biomarker and correlated with immune infifiltrates in SKCM patients.
Collapse
|
|
7
|
Zhou Y, Zhao Y, Ma W, Zhang L, Jiang Y, Dong W. USF1-CHCHD4 axis promotes lung adenocarcinoma progression partially via activating the MYC pathway. Discov Oncol 2022; 13:136. [PMID: 36482116 PMCID: PMC9732179 DOI: 10.1007/s12672-022-00600-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND This study aimed to identify genes related to lung adenocarcinoma (LUAD) and investigate the effects and molecular mechanisms of coiled-coil-helix-coiled-coil-helix domain containing 4 (CHCHD4) in the progression of LUAD. METHODS The GEPIA database was used to evaluate the differential expression of CHCHD4 and the survival data of LUAD patients compared to controls. TCGA-LUAD database, JASPAR website, and GSEA were used to analyse the relationship between CHCHD4 and the upstream stimulating factor 1 (USF1) or MYC pathways. The proliferation, apoptosis, migration, and invasion of LUAD cells were evaluated using cell counting kit-8, 5-ethynyl-2'-deoxyuridine, colony formation, flow cytometry, wound healing, and transwell assays. qRT-PCR, western blotting, and immunohistochemistry were used to detect the mRNA and protein expression, respectively. Furthermore, xenograft tumours from nude mice were used to verify the effect of CHCHD4 on LUAD in vivo. RESULTS CHCHD4 overexpression was found in LUAD tumor tissues and cells, and high CHCHD4 was associated with a poor prognosis. Interestingly, CHCHD4 knockdown suppressed the malignant phenotype of the LUAD cells. Moreover, we found that USF1 upregulated CHCHD4 and promoted LUAD progression. CHCHD4 knockdown also inhibited the progression of LUAD. In addition, CHCHD4 knockdown suppressed xenograft tumour growth. CONCLUSION USF1-CHCHD4 axis can promote LUAD progress, which may be through activating MYC pathway.
Collapse
Affiliation(s)
- Yuhui Zhou
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan, 250021, People's Republic of China
| | - Yunxia Zhao
- Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, People's Republic of China
| | - Wei Ma
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan, 250021, People's Republic of China
| | - Lin Zhang
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan, 250021, People's Republic of China
| | - Yuanzhu Jiang
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan, 250021, People's Republic of China
| | - Wei Dong
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan, 250021, People's Republic of China.
| |
Collapse
|
|
8
|
Li Z, Ma Z, Xue H, Shen R, Qin K, Zhang Y, Zheng X, Zhang G. Chromatin Separation Regulators Predict the Prognosis and Immune Microenvironment Estimation in Lung Adenocarcinoma. Front Genet 2022; 13:917150. [PMID: 35873497 PMCID: PMC9305311 DOI: 10.3389/fgene.2022.917150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 05/23/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Abnormal chromosome segregation is identified to be a common hallmark of cancer. However, the specific predictive value of it in lung adenocarcinoma (LUAD) is unclear. Method: The RNA sequencing and the clinical data of LUAD were acquired from The Cancer Genome Atlas (TACG) database, and the prognosis-related genes were identified. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were carried out for functional enrichment analysis of the prognosis genes. The independent prognosis signature was determined to construct the nomogram Cox model. Unsupervised clustering analysis was performed to identify the distinguishing clusters in LUAD-samples based on the expression of chromosome segregation regulators (CSRs). The differentially expressed genes (DEGs) and the enriched biological processes and pathways between different clusters were identified. The immune environment estimation, including immune cell infiltration, HLA family genes, immune checkpoint genes, and tumor immune dysfunction and exclusion (TIDE), was assessed between the clusters. The potential small-molecular chemotherapeutics for the individual treatments were predicted via the connectivity map (CMap) database. Results: A total of 2,416 genes were determined as the prognosis-related genes in LUAD. Chromosome segregation is found to be the main bioprocess enriched by the prognostic genes. A total of 48 CSRs were found to be differentially expressed in LUAD samples and were correlated with the poor outcome in LUAD. Nine CSRs were identified as the independent prognostic signatures to construct the nomogram Cox model. The LUAD-samples were divided into two distinct clusters according to the expression of the 48 CSRs. Cell cycle and chromosome segregation regulated genes were enriched in cluster 1, while metabolism regulated genes were enriched in cluster 2. Patients in cluster 2 had a higher score of immune, stroma, and HLA family components, while those in cluster 1 had higher scores of TIDES and immune checkpoint genes. According to the hub genes highly expressed in cluster 1, 74 small-molecular chemotherapeutics were predicted to be effective for the patients at high risk. Conclusion: Our results indicate that the CSRs were correlated with the poor prognosis and the possible immunotherapy resistance in LUAD.
Collapse
Affiliation(s)
- Zhaoshui Li
- Qingdao Medical College, Qingdao University, Qingdao, China
- Cardiothoracic Surgery Department, Qingdao Hiser Hospital Affiliated to Qingdao University, Qingdao, China
| | - Zaiqi Ma
- Cardiothoracic Surgery Department, Qingdao Hiser Hospital Affiliated to Qingdao University, Qingdao, China
| | - Hong Xue
- Heart Center Department, Qingdao Hiser Hospital Affiliated to Qingdao University, Qingdao, China
| | - Ruxin Shen
- Qingdao Medical College, Qingdao University, Qingdao, China
| | - Kun Qin
- Qingdao Medical College, Qingdao University, Qingdao, China
| | - Yu Zhang
- Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xin Zheng
- Cancer Center Department, Qingdao Hiser Hospital Affiliated to Qingdao University, Qingdao, China
- *Correspondence: Xin Zheng, ; Guodong Zhang,
| | - Guodong Zhang
- Thoracic Surgery Department, Shandong Cancer Hospital Affiliated to Shandong First Medical University, Jinan, China
- *Correspondence: Xin Zheng, ; Guodong Zhang,
| |
Collapse
|
|
9
|
Fischer T, Hartmann O, Reissland M, Prieto-Garcia C, Klann K, Pahor N, Schülein-Völk C, Baluapuri A, Polat B, Abazari A, Gerhard-Hartmann E, Kopp HG, Essmann F, Rosenfeldt M, Münch C, Flentje M, Diefenbacher ME. PTEN mutant non-small cell lung cancer require ATM to suppress pro-apoptotic signalling and evade radiotherapy. Cell Biosci 2022; 12:50. [PMID: 35477555 PMCID: PMC9044846 DOI: 10.1186/s13578-022-00778-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 03/27/2022] [Indexed: 12/13/2022] Open
Abstract
Background Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy. Results We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model. Conclusion PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.
Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00778-7.
Collapse
Affiliation(s)
- Thomas Fischer
- Department of Radiation Oncology, University Hospital Würzburg, Würzburg, Germany.,Department of Biochemistry and Molecular Biology, Protein Stability and Cancer Group, University of Würzburg, Würzburg, Germany.,Comprehensive Cancer Centre Mainfranken, Würzburg, Germany
| | - Oliver Hartmann
- Department of Biochemistry and Molecular Biology, Protein Stability and Cancer Group, University of Würzburg, Würzburg, Germany.,Mildred Scheel Early Career Center, Würzburg, Germany
| | - Michaela Reissland
- Department of Biochemistry and Molecular Biology, Protein Stability and Cancer Group, University of Würzburg, Würzburg, Germany.,Mildred Scheel Early Career Center, Würzburg, Germany
| | - Cristian Prieto-Garcia
- Department of Biochemistry and Molecular Biology, Protein Stability and Cancer Group, University of Würzburg, Würzburg, Germany.,Mildred Scheel Early Career Center, Würzburg, Germany
| | - Kevin Klann
- Protein Quality Control Group, Institute of Biochemistry II, Goethe University, Frankfurt, Germany
| | - Nikolett Pahor
- Department of Biochemistry and Molecular Biology, Protein Stability and Cancer Group, University of Würzburg, Würzburg, Germany.,Mildred Scheel Early Career Center, Würzburg, Germany
| | | | - Apoorva Baluapuri
- Department of Biochemistry and Molecular Biology, Cancer Systems Biology Group, Würzburg, Germany
| | - Bülent Polat
- Department of Radiation Oncology, University Hospital Würzburg, Würzburg, Germany.,Comprehensive Cancer Centre Mainfranken, Würzburg, Germany
| | - Arya Abazari
- Department of Radiation Oncology, University Hospital Würzburg, Würzburg, Germany
| | - Elena Gerhard-Hartmann
- Comprehensive Cancer Centre Mainfranken, Würzburg, Germany.,Institute for Pathology, University of Würzburg, Würzburg, Germany
| | | | - Frank Essmann
- Institute for Clinical Pharmacology, Robert Bosch Hospital, Stuttgart, Germany
| | - Mathias Rosenfeldt
- Comprehensive Cancer Centre Mainfranken, Würzburg, Germany.,Institute for Pathology, University of Würzburg, Würzburg, Germany
| | - Christian Münch
- Protein Quality Control Group, Institute of Biochemistry II, Goethe University, Frankfurt, Germany
| | - Michael Flentje
- Department of Radiation Oncology, University Hospital Würzburg, Würzburg, Germany
| | - Markus E Diefenbacher
- Department of Biochemistry and Molecular Biology, Protein Stability and Cancer Group, University of Würzburg, Würzburg, Germany. .,Mildred Scheel Early Career Center, Würzburg, Germany. .,Comprehensive Cancer Centre Mainfranken, Würzburg, Germany. .,Lehrstuhl für Biochemie und Molekularbiologie, Biozentrum, Am Hubland, 97074, Würzburg, Germany.
| |
Collapse
|
|
10
|
Qiu M, Chen M, Lan Z, Liu B, Xie J, Li X. Plasmacytoma variant translocation 1 stabilized by EIF4A3 promoted malignant biological behaviors of lung adenocarcinoma by generating circular RNA LMNB2. Bioengineered 2022; 13:10123-10140. [PMID: 35435126 PMCID: PMC9161831 DOI: 10.1080/21655979.2022.2063666] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Affiliation(s)
- Minglian Qiu
- Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Jiangxi, China
| | - Meizhen Chen
- Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Jiangxi, China
| | - Zhongping Lan
- Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Jiangxi, China
| | - Bo Liu
- Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Jiangxi, China
| | - Jinbao Xie
- Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Jiangxi, China
| | - Xu Li
- Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Jiangxi, China
| |
Collapse
|
|
11
|
Fukui T, Sakai K, Sasaki J, Kakegawa MI, Igawa S, Mitsufuji H, Takeda M, Takahama T, Nakagawa K, Nishio K, Naoki K. Implementation of clinical sequencing for molecular profiling in patients with advanced cancer. Cancer Biomark 2021; 31:119-126. [PMID: 33896820 DOI: 10.3233/cbm-200781] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND The advancement of cancer genomics has allowed for multiplex gene assays using next-generation sequencing (NGS) to be practically implemented, however, a clinical practice system remains to be established. OBJECTIVE We evaluated the feasibility of clinical sequencing using NGS-based multiplex gene assays between cooperating medical institutions in patients with advanced cancers. METHODS In this observational study, DNA and RNA samples prepared from existing tumor tissues were subjected to comprehensive genomic profiling using targeted sequencing. RESULTS From January 2017 to March 2019, 36 samples from 33 patients were assessed. Of all patients, 27 (82%) had lung cancer, with the median age of 50 years (range 38-83). Multiplex gene panel tests were successfully carried out on 35/36 (97%) samples. Potentially actionable gene alterations were identified in 10/30 (33%) samples (3 HER2, 2 KRAS, 2 ALK, 1 PIK3CA, 1 RET, and 1 CDKN2A). In the 6 samples examined for resistant mechanisms, ALK I1171N mutation and MET copy number gain were detected in 2 patients with ALK rearrangement-positive lung cancer. CONCLUSIONS Clinical sequencing using NGS-based multiplex gene assays between collaborating domestic medical institutions was feasible, with a success rate of > 97%. Overall, clinical sequencing benefits therapeutic decision-making in patients with advanced cancer.
