scholarly journals Epigenetic Reprogramming of Tumor-Associated Fibroblasts in Lung Cancer: Therapeutic Opportunities

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3782
Author(s):  
Jordi Alcaraz ◽  
Rafael Ikemori ◽  
Alejandro Llorente ◽  
Natalia Díaz-Valdivia ◽  
Noemí Reguart ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transcriptional Repression ◽  
Epigenetic Reprogramming ◽  
Environmental Cues ◽  
Special Focus ◽  
Dna Hypomethylation ◽  
Desmoplastic Stroma ◽  
Cancer Types ◽  
Key Steps ◽  
Histone Core

Lung cancer is the leading cause of cancer-related death worldwide. The desmoplastic stroma of lung cancer and other solid tumors is rich in tumor-associated fibroblasts (TAFs) exhibiting an activated/myofibroblast-like phenotype. There is growing awareness that TAFs support key steps of tumor progression and are epigenetically reprogrammed compared to healthy fibroblasts. Although the mechanisms underlying such epigenetic reprogramming are incompletely understood, there is increasing evidence that they involve interactions with either cancer cells, pro-fibrotic cytokines such as TGF-β, the stiffening of the surrounding extracellular matrix, smoking cigarette particles and other environmental cues. These aberrant interactions elicit a global DNA hypomethylation and a selective transcriptional repression through hypermethylation of the TGF-β transcription factor SMAD3 in lung TAFs. Likewise, similar DNA methylation changes have been reported in TAFs from other cancer types, as well as histone core modifications and altered microRNA expression. In this review we summarize the evidence of the epigenetic reprogramming of TAFs, how this reprogramming contributes to the acquisition and maintenance of a tumor-promoting phenotype, and how it provides novel venues for therapeutic intervention, with a special focus on lung TAFs.

scholarly journals Cyclovirobuxine D Induced-Mitophagy through the p65/BNIP3/LC3 Axis Potentiates Its Apoptosis-Inducing Effects in Lung Cancer Cells

2021 ◽  
Vol 22 (11) ◽  
pp. 5820
Author(s):  
Cheng Zeng ◽  
Tingting Zou ◽  
Junyan Qu ◽  
Xu Chen ◽  
Suping Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Transcriptional Repression ◽  
Therapeutic Strategy ◽  
Ectopic Expression ◽  
Lung Cancer Cells ◽  
Lung Cancer Patients ◽  
Cellular Context ◽  
Subcutaneous Xenograft ◽  
Buxus Microphylla

Mitophagy plays a pro-survival or pro-death role that is cellular-context- and stress-condition-dependent. In this study, we revealed that cyclovirobuxine D (CVB-D), a natural compound derived from Buxus microphylla, was able to provoke mitophagy in lung cancer cells. CVB-D-induced mitophagy potentiates apoptosis by promoting mitochondrial dysfunction. Mechanistically, CVB-D initiates mitophagy by enhancing the expression of the mitophagy receptor BNIP3 and strengthening its interaction with LC3 to provoke mitophagy. Our results further showed that p65, a transcriptional suppressor of BNIP3, is downregulated upon CVB-D treatment. The ectopic expression of p65 inhibits BNIP3 expression, while its knockdown significantly abolishes its transcriptional repression on BNIP3 upon CVB-D treatment. Importantly, nude mice bearing subcutaneous xenograft tumors presented retarded growth upon CVB-D treatment. Overall, we demonstrated that CVB-D treatment can provoke mitophagy and further revealed that the p65/BNIP3/LC3 axis is one potential mechanism involved in CVB-D-induced mitophagy in lung cancer cells, thus providing an effective antitumor therapeutic strategy for the treatment of lung cancer patients

scholarly journals 77 Prevalence of secondary immunotherapeutic targets in the absence of established immune biomarkers in solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A86-A86
Author(s):  
Paul DePietro ◽  
Mary Nesline ◽  
Yong Hee Lee ◽  
RJ Seager ◽  
Erik Van Roey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Reference Population ◽  
List Type ◽  
Tumor Type ◽  
Genomic Profiling ◽  
Rna Seq ◽  
Immune Biomarkers ◽  
Cancer Types ◽  
Immune Related Genes

