scholarly journals XPC-Related Protection Against Carcinogen-Induced Lung Adenocarcinoma is Independent of Lung Inflammation

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Isaac Lamb ◽  
Huaxin Zhou ◽  
Patricia Smith ◽  
Catherine R. Sears, M.D.
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Squamous Cell ◽  
Critical Role ◽  
Genotypic Variation ◽  
Lung Carcinogenesis ◽  
Local Inflammation ◽  
Develop Lung Cancer ◽  
Lung Cancers ◽  
Tnf Α

Background and Hypothesis: Cigarette smoke (CS) exposure causes lung cancer, with both DNA damage and local inflammation playing a critical role in development. Our previous research links the DNA repair protein Xeroderma Pigmentosum Group C (XPC) with protection against lung cancer in CS- and carcinogen-exposed mouse models. In mice (XPC-deficient and wild-type [WT] littermates) exposed to continuous CS for 9 months, neither XPC-deficient nor WT mice develop lung cancer. XPC-deficient but not WT mice exposed to 5 months CS + 4 months air control (AC) (recovery model) develop lung cancer. In a direct carcinogen model, XPC-deficiency accelerates NTCU lung squamous cell development. Our hypothesis is that lung cancers in XPC-deficient mice are independent of treatment alterations in BAL inflammation. Experimental Design or Project Methods: Acellular bronchoalveolar lavage (BAL) samples from the three different mouse CS and carcinogen models were analyzed for the inflammatory cytokines IL-6, IL10, IL-12p70, IL-17A, IFN-γ, MCP-1, and TNF-α by a cytometric bead array (BD Biosciences) using a flow cytometer (FACScan) according to the manufacturer’s instructions. Raw data (mean fluorescence intensity) was analyzed by BD CBA Software. Statistical comparisons were by ANOVA, with p<0.05 considered significant. Results: All measured cytokine levels were low or undetectable in BAL from AC and CS mice, with no significant XPC genotype or treatment-related changes in the measured cytokines. Differences were observed in TNF-α and IL-6 between continuous and recovery CS models independent of treatment or genotype. NTCU caused a significant increase in BAL IL-6 independent of genotype. IL-17a was elevated in NTCU-treated mice that developed lung squamous cell carcinoma. Conclusion and Potential Impact: The XPC genotypic variation seen in lung carcinogenesis appears to be independent of BAL cytokines, suggesting that the variation is due to DNA damage rather than differences in local inflammation. Further mechanistic investigations will focus on DNA damage and repair as drivers of XPC-deficient lung cancers.  

scholarly journals The chemokine CXCL13 in lung cancers associated with environmental polycyclic aromatic hydrocarbons pollution

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Gui-Zhen Wang ◽  
Xin Cheng ◽  
Bo Zhou ◽  
Zhe-Sheng Wen ◽  
Yun-Chao Huang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Polycyclic Aromatic Hydrocarbons ◽  
Cigarette Smoke ◽  
Aromatic Hydrocarbons ◽  
Critical Role ◽  
Lung Epithelial Cells ◽  
Lung Carcinogenesis ◽  
Lung Cancers ◽  
Polycyclic Aromatic ◽  
Smoky Coal

More than 90% of lung cancers are caused by cigarette smoke and air pollution, with polycyclic aromatic hydrocarbons (PAHs) as key carcinogens. In Xuanwei City of Yunnan Province, the lung cancer incidence is among the highest in China, attributed to smoky coal combustion-generated PAH pollution. Here, we screened for abnormal inflammatory factors in non-small cell lung cancers (NSCLCs) from Xuanwei and control regions (CR) where smoky coal was not used, and found that a chemokine CXCL13 was overexpressed in 63/70 (90%) of Xuanwei NSCLCs and 44/71 (62%) of smoker and 27/60 (45%) of non-smoker CR patients. CXCL13 overexpression was associated with the region Xuanwei and cigarette smoke. The key carcinogen benzo(a)pyrene (BaP) induced CXCL13 production in lung epithelial cells and in mice prior to development of detectable lung cancer. Deficiency in Cxcl13 or its receptor, Cxcr5, significantly attenuated BaP-induced lung cancer in mice, demonstrating CXCL13’s critical role in PAH-induced lung carcinogenesis.