Collapse
Affiliation(s)
- Tomoya Fukui
- Department of Respiratory Medicine, Kitasato University School of Medicine, Kanagawa, Japan
| | - Kazuko Sakai
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Jiichiro Sasaki
- Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Kanagawa, Japan
| | | | - Satoshi Igawa
- Department of Respiratory Medicine, Kitasato University School of Medicine, Kanagawa, Japan
| | - Hisashi Mitsufuji
- Fundamental Nursing, Kitasato University School of Nursing, Kanagawa, Japan
| | - Masayuki Takeda
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Takayuki Takahama
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuto Nishio
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Katsuhiko Naoki
- Department of Respiratory Medicine, Kitasato University School of Medicine, Kanagawa, Japan
| |
Collapse
|
|
12
|
Li W, Li Y, Guo L, Liu Y, Yang L, Ying J. Metastatic NSCLCs With Limited Tissues: How to Effectively Identify Driver Alterations to Guide Targeted Therapy in Chinese Patients. JTO Clin Res Rep 2021; 2:100167. [PMID: 34590019 PMCID: PMC8474491 DOI: 10.1016/j.jtocrr.2021.100167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 03/09/2021] [Accepted: 03/12/2021] [Indexed: 11/22/2022] Open
Abstract
INTRODUCTION Molecular diagnostics of newly diagnosed patients with metastatic NSCLC (mNSCLC) with limited tissue samples often face several obstacles in routine practice using next-generation sequencing (NGS), mainly owing to insufficient tissue or DNA; thus, how to effectively identify the molecular profiling of these cases to accurately guide targeted therapy remains elusive. We evaluated whether an optimized workflow with the combined use of multiple technologies could be helpful. METHODS Tissue NGS was used as the frontline method. Amplification refractory mutation system polymerase chain reaction, immunohistochemistry, fluorescence in situ hybridization, and plasma NGS were used as supplements. RESULTS Among 208 mNSCLC cases with limited tissue (cohort 1), molecular genotyping using single-tissue NGS failed in 42 (20.2%) and actionable alterations were identified in only 112 of 208 cases (53.8%). In comparison, the optimized workflow in 1184 additional mNSCLC cases with limited tissue (cohort 2) increased the discovery rate of actionable alterations from 59.7% detected by tissue NGS to 70.4%. It was because that driver alterations were identified using amplification refractory mutation system polymerase chain reaction plus immunohistochemistry or fluorescence in situ hybridization in 53 of 78 (67.9%) tissue NGS-failed cases, and using plasma NGS in 73 of 143 (51.0%) tissue NGS-failed cases, which led to matched targeted therapies in 57 cases with clinical response. Moreover, the median turnaround time of the optimized workflow was significantly shorter than that of repeated biopsy for tissue NGS (p < 0.001). CONCLUSIONS The optimized workflow can improve mutation detection and may avoid repeated biopsy, thus allowing the timely initiation of targeted therapies for patients with newly diagnosed mNSCLC.
Collapse
Affiliation(s)
- Weihua Li
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yan Li
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Lei Guo
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yutao Liu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Lin Yang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Jianming Ying
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| |
Collapse
|
|
13
|
Jin CY, Du L, Nuerlan AH, Wang XL, Yang YW, Guo R. High expression of RRM2 as an independent predictive factor of poor prognosis in patients with lung adenocarcinoma. Aging (Albany NY) 2020; 13:3518-3535. [PMID: 33411689 PMCID: PMC7906179 DOI: 10.18632/aging.202292] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 10/27/2020] [Indexed: 12/24/2022]
Abstract
Ribonucleotide reductase subunit M2 may play a role as a potential prognostic biomarker in several cancers. In this study, we evaluated whether RRM2 gene expression is associated with the prognosis of patients with lung adenocarcinoma (LUAD) using publicly available data from The Cancer Genome Atlas (TCGA). Wilcoxon signed-rank test and logistic regression were performed to evaluate the association between RRM2 expression and clinical features in patients with LUAD. Kaplan-Meier and Cox regression methods were used to examine the effect of RRM2 expression level in the overall survival, and a nomogram was performed to illustrate the correlation between the RRM2 gene expression and the risk of LUAD. TCGA data set was used for gene set enrichment analysis (GSEA). We also performed a further experiment in vitro to assess the effect of RRM2 expression on the proliferation and invasive abilities of LUAD cells and its key signaling pathway proteins. Our results revealed that the expression level of RRM2 in patients with LUAD was much higher than that in normal tissues (p = 3.99e-32). High expression of RRM2 was significantly associated with tumor stage (IV vs. I: OR = 3.02, p = 0.012) and TNM classification (T2 vs. T1: OR = 1.88, p = 0.001; N2 vs. N0: OR = 2.69, p < 0.001). Kaplan-Meier survival analysis showed that high expression of RRM2 was associated with a worse prognosis of LUAD compared low expression of RRM2 (p = 7.86e-04). Multivariate analysis showed that high RRM2 expression was an independent factor affecting overall survival (HR = 1.29, p < 0.001). The association between RRM2 gene expression and the risk of LUAD was presented in a nomogram. GSEA revealed that the cell cycle, p53 signaling pathway, DNA replication, small cell lung cancer, apoptosis, and pathways in cancer were differentially enriched in patients with high expression of RRM2. RRM2 over-expression promoted the proliferation and invasive abilities of LUAD cells. RRM2 over-expression increased the activation of Bcl-2 and E-cadherin signaling pathways, and reduced the activation of p53 signaling pathway. In summary, high RRM2 expression is an independent predictive factor of poor prognosis in patients with lung adenocarcinoma.
Collapse
Affiliation(s)
- Cheng-Yu Jin
- Department of Chest Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, Xinjiang, China
| | - Liang Du
- Department of Chest Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, Xinjiang, China
| | - A-Han Nuerlan
- Department of Chest Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, Xinjiang, China
| | - Xiao-Lei Wang
- Department of Chest Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, Xinjiang, China
| | - Yong-Wei Yang
- Department of Chest Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, Xinjiang, China
| | - Rui Guo
- Department of Chest Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, Xinjiang, China
| |
Collapse
|
|
14
|
Wihadmadyatami H, Hening P, Kustiati U, Kusindarta DL, Triyono T, Supriatno S. Ocimum sanctum Linn. ethanolic extract inhibits angiogenesis in human lung adenocarcinoma (a549) cells. Vet World 2020; 13:2028-2032. [PMID: 33132621 PMCID: PMC7566237 DOI: 10.14202/vetworld.2020.2028-2032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 07/31/2020] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND AND AIM Ocimum sanctum (OS) is a herbal plant, which is easy to find and is widely used as an alternative medication. The previous studies have shown that several species of OS extract have therapeutic properties, and in some cases, antitumor properties. Furthermore, several data have shown the antiproliferative effects of OS extract in cases of breast cancer, human fibrosarcoma, and oral cancer. Lung adenocarcinoma is a major cause of male cancer worldwide; however, the effect of OS (of Indonesian origin) on the metastasis of human alveolar pulmonary adenocarcinoma A549 cells remains unclear. This study aimed to analyze the antiangiogenic effects of OS ethanolic extract in A549 lung adenocarcinoma cells. MATERIALS AND METHODS An angiogenesis assay was performed by seeding A549 cells on extracellular matrix solution and observing tube formation using an inverted microscope. Enzyme-linked immunosorbent assay for αvβ3, matrix metalloproteinase (MMP)-2, and MMP-9 was performed by analyzing the cell lysate after a given treatment. RESULTS OS ethanolic extract significantly inhibited tube formation of A549 cells and suppressed the expression of integrin αvβ3, MMP-2, and MMP-9. CONCLUSION Our findings indicate that OS ethanolic extract disrupts angiogenesis of A549 cells, which may result from the disruption of cell migration and proliferation as a consequence of downregulation of αvβ3, MMP-2, and MMP-9. Taken together, OS ethanolic extract may represent a good therapeutic candidate for the treatment of metastasis in lung adenocarcinoma. Further studies are warranted to further establish the efficacy of OS in the treatment of lung adenocarcinoma.
Collapse
Affiliation(s)
- Hevi Wihadmadyatami
- Department of Anatomy, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Puspa Hening
- Integrated Laboratory for Research and Testing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Ulayatul Kustiati
- Department of Anatomy, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Dwi Liliek Kusindarta
- Department of Anatomy, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Teguh Triyono
- Department of Clinical Pathology, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Supriatno Supriatno
- Department of Oral Medicine, Faculty of Dentistry, Universitas Gadjah Mada, Yogyakarta Indonesia
| |
Collapse
|
|
15
|
Xu Z, Wang Y, Xiong J, Cui F, Wang L, Peng H. NUSAP1 knockdown inhibits cell growth and metastasis of non-small-cell lung cancer through regulating BTG2/PI3K/Akt signaling. J Cell Physiol 2019; 235:3886-3893. [PMID: 31603257 DOI: 10.1002/jcp.29282] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 08/26/2019] [Indexed: 02/06/2023]
Abstract
Non-small-cell lung cancer (NSCLC) is the most common malignancy along with high mortality rate worldwide. Recently, nucleolar and spindle-associated protein 1 (NUSAP1) has been reported to be involved in the malignant progression of several cancers. However, in NSCLC, the biological function of NUSAP1 and its molecular mechanism have not been reported. Here, our findings indicated that the NUSAP1 messenger RNA expression level was remarkably upregulated in NSCLC tissues compared with that of adjacent normal tissues. We also found that NUSAP1 gene expression was notably upregulated in NSCLC cell lines (A549, 95-D, H358, and H1299) compared with that of normal human bronchial epithelial cell line (16HBE). Subsequently, the biological function of NUSAP1 was investigated in A549 and H358 cells transfected with NUSAP1 small interfering RNA (siRNA), respectively. Results showed that NUSAP1 knockdown inhibited NSCLC cell proliferation, and promoted cell apoptosis. Furthermore, the number of cell migration and invasion was significantly suppressed by NUSAP1 knockdown. In addition, our results indicated that NUSAP1 knockdown increased the gene expression of B-cell translocation gene 2 (BTG2), but decreased the expression levels of phosphoinositide 3-kinase (PI3K) and phosphorylated serine/threonine kinase (p-AKT). BTG2 siRNA partly abrogates the effect of NUSAP1 knockdown on BTG2 gene expression. Fumonisin B1 (FB1), a AKT activator, reversed the effect of NUSAP1 knockdown on the biological function in NSCLC. Taken together, NUSAP1 knockdown promotes NSCLC cell apoptosis, and inhibits cell proliferation, cell migration, and invasion, which is associated with regulating BTG2/PI3K/Akt signal pathway. Our findings suggest that NUSAP1 is a promising molecular target for NSCLC treatment.