BackgroundImmune checkpoint inhibitor-based therapies have achieved impressive success in the treatment of several cancer types. Predictive immune biomarkers, including PD-L1, MSI and TMB are well established as surrogate markers for immune evasion and tumor-specific neoantigens across many tumors. Positive detection across cancer types varies, but overall ~50% of patients test negative for these primary immune markers.1 In this study, we investigated the prevalence of secondary immune biomarkers outside of PD-L1, TMB and MSI.MethodsComprehensive genomic and immune profiling, including PD-L1 IHC, TMB, MSI and gene expression of 395 immune related genes was performed on 6078 FFPE tumors representing 34 cancer types, predominantly composed of lung cancer (36.7%), colorectal cancer (11.9%) and breast cancer (8.5%). Expression levels by RNA-seq of 36 genes targeted by immunotherapies in solid tumor clinical trials, identified as secondary immune biomarkers, were ranked against a reference population. Genes with a rank value ≥75th percentile were considered high and values were associated with PD-L1 (positive ≥1%), MSI (MSI-H or MSS) and TMB (high ≥10 Mut/Mb) status. Additionally, secondary immune biomarker status was segmented by tumor type and cancer immune cycle roles.ResultsIn total, 41.0% of cases were PD-L1+, 6.4% TMB+, and 0.1% MSI-H. 12.6% of cases were positive for >2 of these markers while 39.9% were triple negative (PD-L1-/TMB-/MSS). Of the PD-L1-/TMB-/MSS cases, 89.1% were high for at least one secondary immune biomarker, with 69.3% having ≥3 markers. PD-L1-/TMB-/MSS tumor types with ≥50% prevalence of high secondary immune biomarkers included brain, prostate, kidney, sarcoma, gallbladder, breast, colorectal, and liver cancer. High expression of cancer testis antigen secondary immune biomarkers (e.g., NY-ESO-1, LAGE-1A, MAGE-A4) was most commonly observed in bladder, ovarian, sarcoma, liver, and prostate cancer (≥15%). Tumors demonstrating T-cell priming (e.g., CD40, OX40, CD137), trafficking (e.g., TGFB1, TLR9, TNF) and/or recognition (e.g., CTLA4, LAG3, TIGIT) secondary immune biomarkers were most represented by kidney, gallbladder, and sarcoma (≥40%), with melanoma, esophageal, head & neck, cervical, stomach, and lung cancer least represented (≥15%).ConclusionsOur studies show comprehensive tumor profiling that includes gene expression can detect secondary immune biomarkers targeted by investigational therapies in ~90% of PD-L1-/TMB-/MSS cases. While genomic profiling could also provide therapeutic choices for a percentage of these patients, detection of secondary immune biomarkers by RNA-seq provides additional options for patients without a clear therapeutic path as determined by PD-L1 testing and genomic profiling alone.ReferenceHuang R S P, Haberberger J, Severson E, et al. A pan-cancer analysis of PD-L1 immunohistochemistry and gene amplification, tumor mutation burden and microsatellite instability in 48,782 cases. Mod Pathol 2021;34: 252–263.

scholarly journals Automated Classification of Lung Cancer Types from Cytological Images Using Deep Convolutional Neural Networks

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Atsushi Teramoto ◽  
Tetsuya Tsukamoto ◽  
Yuka Kiriyama ◽  
Hiroshi Fujita
Keyword(s):  
Lung Cancer ◽  
Cell Carcinoma ◽  
Graphics Processing Unit ◽  
Processing Unit ◽  
Automated Classification ◽  
Deep Convolutional Neural Networks ◽  
Lung Cancers ◽  
Microscopic Images ◽  
Cancer Types