DO PROINFLAMMATORY CYTOKINES SERVE AS DIAGNOSTIC OR PROGNOSTIC INDICATORS FOR TUMOR TYPE, STAGE, SIZE, STANDARDIZED UPTAKE VALUE, AND LYMPHOVASCULAR INVASION IN LUNG CANCER?

2021 ◽  
pp. 203-208
Author(s):  
Nilgün Kanlıoğlu Kuman ◽  
Leyla Didem Kozacı ◽  
Serdar Şen ◽  
Ekrem Şentürk ◽  
Salih Çokpınar ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lymphovascular Invasion ◽  
Standardized Uptake Value ◽  
Histological Type ◽  
Prognostic Indicators ◽  
Tumor Type ◽  
Acute Phase Reactants ◽  
Lung Cancers ◽  
Tnf Α ◽  
Type Size

Objectives: The number of human studies on the association and clinical signicance of alterations in IL-6, sP-Selectin, TNF-α, BNP-32, or procalcitonin (PCT) in lung cancer is small. We aimed to investigate the alterations of proinammatory cytokines and acute-phase reactants in blood and pleural uid and determine their clinical diagnostic or prognostic signicances regarding tumor type, stage, size, standardized uptake value (SUV), and lymphovascular invasion (LVI). Methods: Levels of IL-6, TNF-α, BNP-32, PCT, and sP-selectin were evaluated in blood samples st th st th th obtained preoperatively and postoperatively on 1 , 6 hours and 1 , 4 , and seven days. They also were evaluated in pleural st uid samples obtained postoperatively on 1 hour, and rst and fourth days. These results were analyzed according to the cell type, size, stage, SUV, and LVI of lung cancer. IL-6 values in plasma and pleural uid had Results: various signicant relationships and correlations with histological type, diameter, SUV, stage, and LVI of the tumor. TNF-α values in plasma or pleural uid had signicant relationships with LVI only. PCT values in plasma or pleural uid had signicant relationships with the tumor's diameter, SUV, and LVI. BNP-32 values in plasma or pleural uid had signicant relationships with histological type and SUV of the tumor. sP-Selectin values in plasma or pleural uid had signicant relationships with the stage and SUV of the tumor. We determined various signicant associations and correlations of proinammatory cytokines wi Conclusions: th histological type, size, stage, LVI, and SUV of lung cancer. Studies on this subject would serve to develop diagnostic and prognostic methods in lung cancers.

Systematic approach for development of new immunotherapeutics for lung cancers through cancer genomics analysis.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3092-3092
Author(s):  
Yataro Daigo ◽  
Atsushi Takano ◽  
Yusuke Nakamura
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Clinical Studies ◽  
Critical Role ◽  
Phase I Clinical Trials ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
High Immunogenicity

3092 Background: Oncoantigens are defined to be proteins that are very specifically expressed in cancer cells and that have the oncogenic activity and high immunogenicity, and are considered to be promising targets for immunotherapy such as therapeutic cancer vaccines. Methods: We have established a strategy as follows to identify new oncoantigens; i) screening of highly transactivated genes in the majority of 120 lung cancers using cDNA microarray representing 27,648 genes coupled with enrichment of tumor cells by laser microdissection, ii) verification of no expression of each candidate gene in normal tissues by northern-blot analysis, iii) validation of the clinicopathological significance of its high level of expression with tissue microarray containing 300 lung cancers, iv) verification of a critical role of each gene in the growth or invasiveness of cancer cells by RNAi and cell growth/invasion assays, v) screening of the epitope peptides recognized by HLA-A*0201- or A*2402-restricted cytotoxic T lymphocyte (CTL). We conducted phase I clinical trials of these therapeutic peptide vaccines for lung cancer patients. Results: We identified 35 oncoantigens and screened dozens of 10-amino-acid peptides, each of which corresponded to a part of TTK, LY6K, IMP-3, CDCA1, KIF20A, CDC45L, and FOXM1, and was a candidate to be presented on the surface of HLA-A*0201 or HLA-A*2402 that induced in vitro CTL response. Phase I clinical studies indicated that five epitope peptides could strongly induce the CTL activity in cancer patients. For example, we conducted a phase I study for HLA-A*2402-positive, advanced non-small cell lung cancer patients who failed to standard therapy, using the combination of 1, 2 or 3 mg/body of each peptides from LY6K, CDCA1, and KIF20A mixed with adjuvant once a week. This cancer vaccine therapy demonstrated tolerability and had very high immunogenicity of even 1 mg/body dose to induce antigen-specific CTLs in cancer patients. Conclusions: Through systematic genomics-based approach and clinical study, we have identified five epitope peptides, which could induce CTLs very effectively in cancer patients, and therefore it warrants further clinical studies. Clinical trial information: NCT01069575.