Collapse
Affiliation(s)
- ZheYuan Xu
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Yang Wang
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Jian Xiong
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - FengXian Cui
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Lan Wang
- Department of Anesthesiology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Hao Peng
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| |
Collapse
|
|
16
|
Yang H, Jiang P, Liu D, Wang HQ, Deng Q, Niu X, Lu L, Dai H, Wang H, Yang W. Matrix Metalloproteinase 11 Is a Potential Therapeutic Target in Lung Adenocarcinoma. Mol Ther Oncolytics 2019; 14:82-93. [PMID: 31024988 PMCID: PMC6477516 DOI: 10.1016/j.omto.2019.03.012] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Accepted: 03/27/2019] [Indexed: 12/29/2022] Open
Abstract
Lung cancer is one of the leading causes of cancer-associated death, with the etiology largely unknown. The aim of this study was to identify key driver genes with therapeutic potentials in lung adenocarcinoma (LUAD). Transcriptome microarray data from four GEO datasets (GEO: GSE7670, GSE10072, GSE68465, and GSE43458) were jointly analyzed for differentially expressed genes (DEGs). Ontologic analysis showed that most of the upregulated DEGs enriched in collagen catabolic and fibril organization processes were regulated by matrix metalloproteinases (MMPs). Matrix metalloproteinase 11 (MMP11), the highest upregulated MMP family member in LUAD-transformed cells, acted in an autocrine manner and was significantly increased in sera of LUAD patients. MMP11 depletion severely impaired LUAD cell proliferation, migration, and invasion in vitro, in line with retarded tumor growth in xenograft models. Treatment of different human LUAD cell lines with anti-MMP11 antibody significantly retarded cell growth and migration. Administration of anti-MMP11 antibody at a dose of 1 μg/g body weight significantly suppressed tumor growth in xenograft models. These findings indicate that MMP11 is a key cancer driver gene in LUAD and is an appealing target for antibody therapy.
Collapse
Affiliation(s)
- Haoran Yang
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
- University of Science and Technology of China, Hefei 230026, China
- Cancer Hospital, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Peng Jiang
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
- University of Science and Technology of China, Hefei 230026, China
- Cancer Hospital, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Dongyan Liu
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
- University of Science and Technology of China, Hefei 230026, China
- Cancer Hospital, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Hong-Qiang Wang
- Biological Molecular Information System Lab., Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Qingmei Deng
- Cancer Hospital, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Xiaojie Niu
- Department of Anatomy, Shanxi Medical University, Taiyuan 030024, China
| | - Li Lu
- Department of Anatomy, Shanxi Medical University, Taiyuan 030024, China
| | - Haiming Dai
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
- Cancer Hospital, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Hongzhi Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
- Cancer Hospital, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Wulin Yang
- Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
- Cancer Hospital, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| |
Collapse
|
|
17
|
Tata P, Gondaliya P, Sunkaria A, Srivastava A, Kalia K. Modulation of CD44, EGFR and RAC Pathway Genes (WAVE Complex) in Epithelial Cancers. Curr Pharm Des 2019; 25:833-848. [PMID: 30799784 DOI: 10.2174/1381612825666190222143044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 02/13/2019] [Indexed: 12/12/2022]
Abstract
Cancer hallmarks help in understanding the diversity of various neoplasms. Epithelial cancers play an immense role in the tumor biology through Epithelial-Mesenchymal Transition (EMT) process. Receptor tyrosine kinase, as well as phosphatidyl ionositol-3 kinase pathways, play an important role in the regulation of cell proliferation, survival, and differentiation during EMT. Till date, numerous studies have shown modulation in the expression profile of potential targets like CD44, EGFR, and Rac in epithelial cancers. CD44 interacts with EGFR and recruits other molecules which further activate the Rac pathway intermediates. This review mainly focused on modulation of genes like CD44, EGFR, and Rac pathway intermediates which play a crucial role in the tumor progression, metastasis, proliferation, and invasion characteristics in epithelial cancers with EMT properties. Hence, targeting Rac pathway might be a more strategically relevant approach in treating epithelial cancers.
Collapse
Affiliation(s)
- Pranathi Tata
- National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Opposite Air Force Station, Gandhinagar, Gujarat-382355, India
| | - Piyush Gondaliya
- National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Opposite Air Force Station, Gandhinagar, Gujarat-382355, India
| | - Aditya Sunkaria
- National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Opposite Air Force Station, Gandhinagar, Gujarat-382355, India
| | - Akshay Srivastava
- National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Opposite Air Force Station, Gandhinagar, Gujarat-382355, India
| | - Kiran Kalia
- National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Opposite Air Force Station, Gandhinagar, Gujarat-382355, India
| |
Collapse
|
|
18
|
Kim I, Eom JS, Kim AR, Lee CH, Lee G, Jo EJ, Kim MH, Mok JH, Lee K, Kim KU, Park HK, Lee MK. Molecular analysis of small tissue samples obtained via transbronchial lung biopsy using radial probe endobronchial ultrasound. PLoS One 2019; 14:e0212672. [PMID: 30807604 PMCID: PMC6391011 DOI: 10.1371/journal.pone.0212672] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Accepted: 02/07/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Radial probe endobronchial ultrasound using a guide sheath (EBUS-GS) is used to diagnose peripheral lung cancer. The aim was to identify the accuracy of molecular analysis that were performed with EBUS-GS specimens in patients with non-small cell lung cancer (NSCLC). METHOD From December 2015 to September 2017, we retrospectively studied 91 patients with peripheral NSCLC who underwent surgery after EBUS-GS. Epidermal growth factor receptor (EGFR) mutational and anaplastic lymphoma kinase (ALK) translocation status obtained from surgical specimens served as the references. RESULTS Compared to the reference data, EGFR mutational testing of EBUS-GS specimens was in 97% agreement, and the κ coefficient was 0.931 (P< 0.001). In addition, on ALK translocation testing, the results of all 91 patients were in agreement with the reference data (concordance rate of 100%, κ coefficient 1.000; P< 0.001). CONCLUSION We found that EBUS-GS could be used for molecular diagnosis, such as EGFR mutational and ALK translocation status, in patients with peripheral NSCLC.
Collapse
Affiliation(s)
- Insu Kim
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
| | - Jung Seop Eom
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea.,Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Ah Rong Kim
- Department of Pathology, Pusan National University School of Medicine, Busan, Korea
| | - Chang Hun Lee
- Department of Pathology, Pusan National University School of Medicine, Busan, Korea
| | - Geewon Lee
- Department of Radiology, Pusan National University School of Medicine, Busan, Korea
| | - Eun Jung Jo
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
| | - Mi-Hyun Kim
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
| | - Jeong Ha Mok
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
| | - Kwangha Lee
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
| | - Ki Uk Kim
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
| | - Hye-Kyung Park
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
| | - Min Ki Lee
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
| |
Collapse
|
|
19
|
Quintanal-Villalonga A, Molina-Pinelo S, Yagüe P, Marrugal Á, Ojeda-Márquez L, Suarez R, Ponce-Aix S, Enguita AB, Carnero A, Ferrer I, Paz-Ares L. FGFR4 increases EGFR oncogenic signaling in lung adenocarcinoma, and their combined inhibition is highly effective. Lung Cancer 2019; 131:112-121. [PMID: 31027687 DOI: 10.1016/j.lungcan.2019.02.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 02/04/2019] [Accepted: 02/07/2019] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Lung adenocarcinoma accounts for approximately half of lung cancer cases. Twenty to 50% of tumors of this type harbor mutations affecting epidermal growth factor receptor (EGFR) expression or activity, which can be therapeutically targeted. EGFR inhibitors in this context exhibit high efficacy and are currently used in the clinical setting. However, not all adenocarcinomas harboring EGFR mutations respond to therapy, so predictive biomarkers of therapeutic outcomes, as well as novel therapies sensitizing these tumors to EGFR inhibition, are needed. MATERIALS AND METHODS We performed in vitro gene overexpression/silencing and tumorigenic surrogate assays, as well as in vitro and in vivo combination treatments with Fibroblast Growth Factor Receptor (FGFR)/EGFR inhibitors. At the clinical level, we determined FGFR4 expression levels in tumors from patients treated with EGFR inhibitors and correlated these with treatment response. RESULTS We describe a cooperative interaction between EGFR and FGFR4, which results in their reciprocal activation with pro-oncogenic consequences in vitro and in vivo. This cooperation is independent of EGFR activating mutations and increases resistance to different EGFR inhibitors. At the therapeutic level, we provide evidence of the synergistic effects of the combination of EGFR and FGFR inhibitors in high FGFR4-expressing, EGFR-activated tumors in vitro and in vivo. Correlated with these results, we found that patients treated with EGFR inhibitors relapse earlier when their tumors exhibit high FGFR4 expression. CONCLUSIONS We propose a novel predictive biomarker for EGFR-targeted therapy, and a highly efficacious combinatory therapeutic strategy to treat EGFR-dependent; this may may extend the use of appropriate inhibitors beyond EGFR-mutated adenocarcinoma patients.
Collapse
Affiliation(s)
- Alvaro Quintanal-Villalonga
- H120-CNIO Lung Cancer Clinical Cancer Research Unit, Fundación de Investigación Biomédica i+12 & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York, United States
| | - Sonia Molina-Pinelo
- Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain; CIBERONC, Madrid, Spain
| | - Patricia Yagüe
- H120-CNIO Lung Cancer Clinical Cancer Research Unit, Fundación de Investigación Biomédica i+12 & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain
| | - Ángela Marrugal
- H120-CNIO Lung Cancer Clinical Cancer Research Unit, Fundación de Investigación Biomédica i+12 & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Laura Ojeda-Márquez
- H120-CNIO Lung Cancer Clinical Cancer Research Unit, Fundación de Investigación Biomédica i+12 & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain
| | - Rocío Suarez
- H120-CNIO Lung Cancer Clinical Cancer Research Unit, Fundación de Investigación Biomédica i+12 & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain
| | - Santiago Ponce-Aix
- Medical Oncology Department, Hospital Universitario Doce de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain
| | - Ana Belén Enguita
- Pathological Anatomy Department, Hospital Universitario Doce de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain; CIBERONC, Madrid, Spain
| | - Irene Ferrer
- H120-CNIO Lung Cancer Clinical Cancer Research Unit, Fundación de Investigación Biomédica i+12 & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain.
| | - Luis Paz-Ares
- H120-CNIO Lung Cancer Clinical Cancer Research Unit, Fundación de Investigación Biomédica i+12 & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; Medical Oncology Department, Hospital Universitario Doce de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; Medical School, Universidad Complutense, Madrid, Spain; CIBERONC, Madrid, Spain.