Lung cancer is a leading cause of death worldwide. Currently, in differential diagnosis of lung cancer, accurate classification of cancer types (adenocarcinoma, squamous cell carcinoma, and small cell carcinoma) is required. However, improving the accuracy and stability of diagnosis is challenging. In this study, we developed an automated classification scheme for lung cancers presented in microscopic images using a deep convolutional neural network (DCNN), which is a major deep learning technique. The DCNN used for classification consists of three convolutional layers, three pooling layers, and two fully connected layers. In evaluation experiments conducted, the DCNN was trained using our original database with a graphics processing unit. Microscopic images were first cropped and resampled to obtain images with resolution of 256 × 256 pixels and, to prevent overfitting, collected images were augmented via rotation, flipping, and filtering. The probabilities of three types of cancers were estimated using the developed scheme and its classification accuracy was evaluated using threefold cross validation. In the results obtained, approximately 71% of the images were classified correctly, which is on par with the accuracy of cytotechnologists and pathologists. Thus, the developed scheme is useful for classification of lung cancers from microscopic images.

scholarly journals Plant Defenses Against Tetranychus urticae: Mind the Gaps

Plants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 464
Author(s):  
M. Estrella Santamaria ◽  
Ana Arnaiz ◽  
Irene Rosa-Diaz ◽  
Pablo González-Melendi ◽  
Gara Romero-Hernandez ◽  
...  
Keyword(s):  
Tetranychus Urticae ◽  
Molecular Interactions ◽  
Plant Defenses ◽  
Special Focus ◽  
Model Species ◽  
Defense Compounds ◽  
Whole Process ◽  
Molecular Events ◽  
Two Spotted Spider Mite ◽  
Key Steps

The molecular interactions between a pest and its host plant are the consequence of an evolutionary arms race based on the perception of the phytophagous arthropod by the plant and the different strategies adopted by the pest to overcome plant triggered defenses. The complexity and the different levels of these interactions make it difficult to get a wide knowledge of the whole process. Extensive research in model species is an accurate way to progressively move forward in this direction. The two-spotted spider mite, Tetranychus urticae Koch has become a model species for phytophagous mites due to the development of a great number of genetic tools and a high-quality genome sequence. This review is an update of the current state of the art in the molecular interactions between the generalist pest T. urticae and its host plants. The knowledge of the physical and chemical constitutive defenses of the plant and the mechanisms involved in the induction of plant defenses are summarized. The molecular events produced from plant perception to the synthesis of defense compounds are detailed, with a special focus on the key steps that are little or totally uncovered by previous research.

scholarly journals IMS2 – An integrated medical software system for early lung cancer detection using ion mobility spectrometry data of human breath

2007 ◽  
Vol 4 (3) ◽  
pp. 186-197 ◽  
Author(s):  
Jan Baumbach ◽  
Alexander Bunkowski ◽  
Sita Lange ◽  
Timm Oberwahrenbrock ◽  
Nils Kleinbölting ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Ion Mobility Spectrometry ◽  
Ion Mobility ◽  
Software System ◽  
Medical Software ◽  
Cancer Types ◽  
The One ◽  
Lung Cancer Detection ◽  
Processing Steps ◽  
Fold Cross Validation

Abstract IMS2 is an Integrated Medical Software system for the analysis of Ion Mobility Spectrometry (IMS) data. It assists medical staff with the following IMS data processing steps: acquisition, visualization, classification, and annotation. IMS2 provides data analysis and interpretation features on the one hand, and also helps to improve the classification by increasing the number of the pre-classified datasets on the other hand. It is designed to facilitate early detection of lung cancer, one of the most common cancer types with one million deaths each year around the world.After reviewing the IMS technology, we first describe the software architecture of IMS2 and then the integrated classification module, including necessary pre-processing steps and different classification methods. The Lung Hospital Hemer (Germany) provided IMS data of 35 patients suffering from lung cancer and 72 samples of healthy persons. IMS2 correctly classifies 99% of the samples, evaluated using 10-fold cross-validation.

scholarly journals Radiation-Stimulated Epigenetic Reprogramming of Adaptive-Response Genes in the Lung: An Evolutionary Gift for Mounting Adaptive Protection against Lung Cancer