| |
Collapse
|
|
20
|
Quintanal-Villalonga A, Molina-Pinelo S, Cirauqui C, Ojeda-Márquez L, Marrugal Á, Suarez R, Conde E, Ponce-Aix S, Enguita AB, Carnero A, Ferrer I, Paz-Ares L. FGFR1 Cooperates with EGFR in Lung Cancer Oncogenesis, and Their Combined Inhibition Shows Improved Efficacy. J Thorac Oncol 2019; 14:641-655. [PMID: 30639621 DOI: 10.1016/j.jtho.2018.12.021] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 11/23/2018] [Accepted: 12/04/2018] [Indexed: 01/13/2023]
Abstract
INTRODUCTION There is substantial evidence for the oncogenic effects of fibroblast growth factor receptor 1 (FGFR1) in many types of cancer, including lung cancer, but the role of this receptor has not been addressed specifically in lung adenocarcinoma. METHODS We performed FGFR1 and EGFR overexpression and co-overexpression assays in adenocarcinoma and in inmortalized lung cell lines, and we also carried out surrogate and interaction assays. We performed monotherapy and combination EGFR/FGFR inhibitor sensitivity assays in vitro and in vivo in cell line- and patient-derived xenografts. We determined FGFR1 mRNA expression in a cohort of patients with anti-EGFR therapy-treated adenocarcinoma. RESULTS We have reported a cooperative interaction between FGFR1 and EGFR in this context, resulting in increased EGFR activation and oncogenic signaling. We have provided in vitro and in vivo evidence indicating that FGFR1 expression increases tumorigenicity in cells with high EGFR activation in EGFR-mutated and EGFR wild-type models. At the clinical level, we have shown that high FGFR1 expression levels predict higher resistance to erlotinib or gefitinib in a cohort of patients with tyrosine kinase inhibitor-treated EGFR-mutated and EGFR wild-type lung adenocarcinoma. Dual EGFR and FGFR inhibition in FGFR1-overexpressing, EGFR-activated models shows synergistic effects on tumor growth in vitro and in cell line- and patient-derived xenografts, suggesting that patients with tumors bearing these characteristics may benefit from combined EGFR/FGFR inhibition. CONCLUSION These results support the extended the use of EGFR inhibitors beyond monotherapy in the EGFR-mutated adenocarcinoma setting in combination with FGFR inhibitors for selected patients with increased FGFR1 overexpression and EGFR activation.
Collapse
Affiliation(s)
- Alvaro Quintanal-Villalonga
- H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation i+12, Madrid, Spain; H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sonia Molina-Pinelo
- Insitute for Biomedical Research in Seville (UHVR, SNRC, Seville University), Seville, Spain; CIBERONC, Madrid, Spain
| | - Cristina Cirauqui
- H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation i+12, Madrid, Spain; H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Laura Ojeda-Márquez
- H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation i+12, Madrid, Spain; H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain
| | - Ángela Marrugal
- H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation i+12, Madrid, Spain; H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Rocío Suarez
- H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation i+12, Madrid, Spain; H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Esther Conde
- CIBERONC, Madrid, Spain; Therapeutic Targets Laboratory, University Hospital HM Sanchinarro, Madrid, Spain
| | - Santiago Ponce-Aix
- CIBERONC, Madrid, Spain; Medical Oncology Department, University Hospital Doce de Octubre Madrid, Spain
| | - Ana Belén Enguita
- Pathological Anatomy Department, University Hospital Doce de Octubre, Madrid, Spain
| | - Amancio Carnero
- Insitute for Biomedical Research in Seville (UHVR, SNRC, Seville University), Seville, Spain; CIBERONC, Madrid, Spain
| | - Irene Ferrer
- H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation i+12, Madrid, Spain; H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain.
| | - Luis Paz-Ares
- H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation i+12, Madrid, Spain; H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain; Medical Oncology Department, University Hospital Doce de Octubre Madrid, Spain; Medical School, Complutense University, Madrid, Spain
| |
Collapse
|
|
21
|
Siriwardhana C, Khadka VS, Chen JJ, Deng Y. Development of a miRNA-seq based prognostic signature in lung adenocarcinoma. BMC Cancer 2019; 19:34. [PMID: 30621620 PMCID: PMC6325795 DOI: 10.1186/s12885-018-5206-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 12/10/2018] [Indexed: 12/29/2022] Open
Abstract
Background We utilized miRNAs expression and clinical data to develop a prognostic signature for patients with lung adenocarcinoma, with respect to their overall survival, to identify high-risk subjects based on their miRNA genomic profile. Methods MiRNA expressions based on miRNA sequencing and clinical data of lung adenocarcinoma patients (n = 479) from the Cancer Genome Atlas were randomly partitioned into non-overlapping Model (n = 320) and Test (n = 159) sets, respectively, for model estimation and validation. Results Among the ten miRNAs identified using the univariate Cox analysis, six from miR-8, miR-181, miR-326, miR-375, miR-99a, and miR-10, families showed improvement of the overall survival chance, while two miRNAs from miR-582 and miR-584 families showed a worsening of survival chances. The final prognostic signature was developed with five miRNAs—miR-375, miR-582-3p, miR-326, miR-181c-5p, and miR-99a-5p—utilizing a stepwise variable selection procedure. Using the KEGG pathway analysis, we found potential evidence supporting their significance in multiple cancer pathways, including non-small cell lung cancer. We defined two risk groups with a score calculated using the Cox regression coefficients. The five-year survival rates for the low-risk group was approximately 48.76% (95% CI = (36.15, 63.93)); however, it was as low as 7.50% (95% CI = (2.34, 24.01)) for the high-risk group. Furthermore, we demonstrated the effect of the genomic profile using the miRNA signature, quantifying survival rates for hypothetical subjects in different pathological stages of cancer. Conclusions The proposed prognostic signature can be used as a reliable tool for identifying high-risk subjects regarding survival based on their miRNA genomic profile. Electronic supplementary material The online version of this article (10.1186/s12885-018-5206-8) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Chathura Siriwardhana
- Bioinformatics and Biostatistics Cores, Department of Complementary and Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI, 96813, USA.
| | - Vedbar S Khadka
- Bioinformatics and Biostatistics Cores, Department of Complementary and Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI, 96813, USA
| | - John J Chen
- Bioinformatics and Biostatistics Cores, Department of Complementary and Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI, 96813, USA
| | - Youping Deng
- Bioinformatics and Biostatistics Cores, Department of Complementary and Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI, 96813, USA.
| |
Collapse
|
|
22
|
Li JJ, Yan S, Pan Y, Liu Z, Liu Y, Deng Q, Tan Q, Woodward ER, Wu N. FGFR genes mutation is an independent prognostic factor and associated with lymph node metastasis in squamous non-small cell lung cancer. Cancer Biol Ther 2018; 19:1108-1116. [PMID: 30403900 DOI: 10.1080/15384047.2018.1480294] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Targeting FGFRs is one of the most promising therapeutic strategies in squamous non-small cell lung cancer (SQCC). However, different FGFR genomic aberrations can be associated with distinct biological characteristics that result in different clinical outcomes or therapeutic consequences. Currently, the full spectrum of FGFR gene aberrations and their clinical significance in SQCC have not been comprehensively studied. Here, we used Next-generation sequencing to investigate the presence of FGFR gene mutations in 143 tumors from patients with stage I, II or III SQCC and who had not been treated with chemotherapy or radiotherapy prior to surgery. FGFR gene mutations were identified in 24 cases, resulting in an overall frequency of 16.9%. Among the mutations, 7% (10/143) were somatic mutations, and 9.8% (14/143) germline mutations. FGFR mutations were significantly associated with an increased risk of lymph node metastasis. SQCC patients with a FGFR somatic mutation had shorter OS (overall survival, log rank P = 0.005) and DFS (disease-free survival，log rank P = 0.004) compared with those without an FGFR mutation. The multivariate analysis confirmed that a somatic mutation was an independent poor prognostic factor for OS (HR: 4.26, 95% CI: 1.49-12.16, P = 0.007) and DFS (HR: 3.16, 95% CI: 1.20-8.35, P = 0.020). Our data indicate that FGFR genes mutation is an independent prognostic factor and associated with lymph node metastasis in stage I to III Chinese SQCC patients.
Collapse
Affiliation(s)
- Jing Jing Li
- a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics , Peking University Cancer Hospital & Institute , Beijing , China
| | - Shi Yan
- b Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Surgery II , Peking University Cancer Hospital & Institute , Beijing , China
| | - Yaqi Pan
- a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics , Peking University Cancer Hospital & Institute , Beijing , China
| | - Zhen Liu
- a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics , Peking University Cancer Hospital & Institute , Beijing , China
| | - Ying Liu
- a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics , Peking University Cancer Hospital & Institute , Beijing , China
| | - Qiuju Deng
- a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics , Peking University Cancer Hospital & Institute , Beijing , China
| | - Qin Tan
- a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics , Peking University Cancer Hospital & Institute , Beijing , China
| | - Emma R Woodward
- c Manchester Centre for Genomic Medicine , Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC) , Manchester , UK
| | - Nan Wu
- b Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Surgery II , Peking University Cancer Hospital & Institute , Beijing , China
| |
Collapse
|
|
23
|
Gill RR, Murphy DJ, Kravets S, Sholl LM, Janne PA, Johnson BE. Success of genomic profiling of non-small cell lung cancer biopsies obtained by trans-thoracic percutaneous needle biopsy. J Surg Oncol 2018; 118:1170-1177. [PMID: 30261097 DOI: 10.1002/jso.25241] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 08/24/2018] [Indexed: 01/05/2023]
Abstract
PURPOSE Genomic profiling for personalized targeted therapy has become standard of care. We report the success of genomic profiling of non-small cell lung cancer (NSCLC) obtained by trans-thoracic needle biopsy (TTNB) in a single center experience. MATERIALS AND METHODS Patients with NSCLC who underwent TTNB for genomic were identified. Pathology specimens were evaluated for tumor adequacy and then analyzed for selected exons of epidermal growth factor receptor, KRAS, BRAF, PIK3CA, and ERBB2. ALK rearrangements were detected with fluorescence in situ hybridization and/or immunohistochemistry. Technical success was recorded and the factors affecting successful profiling were evaluated. Complications (pneumothorax, hemorrhage, and admission) were recorded. Comparison of yield and complications were done between the two groups (core biopsy and fine needle aspiration only group). Utility of PET-CT to guide the needle track for optimized yield was assessed in a subset of patients. RESULTS Between December 6, 2009, and December 30, 2016, 765 patients with NSCLC underwent TTNB. Five-hundred and seventy-seven of 765 (75%) of all TTNB were profiled, for genomic analysis. Five-hundred and eight of 577 (88%) were successfully profiled. The number of samples obtained ranged from 1 to 10 (1 to 2 cm, 18 to 20 G). Lesions biopsied ranged in size from 0.6 to 16 cm. No statistically significant difference was observed in the incidence of pneumothorax between two groups (P = 0.26). PET guidance was not found to be statistically significant ( P = 0.79) in the overall yield. CONCLUSION Computed tomographic guided TTNB is a safe and efficacious technique for genomic profiling, enables the acquisition of sufficient tissue for genetic mutation analyses allowing for personalized therapy with an acceptable complication rate.
Collapse
Affiliation(s)
- Ritu R Gill
- Department of Radiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - David John Murphy
- Department of Radiology, Guy's & St Thomas, NHS Foundation Trust & King's College, London, UK
| | - Sasha Kravets
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Lynnette Mary Sholl
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Pasi Antero Janne
- Department of Medical Oncology, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Bruce Evan Johnson
- Department of Medical Oncology, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| |
Collapse
|
|
24
|
Michael CW, Faquin W, Jing X, Kaszuba F, Kazakov J, Moon E, Toloza E, Wu RI, Moreira AL. Committee II: Guidelines for cytologic sampling techniques of lung and mediastinal lymph nodes. Diagn Cytopathol 2018; 46:815-825. [PMID: 30195266 DOI: 10.1002/dc.23975] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 04/25/2018] [Accepted: 04/27/2018] [Indexed: 12/19/2022]
Abstract
The Papanicolaou Society of Cytopathology has developed a set of guidelines for pulmonary cytology including indications for bronchial brushings, washings, and endobronchial ultrasound guided transbronchial fine-needle aspiration (EBUS-TBNA), technical recommendations for cytological sampling, recommended terminology and classification schemes, recommendations for ancillary testing and recommendations for post-cytological management and follow-up. All recommendations are based on the expertise of the authors, an extensive literature review and feedback from presentations at national and international conferences. This document selectively presents the results of these discussions. The present document summarizes recommendations regarding techniques used to obtain cytological and small histologic specimens from the lung and mediastinal lymph nodes including rapid on-site evaluation (ROSE), and the triage of specimens for immunocytochemical and molecular studies.
Collapse
Affiliation(s)
- C W Michael
- Department of Pathology and Laboratory Medicine, University Hospitals Cleveland Medical Center/Case Western Reserve University, Cleveland, Ohio
| | - W Faquin
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - X Jing
- Department of Pathology, University of Michigan, Ann Arbor, Michigan
| | - F Kaszuba
- Division of Pulmonary, Critical Care and Sleep Medicine, H. Lee Moffitt Cancer Center/University of South Florida, Tampa, Florida
| | - J Kazakov
- Department of Internal Medicine, University Hospitals Cleveland Medical Center/Case Western Reserve University, Cleveland, Ohio
| | - E Moon
- Department of Internal Medicine, University of Pennsylvania Health System and Perelman School of Medicine, Philadelphia, Pennsylvania
| | - E Toloza
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center/University of South Florida, Tampa, Florida
| | - R I Wu
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Health system and Perelman School of Medicine, Philadelphia, Pennsylvania
| | - A L Moreira
- Department of Pathology, New York University Langone Health, New York, New York
| |
Collapse
|
|
25
|
Shi Z, Zheng X, Shi R, Song C, Yang R, Zhang Q, Wang X, Lu J, Yu Y, Jiang T. Score for lung adenocarcinoma in China with EGFR mutation of exon 19: Combination of clinical and radiological characteristics analysis. Medicine (Baltimore) 2018; 97:e12537. [PMID: 30235778 PMCID: PMC6160170 DOI: 10.1097/md.0000000000012537] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 08/31/2018] [Indexed: 01/17/2023] Open
Abstract
BACKGROUD The biopsy samples might be the only tumor material available for testing the EGFR mutation status in some cases, but these samples are often composed of variable ratios of tumor to normal cells. In this study, we sought to build a scoring system to predict Epidermal growth factor receptor (EGFR) exon 19 mutation in lung adenocarcinoma by clinical and radiological features. METHODS Enrolled in this study were 601 patients with lung adenocarcinoma. Qualitative evaluation of the clinical and radiological features included 25 aspects. Statistical analysis was used to assess the association of these features between the EGFR wild type and exon 19 mutation, based on a clinical scoring system built by the statistical model and the experience of the radiologists. RESULTS EGRF-exon-19-mutation was associated with the female gender [odds ratios (OR), 2.573; 95% confidence intervals (CI), 1.689-3.920], tumor maximum diameter (OR, 0.357; 95% CI, 0.235-0.542), the absence of emphysema (OR, 0.202; 95% CI, 0.110-0.368), the absence of fibrosis (OR, 0.168; 95% CI, 0.083-0.339), and pleural retraction (OR, 2.170; 95% CI, 1.434-3.285). The clinical scoring model assigned 3 points to the female gender, 2 points to small tumor maximum diameter (≤34.5 mm), 2 to the absence of emphysema, 2 to the absence of fibrosis, and 1 to the presence of pleural retraction. CONCLUSIONS The scoring system based on the statistical analysis of clinical and radiological features may be a new alternative to the prediction of EGFR mutation subtypes.
Collapse
Affiliation(s)
| | - Xuan Zheng
- Clinical Nutrition Department, Changhai Hospital, Second Military Medical University, Shanghai
| | | | | | - Runhong Yang
- Department of Radiology, Yanan University Affiliated Hospital, Shanxi
| | | | | | | | - Yongwei Yu
- Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | | |
Collapse
|
|
26
|
Zhou GZ, Li AF, Sun YH, Sun GC. A novel synthetic curcumin derivative MHMM-41 induces ROS-mediated apoptosis and migration blocking of human lung cancer cells A549. Biomed Pharmacother 2018; 103:391-398. [PMID: 29674274 DOI: 10.1016/j.biopha.2018.04.086] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Revised: 04/10/2018] [Accepted: 04/10/2018] [Indexed: 11/17/2022] Open
Abstract
Many curcumin derivatives were produced and characterized to improve the physiochemical instability and low solubility of curcumin. Here, MHMM-41 (a novel curcumin derivative) was used to treat non-small lung cancer cells of human (known as A549) and to identify its anti-proliferative activities. Our results suggested that MHMM-41 display no significant cytotoxicity toward normal human lung fibroblast 2BS cells and mouse embryonal fibroblast 3T3 cells. It also had better anti-proliferative activity than curcumin in A549 cells. Further study showed a significant increase of apoptotic A549 cells in time and dose dependent manners. The activation of caspase-3, 8, 9, 12, Bax and PARP proteins were detected. Consequently, MHMM-41 treatment led to the reduction of mitochondrial membrane potential by JC-1 staining and characteristic nuclei fragmentation by Hoechst 33,342 staining, respectively, which showed that A549 apoptosis could be triggered by the extrinsic and intrinsic mitochondrial pathways. The release of ROS was also measured by flow cytometry. Further, wound healing assay and transwell experiments confirmed the anti-migration ability of MHMM-41 in A549 cells. Our current study suggested the potentials of MHMM-41 to inhibit the A549 cell proliferation. However, the intensive mechanical research on the anti-proliferation of A549 cells needs to be performed in the future.
Collapse
Affiliation(s)
- Guang-Zhou Zhou
- Department of Biotechnology, College of Bioengineering, Henan University of Technology, Zhengzhou, Henan, 450001, China.
| | - A-Fang Li
- Department of Biotechnology, College of Bioengineering, Henan University of Technology, Zhengzhou, Henan, 450001, China
| | - Yan-He Sun
- Department of Biotechnology, College of Bioengineering, Henan University of Technology, Zhengzhou, Henan, 450001, China
| | - Gang-Chun Sun
- College of Chemistry and Chemical Engineering, Henan University of Technology, Zhengzhou, 450001, China.
| |
Collapse
|
|
27
|
Quintanal-Villalonga Á, Mediano M, Ferrer I, Meléndez R, Carranza-Carranza A, Suárez R, Carnero A, Molina-Pinelo S, Paz-Ares L. Histology-dependent prognostic role of pERK and p53 protein levels in early-stage non-small cell lung cancer. Oncotarget 2018; 9:19945-19960. [PMID: 29731995 PMCID: PMC5929438 DOI: 10.18632/oncotarget.24977] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 03/11/2018] [Indexed: 12/17/2022] Open
Abstract
Lung tumors represent a major health problem. In early stage NSCLC tumors, surgical resection is the preferred treatment, but 30-55% of patients will relapse within 5 years after surgery. Thus, the identification of prognostic biomarkers in early stage NSCLC patients, especially those which are therapeutically addressable, is crucial to enhance survival of these patients. We determined the immunohistochemistry expression of key proteins involved in tumorigenesis and oncogenic signaling, p53, EGFR, pAKT and pERK, and correlated their expression level to clinicopathological characteristics and patient outcome. We found EGFR expression is higher in the squamous cell carcinomas than in adenocarcinomas (p=0.043), and that nuclear p53 staining correlated with lower differentiated squamous tumors (p=0.034). Regarding the prognostic potential of the expression of these proteins, high pERK levels proved to be an independent prognostic factor for overall (p<0.001) and progression-free survival (p<0.001) in adenocarcinoma patients, but not in those from the squamous histology, and high p53 nuclear levels were identified as independent prognostic factor for progression-free survival (p=0.031) only in squamous cell carcinoma patients. We propose a role as early prognostic biomarkers for pERK protein levels in adenocarcinoma, and for nuclear p53 levels in squamous cell lung carcinoma. The determination of these potential biomarkers in the adequate histologic context may predict the outcome of early stage NSCLC patients, and may offer a therapeutic opportunity to enhance survival of these patients.
Collapse
Affiliation(s)
- Álvaro Quintanal-Villalonga
- H120-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación 12 de Octubre and CNIO, Madrid, Spain
| | - Mariló Mediano
- Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.,Hospital Universitario Virgen del Rocío (HUVR), Sevilla, Spain
| | - Irene Ferrer
- H120-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación 12 de Octubre and CNIO, Madrid, Spain.,CiberOnc, Madrid, Spain
| | - Ricardo Meléndez
- Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain
| | - Andrés Carranza-Carranza
- Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.,Hospital Universitario Virgen del Rocío (HUVR), Sevilla, Spain
| | - Rocío Suárez
- H120-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación 12 de Octubre and CNIO, Madrid, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain
| | - Sonia Molina-Pinelo
- Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.,CiberOnc, Madrid, Spain
| | - Luis Paz-Ares
- H120-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación 12 de Octubre and CNIO, Madrid, Spain.,Medical Oncology Department, Hospital Universitario Doce de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.,Medical School, Universidad Complutense, Madrid, Spain.,CiberOnc, Madrid, Spain
| |
Collapse
|
|
28
|
Ding X, Zhong T, Jiang L, Huang J, Xia Y, Hu R. miR-25 enhances cell migration and invasion in non-small-cell lung cancer cells via ERK signaling pathway by inhibiting KLF4. Mol Med Rep 2018; 17:7005-7016. [PMID: 29568911 PMCID: PMC5928655 DOI: 10.3892/mmr.2018.8772] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 12/08/2017] [Indexed: 01/10/2023] Open
Abstract
In recent years, microRNAs (miRNAs/miRs) have gained increasing interest in cancer research. Increasing evidences demonstrated that miRNAs are important for tumor early detection and prognosis. The present study aimed to explore the function of miR-25 in non-small-cell lung cancer (NSCLC) and its underlying mechanisms. The expression levels of miR-25 and Krüppel-like factor 4 (KLF4) were assessed in 31 pairs of tissue from patients with NSCLC. In addition, the biological roles of miR-25 in NSCLC were analyzed via a cell wound healing assay, Transwell invasion and migration assays. Target genes of miR-25 were predicted using TargetScan and verified via a dual luciferase activity assay, western blotting and reverse transcription-quantitative polymerase chain reaction. The downstream signaling pathway was confirmed by western blot analysis. In the present study, miR-25 was overexpressed in 31 NSCLC samples compared with in corresponding normal tissues. Overexpression of miR-25 using miR-25 mimics markedly promoted NSCLC cell migration and invasion, while inhibition of miR-25 exerted the opposite effect. KLF4 was suggested to be a novel target gene of miR-25 in NSCLC cells. Knockdown of KLF4 promoted the migration and invasion of NSCLC cells, whereas rescue of KLF4 expression reduced cell motion ability in miR-25-overexpressing NSCLC cells. Furthermore, it was demonstrated that miR-25 activated the extracellular signal-regulated kinase (ERK) signaling pathway, which eventually led to increased vimentin, matrix metalloproteinase 11 and N-cadherin levels, and the downregulation of E-cadherin expression by inhibiting the expression of KLF4. In conclusion, miR-25 was demonstrated to activate the ERK signaling pathway by directly targeting KLF4, promoting cell migration and invasion. The findings of the present study indicated that miR-25 or KLF4 may serve as a therapeutic target for the treatment of NSCLC.