Dose-Response ◽  
2008 ◽  
Vol 7 (2) ◽  
pp. dose-response.0 ◽  
Author(s):  
Bobby R. Scott ◽  
Steven A. Belinsky ◽  
Shuguang Leng ◽  
Yong Lin ◽  
Julie A. Wilder ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adaptive Response ◽  
Risk Model ◽  
Epigenetic Reprogramming ◽  
Histone Deacetylation ◽  
Early Years ◽  
High Dose ◽  
Alpha Radiation ◽  
Adaptive Protection ◽  
Radiation Induced

Humans are continuously exposed to low-level ionizing radiation from natural sources. However, harsher radiation environments persisted during our planet's early years and mammals survived via an evolutionary gift - a system of radiation-induced natural protective measures (adaptive protection). This system includes antioxidants, DNA repair, apoptosis of severely damaged cells, epigenetically regulated apoptosis ( epiapoptosis) pathways that selectively remove precancerous and other aberrant cells, and immunity against cancer. We propose a novel model in which the protective system is regulated at least in part via radiation-stress-stimulated epigenetic reprogramming (epireprogramming) of adaptive-response genes. High-dose radiation can promote epigenetically silencing of adaptive-response genes ( episilencing), for example via promoter-associated DNA and/or histone methylation and/or histone deacetylation. Evidence is provided for low linear-energy-transfer (LET) radiation-activated natural protection (ANP) against high-LET alpha-radiation-induced lung cancer in plutonium-239 exposed rats and radon-progeny-exposed humans. Using a revised hormetic relative risk model for cancer induction that accounts for both epigenetic activation ( epiactivation) and episilencing of genes, we demonstrate that, on average, >80% of alpha-radiation-induced rat lung cancers were prevented by chronic, low-rate gamma-ray ANP. Interestingly, lifetime exposure to residential radon at the Environmental Protection Agency's action level of 4 pCi L−1 appears to be associated with on average a > 60% reduction in lung cancer cases, rather than an increase. We have used underlined italics to indicate newly introduced terminology.

scholarly journals Antibiotic Consumption Patterns in European Countries May Be Associated with the Incidence of Major Carcinomas

Antibiotics ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 643
Author(s):  
Gábor Ternák ◽  
Károly Berényi ◽  
András Sümegi ◽  
Ágnes Szenczi ◽  
Barbara Fodor ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Incidence Rate ◽  
Broad Spectrum ◽  
Pearson Correlation ◽  
Antibiotic Consumption ◽  
European Countries ◽  
Intestinal Microbiome ◽  
Consumption Pattern ◽  
Cancer Prevalence ◽  
Cancer Types

The possible role of the altered intestinal microbiome in the development of malignancies has been raised recently in several publications. Among external factors, antibiotics are considered to be the most important agent capable of producing dysbiosis in the gut flora, either temporally or permanently. The human microbiome has several beneficial effects in terms of maintaining appropriate human health, but its alteration has been implicated in the development of many illnesses. Our basic aim was to explore a possible relationship between the consumption of different antibiotic classes and the incidence of the most common cancer types (male, female) in European countries. A database of the average, yearly antibiotic consumption (1997–2018) has been developed and the consumption figures were compared to the eight, most frequent cancer incidence calculated for 2018 in 30 European countries. Pearson correlation has indicated different degrees of positive (supportive) and negative (inhibitor) significant associations between antibiotic consumption figures and cancer prevalence. It has been observed that certain antibiotic classes with positive correlation probably augment the incidence of certain cancer types, while others, with negative correlation, may show some inhibitory effect. The relatively higher or lower consumption pattern of different classes of antibiotics could be related to certain cancer prevalence figures in different European countries. Our results indicated that countries with relatively high consumption of narrow-spectrum penicillin (J01CE, J01CF) and tetracycline (J01A), like certain Scandinavian countries, showed a higher incidence of female colorectal cancer, female lung cancer, melanoma, breast, prostate and uterus corpus cancer. Countries with relatively higher consumption of broad-spectrum penicillin (J01CA, J01CR) and some broad-spectrum antibiotics (J01D, J01F, J01M), like Greece, Hungary, Slovakia, France, etc. showed a higher incidence rate of male lung cancer and male bladder cancer. The higher incidence rate of different cancer types showed association with the higher consumption of antibiotics with “augmenting” properties and with less consumption of antibiotics with “inhibitory” properties.

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