Collapse
Affiliation(s)
- Xiaoli Ding
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Tianyu Zhong
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Lixia Jiang
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Junyun Huang
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Yu Xia
- Graduate Student Major of Laboratory Medicine of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Rong Hu
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| |
Collapse
|
|
29
|
Bak SH, Park H, Lee HY, Kim Y, Kim HL, Jung SH, Kim H, Kim J, Park K. Imaging genotyping of functional signaling pathways in lung squamous cell carcinoma using a radiomics approach. Sci Rep 2018; 8:3284. [PMID: 29459639 PMCID: PMC5818618 DOI: 10.1038/s41598-018-21706-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 02/09/2018] [Indexed: 01/06/2023] Open
Abstract
Imaging features can be useful for identifying distinct genomic differences and have predictive power for certain phenotypes attributed to genomic mutations. We aimed to identify predictive imaging biomarkers that underpin genomic alterations and clinical outcomes in lung squamous cell carcinoma (SQCC) using a radiomics approach. In 57 patients with lung SQCC who underwent preoperative computed tomography (CT) and whole-exome DNA sequencing, 63 quantitative imaging features were extracted from CT and 73 clinicoradiological features including imaging features were classified into 8 categories: clinical, global, histogram-based, lung cancer-specific, shape, local, regional, and emphysema. Mutational profiles for core signaling pathways of lung SQCC were classified into five categories: redox stress, apoptosis, proliferation, differentiation, and chromatin remodelers. Range and right lung volume was significantly associated with alternation of apoptosis and proliferation pathway (p = 0.03, and p = 0.03). Energy was associated with the redox stress pathway (p = 0.06). None of the clinicoradiological features showed any significant association with the alteration of differentiation and chromatin remodelers pathway. This study showed that radiomic features indicating five different functional pathways of lung SQCC were different form one another. Radiomics approaches to lung SQCC have the potential to noninvasively predict alterations in core signaling pathways and clinical outcome.
Collapse
Affiliation(s)
- So Hyeon Bak
- Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Radiology, Kangwon National University Hospital, Chuncheon, Korea
| | - Hyunjin Park
- School of Electronic and Electrical Engineering, Sungkyunkwan University, Suwon, Korea.,Center for Neuroscience Imaging Research (CNIR), Institute for Basic Science, Suwon, Korea
| | - Ho Yun Lee
- Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
| | - Youngwook Kim
- Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyung-Lae Kim
- Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Korea
| | - Sin-Ho Jung
- Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Hyeseung Kim
- Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Jonghoon Kim
- Department of Electronic Electrical and Computer Engineering, Sungkyunkwan University, Suwon, Korea
| | - Keunchil Park
- Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
| |
Collapse
|
|
30
|
Cai H, Wang C. Surviving With Smog and Smoke: Precision Interventions? Chest 2017; 152:925-929. [PMID: 28694198 DOI: 10.1016/j.chest.2017.06.030] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 06/20/2017] [Accepted: 06/30/2017] [Indexed: 12/16/2022] Open
Abstract
Despite continuous efforts of regional governmental agencies, air pollution remains a major threat to public health worldwide. In January 2017, a severe episode of smog similar to the Great Smog of 1952 occurred in London. The longest episode of Chinese haze also developed in Beijing, during which levels of particulate matter < 2.5 μm rose to 500 μg/m3. European smog and Chinese haze are associated with large numbers of premature deaths each year, at 400,000 and 1.2 million, respectively, primarily from respiratory diseases, cerebrovascular diseases, and ischemic heart diseases. In addition to air pollution, some are exposed to other harmful environmental factors, such as secondhand smoke. For countries with large populations of smokers, such as China, India, the United States, and Russia, surviving both smog and smoke is a serious problem. With novel genomic and epigenomic studies revealing air pollution- and smoking-induced mutational signatures and epigenetic editing in diseases such as lung cancer, it has become feasible to develop precision strategies for early intervention in the disease-causing pathways driven by the specific mutations or epigenetic regulations, or both. New therapies guided by gene-drug interactions and genomic biomarkers may also be developed. We discuss both perspectives regarding the urgent need to manage the toxic effects of smog and smoke for the benefit of global health and the novel concept of precision intervention to protect the exposed individuals when exposure to smog and secondhand smoke cannot be voluntarily avoided or easily modified.
Collapse
Affiliation(s)
- Hua Cai
- National Clinical Research Center for Respiratory Diseases, Center for Respiratory Diseases, Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China; Division of Molecular Medicine, Department of Anesthesiology, Division of Cardiology, Department of Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, Los Angeles, CA.
| | - Chen Wang
- Division of Molecular Medicine, Department of Anesthesiology, Division of Cardiology, Department of Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, Los Angeles, CA
| |
Collapse
|
|
31
|
Shi Z, Zheng X, Shi R, Song C, Yang R, Zhang Q, Wang X, Lu J, Yu Y, Liu Q, Jiang T. Radiological and Clinical Features associated with Epidermal Growth Factor Receptor Mutation Status of Exon 19 and 21 in Lung Adenocarcinoma. Sci Rep 2017; 7:364. [PMID: 28336963 PMCID: PMC5428650 DOI: 10.1038/s41598-017-00511-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 02/28/2017] [Indexed: 11/23/2022] Open
Abstract
The exon 19 and 21 in Epidermal Growth Factor Receptor (EGFR) mutation are the most common subtype of lung adenocarcinoma, and the strongest predictive biomarker for progression-free survival and tumor response. Although some studies have shown differences in radiological features between cases with and without EFGR mutations, they lacked necessary stratification. This article is to evaluate the association of CT features between the wild type and the subtype (exon 19 and 21) of EGFR mutations in patients with lung adenocarcinoma. Of the 721 finally included patients, 132 were positive for EGFR mutation in exon 19, 140 were positive for EGFR mutation in exon 21, and 449 were EGFR wild type. EGFR mutation in exon 19 was associated with a small-maximum diameter (28.51 ± 14.07) (p < 0.0001); sex (p < 0.0001); pleural retraction (p = 0.0034); and the absence of fibrosis (p < 0.0001), while spiculated margins (p = 0.0095), subsolid density (p < 0.0001) and no smoking (p < 0.0001) were associated with EGFR mutation in exon 21. Receiver Operating Characteristic (ROC) curves suggested that the maximum Area Under the Curve (AUC) was related to the female gender (AUC = 0.636) and the absence of smoking (AUC = 0.681). This study demonstrated the radiological and clinical features could be used to prognosticate EGFR mutation subtypes in exon 19 and 21.
Collapse
Affiliation(s)
- Zhang Shi
- Department of Radiology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Xuan Zheng
- Clinical Nutrition Department, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Ruifeng Shi
- Department of Radiology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Changen Song
- Department of Radiology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Runhong Yang
- Department of Radiology, Yanan University affiliated hospital, Shanxi, China
| | - Qianwen Zhang
- Department of Radiology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Xinrui Wang
- Department of Radiology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Jianping Lu
- Department of Radiology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Yongwei Yu
- Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai, China.
| | - Qi Liu
- Department of Radiology, Changhai Hospital, Second Military Medical University, Shanghai, China.
| | - Tao Jiang
- Department of Radiology, Changhai Hospital, Second Military Medical University, Shanghai, China.
| |
Collapse
|
|
32
|
Shi J, Yuan M, Wang ZD, Xu XL, Hong L, Sun S. Comprehensive profiling and quantitation of oncogenic mutations in non-small cell lung carcinoma using single-molecule amplification and re-sequencing technology. Tumour Biol 2017; 39:1010428317691413. [PMID: 28218040 DOI: 10.1177/1010428317691413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The carcinogenesis of non-small cell lung carcinoma has been found to associate with activating and resistant mutations in the tyrosine kinase domain of specific oncogenes. Here, we assessed the type, frequency, and abundance of epithelial growth factor receptor, KRAS, BRAF, and ALK mutations in 154 non-small cell lung carcinoma specimens using single-molecule amplification and re-sequencing technology. We found that epithelial growth factor receptor mutations were the most prevalent (44.2%), followed by KRAS (18.8%), ALK (7.8%), and BRAF (5.8%) mutations. The type and abundance of the mutations in tumor specimens appeared to be heterogeneous. Thus, we conclude that identification of clinically significant oncogenic mutations may improve the classification of patients and provide valuable information for determination of the therapeutic strategies.
Collapse
Affiliation(s)
- Jian Shi
- 1 Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Meng Yuan
- 2 College of Science and Technology, China Three Gorges University, Yichang, China
| | - Zhan-Dong Wang
- 3 Department of Pathology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiao-Li Xu
- 4 Department of Medical Record Library, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lei Hong
- 1 Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Shenglin Sun
- 1 Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| |
Collapse
|
|
33
|
Li Z, Huang J, Yuan H, Chen Z, Luo Q, Lu S. SIRT2 inhibits non-small cell lung cancer cell growth through impairing Skp2-mediated p27 degradation. Oncotarget 2017; 7:18927-39. [PMID: 26942878 PMCID: PMC4951341 DOI: 10.18632/oncotarget.7816] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 02/14/2016] [Indexed: 12/14/2022] Open
Abstract
Skp2 is a component of the E3 ubiquitin ligase which promotes the ubiquitination-associated degradation of a cyclin-dependent kinase inhibitor, p27, resulting in increases in non-small cell lung cancer (NSCLC) cell growth. We recently showed that down-regulation of Sirtuin deacetylases 2 (SIRT2) in NSCLC increased cancer cell growth through suppressing p27. However, the underlying mechanisms remain unknown. Here, we examined the relationship between SIRT2 and Skp2 in regulation of NSCLC cell growth through p27. We found that the levels of SIRT2 significantly decreased, while the levels of Skp2 significantly increased in NSCLC specimens, compared to the paired non-tumor lung tissue. The levels of SIRT2 and Skp2 inversely correlated. Low SIRT2 levels were associated with poor patients' survival. Moreover, in several lung cancer cell lines, the SIRT2 levels significantly decreased and the Skp2 levels significantly increased. Overexpression of SIRT2 promoted Skp2 deacetylation and degradation, resulting in increases in p27 and suppression of NSCLC cell growth, whereas knockdown of Skp2 inhibited Skp2 deacetylation and degradation, resulting in decreases in p27 and increases in NSCLC cell growth. The deacetylation of Skp2 by SIRT2 and degradation of p27 by Skp2 were significantly inhibited by histone deacetylase inhibitor and proteasome inhibitor, respectively. Finally, SIRT2 and Skp2 co-immunoprecipitated in NSCLC cells. Together, our data suggest that SIRT2 may induce Skp2 deacetylation and subsequent degradation to abolish the effects of Skp2 on p27 to affect NSCLC cell growth. Thus, re-expression of SIRT2 may be a promising strategy for treating NSCLC.
Collapse
Affiliation(s)
- Ziming Li
- Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China
| | - Jia Huang
- Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China
| | - Hong Yuan
- Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China
| | - Zhiwei Chen
- Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China
| | - Qingquan Luo
- Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China
| | - Shun Lu
- Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China
| |
Collapse
|
|
34
|
Weissferdt A, Kalhor N, Correa AM, Moran CA. "Sarcomatoid" carcinomas of the lung: a clinicopathological study of 86 cases with a new perspective on tumor classification. Hum Pathol 2016; 63:14-26. [PMID: 27993578 DOI: 10.1016/j.humpath.2016.12.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 11/22/2016] [Accepted: 12/01/2016] [Indexed: 12/29/2022]
Abstract
Pulmonary sarcomatoid carcinoma includes a heterogenous group of tumors difficult to diagnose and treat. We report the clinicopathological features of 86 such tumors, including 74 pleomorphic and 12 spindle cell carcinomas, and propose a novel approach to the classification of these neoplasms in an attempt to better guide patient management. The patients were 47 men and 39 women aged 36 to 87 years (mean, 63 years) who primarily presented with shortness of breath, cough, and chest pain. Eighty-six percent of patients had a smoking history. Histologically, the pleomorphic carcinomas consisted of spindle and/or giant cells with varying proportions of conventional non-small cell carcinoma in the form of adenocarcinoma (n=29), squamous cell carcinoma (n=10), or large cell carcinoma (n=18); 17 cases contained a mix of spindle and giant cells only. The 12 spindle cell carcinomas consisted of spindle cells only. Based on the combined histopathologic and immunohistochemical features of these tumors, we were able to reanalyze the spectrum of these lesions and reclassify them accordingly. Statistical analysis revealed an overall survival at 3, 5, and 10 years of 42.9%, 34.6%, and 23.5%, respectively, and a median survival of 15 months. Log-rank test showed that in multivariate analysis, only pathological T stage was a factor associated with prognosis. The current classification of pulmonary sarcomatoid carcinomas precludes optimal triaging of these tumors with the risk of denying patients access to novel treatment. Our proposal for a reclassification of these tumors would more accurately guide patient management and facilitate targeted therapies.
Collapse
Affiliation(s)
- Annikka Weissferdt
- Department of Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Neda Kalhor
- Department of Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Arlene M Correa
- Department of Thoracic Surgery, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Cesar A Moran
- Department of Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA
| |
Collapse
|
|
35
|
Chiba M, Togashi Y, Tomida S, Mizuuchi H, Nakamura Y, Banno E, Hayashi H, Terashima M, De Velasco MA, Sakai K, Fujita Y, Mitsudomi T, Nishio K. MEK inhibitors against MET-amplified non-small cell lung cancer. Int J Oncol 2016; 49:2236-2244. [PMID: 27748834 PMCID: PMC5118002 DOI: 10.3892/ijo.2016.3736] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 09/30/2016] [Indexed: 12/12/2022] Open
Abstract
Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFR-mutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC.
Collapse
Affiliation(s)
- Masato Chiba
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
- Department of Thoracic Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
| | - Yosuke Togashi
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
- Division of Cancer Immunology, EPOC, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
| | - Shuta Tomida
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
- Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan
| | - Hiroshi Mizuuchi
- Department of Thoracic Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
- Department of Thoracic Surgery, Kitakyushu Municipal Medical Center, Kitakyushu, Fukuoka 802-0077, Japan
| | - Yu Nakamura
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
| | - Eri Banno
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
| | - Hidetoshi Hayashi
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
| | - Masato Terashima
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
| | - Marco A. De Velasco
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
| | - Kazuko Sakai
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
| | - Yoshihiko Fujita
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
| | - Tetsuya Mitsudomi
- Department of Thoracic Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
| | - Kazuto Nishio
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
| |
Collapse
|
|
36
|
Affiliation(s)
- Surinder K Jindal
- Jindal Clinics, SCO 21, Dakshin Marg, Sector 20D, Near Guru Ravi Das Bhawan, Chandigarh 160 020, India
| |
Collapse
|
|
37
|
ZNF32 contributes to the induction of multidrug resistance by regulating TGF-β receptor 2 signaling in lung adenocarcinoma. Cell Death Dis 2016; 7:e2428. [PMID: 27763636 PMCID: PMC5133992 DOI: 10.1038/cddis.2016.328] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 09/06/2016] [Accepted: 09/14/2016] [Indexed: 02/05/2023]
Abstract
Multidrug resistance (MDR) is one of the most important contributors to the high mortality of cancer and remains a major concern. We previously found that zinc finger protein 32 (ZNF32), an important transcription factor associated with cancer in Homo sapiens, protects tumor cells against cell death induced by oxidative stress and other stimuli. We thus hypothesized that ZNF32 might enable the tolerance of cancer cells to anti-tumor drugs because higher ZNF32 expression has been found in cancer tissues and in drug-resistant lung adenocarcinoma (AC) cells. In this study, we found that ZNF32 is upregulated by Sp1 (specificity protein 1) in response to drug treatment and that ZNF32 promotes drug resistance and protects AC cells against cisplatin or gefitinib treatment. ZNF32 overexpression in AC cells conferred resistance to EGFR (epidermal growth factor receptor) inhibitors by enhancing MEK/ERK activation. Moreover, ZNF32 was found to directly bind to the TGF-βR2 (transforming growth factor-beta receptor 2) promoter to promote its expression, and ZNF32-induced resistance was mediated by enhancing TGF-βR2 expression and activating the TGF-βR2/SMAD2 pathway. In both a mouse model and ex vivo cultured patient samples, a high level of ZNF32 expression was closely associated with worse overall survival and cisplatin resistance. ZNF32 appears to be a potential inducer of drug resistance that could increase the expression of the drug resistance-associated gene TGF-βR2 and subsequently facilitate the induction of drug resistance during both conventional chemotherapy and novel target therapy. Thus, ZNF32-associated target therapy is a potential novel adjuvant therapy that might effectively prevent the occurrence of multidrug resistance (MDR) during chemotherapy and improve the survival of patients with AC.
Collapse
|
|
38
|
Inhibition of autophagy enhances heat-induced apoptosis in human non-small cell lung cancer cells through ER stress pathways. Arch Biochem Biophys 2016; 607:55-66. [DOI: 10.1016/j.abb.2016.08.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 08/17/2016] [Accepted: 08/22/2016] [Indexed: 12/11/2022]
|
|
39
|
Fernández-López C, Expósito-Hernández J, Arrebola-Moreno JP, Calleja-Hernández MÁ, Expósito-Ruíz M, Guerrero-Tejada R, Linares I, Cabeza-Barrera J. Trends in phase III randomized controlled clinical trials on the treatment of advanced non-small-cell lung cancer. Cancer Med 2016; 5:2190-7. [PMID: 27449070 PMCID: PMC5055155 DOI: 10.1002/cam4.782] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Revised: 04/29/2016] [Accepted: 05/02/2016] [Indexed: 12/02/2022] Open
Abstract
The objective of this review was to analyze trends in outcomes and in the quality of phase III randomized controlled trials on advanced NSCLC published between 2000 and 2012, selecting 76 trials from a total of 122 retrieved in a structured search. Over the study period, the number of randomized patients per trial increased by 14 per year (P = 0.178). The sample size significantly increased between 2000 and 2012 in trials of targeted agents (460.1 vs. 740.8 patients, P = 0.009), trials of >1 drug (360.4 vs. 584.8, P = 0.014), and those including patients with good performance status (675.3 vs. 425.6; P = 0.003). Quality of life was assessed in 46 trials (60.5%), and significant improvements were reported in 10 of these (21.7%). Platinum-based regimens were the most frequently investigated (86.8% of trials). Molecular-targeted agents were studied in 25.0% of chemotherapy arms, and the percentage of trials including these agents increased each year. The median (interquartile range) overall survival (MOS) was 9.90 (3.5) months with an increase of 0.384 months per year of publication (P < 0.001). A statistically significant improvement in MOS was obtained in only 13 (18.8%) trials. The median progression-free survival was 4.9 (1.9) months, with a nonsignificant increase of 0.026 months per year (P > 0.05). There has been a continuous but modest improvement in the survival of patients with advanced NSCLC over the past 12 years. Nevertheless, the quality of clinical trials and the benefit in outcomes should be carefully considered before the incorporation of novel approaches into clinical practice.
Collapse
Affiliation(s)
- Cristina Fernández-López
- Department of Pharmacy, Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada, Granada, Spain.
| | | | | | - Miguel Ángel Calleja-Hernández
- Department of Pharmacy, Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada, Granada, Spain
| | - Manuela Expósito-Ruíz
- Unit Research Support, Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada, Granada, Spain
| | - Rosa Guerrero-Tejada
- Department of Oncology, Virgen de las Nieves Universitary Hospital, Granada, Spain
| | - Isabel Linares
- Department of Oncology, Virgen de las Nieves Universitary Hospital, Granada, Spain
| | - José Cabeza-Barrera
- Department of Pharmacy, Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada, Granada, Spain
| |
Collapse
|
|
40
|
Molecular characterization of pulmonary sarcomatoid carcinoma: analysis of 33 cases. Mod Pathol 2016; 29:824-31. [PMID: 27174587 DOI: 10.1038/modpathol.2016.89] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 04/08/2016] [Accepted: 04/14/2016] [Indexed: 12/12/2022]
Abstract
Several targetable genetic alterations have been found in lung cancer, predominantly in adenocarcinomas, which have led to important therapeutic advancements with the advent of targeted therapy. In contrast, the molecular features and presence of targetable genetic abnormalities in pulmonary sarcomatoid carcinomas are largely unknown. Thirty-three cases of pulmonary sarcomatoid carcinoma were tested for approximately 2800 mutations in 50 oncogenes and tumor-suppressor genes, including EGFR, KRAS, NRAS, TP53, BRAF, ERBB2, JAK3, AKT1, ATM, MET, KIT, and PIK3CA. ALK immunostaining was performed, and ALK FISH was performed on cases with any degree of staining. Twenty-four of the 33 cases (72%) had at least one genetic abnormality: 19 cases (58%) had TP53 mutations; 10 cases (30%) had KRAS mutations; AKT1, JAK3, BRAF, NRAS, and PIK3CA mutations were observed in 1 case each (3%). Six of the 19 cases (32%) with a mutation in TP53 had simultaneous mutations in KRAS (18%). The cases with alterations in JAK3, BRAF, and NRAS also had mutations in TP53. The case showing a mutation in PIK3CA had a mutation in KRAS. No EGFR mutations were observed. One case had ALK gene rearrangement. ALK rearrangement was observed in a single case of sarcomatoid carcinoma (3%), which has currently available targeted therapy. Four tumors had mutations in genes with experimental molecular-based therapy, including BRAF, NRAS, PIK3CA, and AKT1. Testing for targetable mutations should be considered for patients with pulmonary sarcomatoid carcinoma, as a subset may benefit from currently approved drugs or clinical trials of novel therapeutic options available for other types of lung cancer.
Collapse
|
|
41
|
Chen X, Tong ZK, Zhou JY, Yao YK, Zhang SM, Zhou JY. MicroRNA-206 inhibits the viability and migration of human lung adenocarcinoma cells partly by targeting MET. Oncol Lett 2016; 12:1171-1177. [PMID: 27446414 DOI: 10.3892/ol.2016.4735] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 05/13/2016] [Indexed: 01/21/2023] Open
Abstract
MicroRNA (miRNA)-based targeting in cancer has emerged as a potential therapeutic strategy. miR-206 has recently been implicated in cancer. However, the role and molecular mechanism of miR-206 in lung adenocarcinoma are still unclear. The present study revealed that miR-206 was downregulated in human lung adenocarcinoma tissues. Overexpression of miR-206 in human lung adenocarcinoma-derived cells significantly inhibited cell viability and migration. Further experiments indicated that the overexpression of miR-206 decreased the expression of MET at the messenger RNA and protein levels via direct targeting of MET in a 3'-untranslated region-dependent manner. The knockdown of MET by small interfering RNA partly led to a phenocopy effect of miR-206. In conclusion, the present study identified miR-206 as a potential tumor suppressor of lung adenocarcinoma that exerts its functions, in part, by negative regulation of MET.
Collapse
Affiliation(s)
- Xi Chen
- Department of Respiratory Diseases, Thoracic Disease Diagnosis and Treatment Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Zhong-Kai Tong
- Department of Respiratory Diseases, Thoracic Disease Diagnosis and Treatment Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Jian-Ya Zhou
- Department of Respiratory Diseases, Thoracic Disease Diagnosis and Treatment Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Ya-Ke Yao
- Department of Respiratory Diseases, Thoracic Disease Diagnosis and Treatment Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Shu-Meng Zhang
- Department of Respiratory Diseases, Thoracic Disease Diagnosis and Treatment Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Jian-Ying Zhou
- Department of Respiratory Diseases, Thoracic Disease Diagnosis and Treatment Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| |
Collapse
|
|
42
|
Gultekin SE, Senguven B, Isik Gonul I, Okur B, Buettner R. Unusual Presentation of an Adenocarcinoma of the Lung Metastasizing to the Mandible, Including Molecular Analysis and a Review of the Literature. J Oral Maxillofac Surg 2016; 74:2007.e1-8. [PMID: 27376181 DOI: 10.1016/j.joms.2016.06.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 06/03/2016] [Accepted: 06/03/2016] [Indexed: 02/07/2023]
Abstract
Lung cancer is the most frequent cause of cancer-related death worldwide. Metastases of non-small cell lung carcinoma to the oral and maxillofacial region are rare. Thus, the diagnosis of a metastatic lesion in the oral cavity is challenging to the clinician and to the pathologist. This report presents a case of a 72-year-old man with metastatic lung adenocarcinoma located in the posterior mandibular region. Next-generation sequencing analysis showed no important mutations in the relevant genes except in the TP53 tumor suppressor gene.
Collapse
Affiliation(s)
- Sibel Elif Gultekin
- Professor and Department Head, Department of Oral Pathology, Faculty of Dentistry, Gazi University, Ankara, Turkey
| | - Burcu Senguven
- Associate Professor, Department of Oral Pathology, Faculty of Dentistry, Gazi University, Ankara, Turkey.
| | - Ipek Isik Gonul
- Associate Professor, Department of Pathology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Begum Okur
- PhD Student, Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Gazi University, Ankara, Turkey
| | - Reinhard Buettner
- Professor and Department Head, Department of Pathology, Faculty of Medicine, University of Cologne, Cologne, Germany
| |
Collapse
|
|
43
|
Kropski JA, Lawson WE, Blackwell TS. Personalizing Therapy in Idiopathic Pulmonary Fibrosis: A Glimpse of the Future? Am J Respir Crit Care Med 2016; 192:1409-11. [PMID: 26669470 DOI: 10.1164/rccm.201509-1789ed] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Jonathan A Kropski
- 1 Department of Medicine Vanderbilt University School of Medicine Nashville, Tennessee
| | - William E Lawson
- 1 Department of Medicine Vanderbilt University School of Medicine Nashville, Tennessee.,2 Department of Veterans Affairs Medical Center Nashville, Tennessee
| | - Timothy S Blackwell
- 1 Department of Medicine Vanderbilt University School of Medicine Nashville, Tennessee.,2 Department of Veterans Affairs Medical Center Nashville, Tennessee.,3 Department of Cell and Developmental Biology and.,4 Department of Cancer Biology Vanderbilt University School of Medicine Nashville, Tennessee
| |
Collapse
|
|
44
|
Yano T, Soejima Y, Sawabe M. Application of low vacuum scanning electron microscopy for Papanicolaou-stained slides for cytopathology examinations. Microscopy (Oxf) 2016; 65:269-73. [PMID: 26957591 DOI: 10.1093/jmicro/dfw005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 02/04/2016] [Indexed: 11/13/2022] Open
Abstract
Papanicolaou (Pap)-stained slides are usually observed using a transmitted light microscope for cytopathology. However, progress in pathological examinations has created a need for new diagnostic tools, because cytopathological preparations do not allow additional examinations without a loss of specimen, unlike histopathology. Low-vacuum scanning electron microscopy (LVSEM) can reveal the surface topography at an ultrastructual resolution without metal coating. The aim of this study was to determine the conditions required for observing Pap-stained slides of oral smears using LVSEM without any loss of specimen and to reexamine the same slides again using light microscopy, while preserving the cytopathological information.
Collapse
Affiliation(s)
- Tetsuya Yano
- Electron Microscope Laboratory, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
| | - Yurie Soejima
- Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
| | - Motoji Sawabe
- Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
| |
Collapse
|
|
45
|
Terashima M, Togashi Y, Sato K, Mizuuchi H, Sakai K, Suda K, Nakamura Y, Banno E, Hayashi H, De Velasco MA, Fujita Y, Tomida S, Mitsudomi T, Nishio K. Functional Analyses of Mutations in Receptor Tyrosine Kinase Genes in Non-Small Cell Lung Cancer: Double-Edged Sword of DDR2. Clin Cancer Res 2016; 22:3663-71. [PMID: 26826182 DOI: 10.1158/1078-0432.ccr-15-2093] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 01/23/2016] [Indexed: 11/16/2022]
Abstract
PURPOSE This study investigated whether mutations of receptor tyrosine kinase (RTK) genes detected using next-generation sequencing (NGS) are suitable therapeutic targets. EXPERIMENTAL DESIGN Fifty surgically resected non-small cell lung cancer (NSCLC) samples were target resequenced using NGS. We then investigated the functions of the identified RTK gene mutations, including their oncogenic potential, in vitro RESULTS Mutations in RTK genes were found in 20 samples (EGFR, 15; ERBB4, 1; ALK, 1; DDR2, 2; FGFR1, 1), mutations in MAPK pathway genes were found in nine samples (KRAS, 7; NRAS, 1; BRAF, 2), and mutations in PI3K pathway genes were found in three samples (PIK3CA, 1; PTEN, 3). Among the mutations in RTKs, the functions of four mutations were unclear (ERBB4 D245G; DDR2 H246R and E655K; FGFR1 A263V). These mutations did not exhibit any transformational activities. Neither the phosphorylation nor the protein expressions of RTKs were changed by the DDR2 H246R, ERBB4 D245G, and FGFR1 A263V mutations, although the expression level of the DDR2 protein harboring the E655K mutation was particularly low. Collagen stimulation decreased cellular proliferation through p38 activation in the DDR2 wild-type-overexpressed cell lines, whereas the growth-suppressive effect was weakened in DDR2 E655K-overexpressed cell lines. Furthermore, the DDR2 E655K protein strongly bound to ubiquitin ligase E3 (Cbl-b), and the mutant protein expression was increased after treatment with a proteasome inhibitor. CONCLUSIONS Our experimental findings suggest that RTK mutations are not always suitable as therapeutic targets. The DDR2 E655K mutation can play a role in cancer progression by reducing the growth-inhibitory effect of collagen. Clin Cancer Res; 22(14); 3663-71. ©2016 AACR.
Collapse
Affiliation(s)
- Masato Terashima
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan
| | - Yosuke Togashi
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan
| | - Katsuaki Sato
- Thoracic Surgery, Kinki University Faculty of Medicine, Osaka, Japan
| | - Hiroshi Mizuuchi
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan. Thoracic Surgery, Kinki University Faculty of Medicine, Osaka, Japan
| | - Kazuko Sakai
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan
| | - Kenichi Suda
- Thoracic Surgery, Kinki University Faculty of Medicine, Osaka, Japan
| | - Yu Nakamura
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan
| | - Eri Banno
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan
| | - Hidetoshi Hayashi
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan
| | - Marco A De Velasco
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan
| | - Yoshihiko Fujita
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan
| | - Shuta Tomida
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan
| | - Tetsuya Mitsudomi
- Thoracic Surgery, Kinki University Faculty of Medicine, Osaka, Japan
| | - Kazuto Nishio
- Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan.
| |
Collapse
|
|
46
|
Ashton-Prolla P, Goldim JR, Vairo FPE, da Silveira Matte U, Sequeiros J. Genomic analysis in the clinic: benefits and challenges for health care professionals and patients in Brazil. J Community Genet 2015; 6:275-83. [PMID: 26040235 PMCID: PMC4524873 DOI: 10.1007/s12687-015-0238-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2015] [Accepted: 05/13/2015] [Indexed: 12/20/2022] Open
Abstract
Despite significant advances in the diagnosis and treatment of genetic diseases in the last two decades, there is still a significant proportion where a causative mutation cannot be identified and a definitive genetic diagnosis remains elusive. New genome-wide or high-throughput multiple gene tests have brought new hope to the field, since they can offer fast, cost-effective and comprehensive analysis of genetic variation. This is particularly interesting in disorders with high genetic heterogeneity. There are, however, limitations and concerns regarding the implementation of genomic analysis in everyday clinical practice, including some particular to emerging and developing economies, as Brazil. They include the limited number of actionable genetic variants known to date, difficulties in determining the clinical validity and utility of novel variants, growth of direct-to-consumer genetic testing using a genomic approach and lack of proper training of health care professionals to adequately request, interpret and use genetic information. Despite all these concerns and limitations, the availability of genomic tests has grown at an extremely rapid pace and commercially available services include initiatives in almost all areas of clinical genetics, including newborn and carrier screening. We discuss the benefits and limitations of genomic testing, as well as the ethical implications and the challenges for genetic education and enough available and qualified health care professionals, to ensure the adequate process of informed consent, meaningful interpretation and use of genomic data and definition of a clear regulatory framework in the particular context of Brazil.
Collapse
Affiliation(s)
- Patrícia Ashton-Prolla
- Serviço de Genetica Medica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil,
| | | | | | | | | |
Collapse
|