scholarly journals Pathological and Prognostic Indications of the mdig Gene in Human Lung Cancer

2021 ◽  
Vol 55 (S2) ◽  
pp. 13-28
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Lung Squamous Cell Carcinoma ◽  
Human Lung Cancer ◽  
Clinical Samples ◽  
Lung Carcinogenesis ◽  
Expression Status

Background/Aims: The mineral-dust-induced gene mdig is a lung-cancer-associated oncogene. The focus of this study is to evaluate the expression status of mdig in lung cancer and to assess its influence in predicting the patient’s overall survival. Methods: Using high-density tissue microarrays and clinical samples of synchronous multiple primary lung cancer (SMPLC), we investigated the expression of mdig through immunohistochemistry and utilized the open-access lung cancer patient databases containing genomic and transcriptomic data from the UCSC Xena and TCGA web platforms to determine the prognostic values of mdig expression status among different subtypes of lung cancer. Results: mdig is upregulated in smokers and in lung squamous cell carcinoma. High mdig expression predicted poor overall survival in lung squamous cell carcinoma and female smokers. Among tumor tissues from SMPLC patients, we not only unraveled the highest positive rate of mdig expression, but also revealed a unique cytoplasmic, rather than nuclear localization of mdig protein. Furthermore, by inspecting some pathological but not cancerous lung tissues, we believe that mdig is required for the transformation of non-cancerous lung cells to the fully-fledged cancer cells. Conclusion: These data suggested that mdig is involved in various stages of lung carcinogenesis, possibly through the epigenetic regulation on some critical cancer-associated genes, and increased mdig expression is an important prognostic factor for some types of lung cancer.

scholarly journals The Regulators Associated With N6-Methyladenosine in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma Reveal New Clinical and Prognostic Markers

2021 ◽  
Vol 9 ◽  
Author(s):  
Shuzhen Tan ◽  
Zesong Li ◽  
Kai Li ◽  
Yingqi Li ◽  
Guosheng Liang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Squamous Cell Carcinoma ◽  
Lung Adenocarcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Prognostic Markers ◽  
Cox Regression ◽  
Lung Squamous Cell Carcinoma ◽  
Lung Cancers ◽  
Pathological Characteristics

N6-methyladenosine (m6A) methylation is of significant importance in the initiation and progression of tumors, but how specific genes take effect in different lung cancers still needs to be explored. The aim of this study is to analyze the correlation between the m6A RNA methylation regulators and the occurrence and development of lung cancer. The data of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) were obtained through the TCGA database. We systematically analyzed the related pathological characteristics and prognostic factors by applying univariate and multivariate Cox regression, as well as LASSO Cox regression. Some of 23 m6A regulators are identified as having high expression in lung cancer. In addition, risk score has been shown to be an independent prognostic factor in lung cancer. Our research not only fully reveals that m6A regulators and clinical pathological characteristics are potentially useful with respect to survival and prognosis in different lung tumors but also can lay a theoretical root for the treatment for lung cancer—notably, to point out a new direction for the development of treatment.

scholarly journals Lung Cancer in Nepal - Histological Typing And Its Relations With Smoking

2003 ◽  
Vol 26 (3) ◽  
pp. 1-8
Author(s):  
H G Shrestha
Keyword(s):  
Lung Cancer ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Smoking Habit ◽  
Left Lung ◽  
Heavy Smoker ◽  
Malignant Tumours ◽  
Lung Cancers ◽  
Long Time

Out of 51 bronchoscopy biopsy, thirty (60%) were of lung cancer which made 5.3% of the whole malignant tumours, i.e. 562 cancers in different sites in 26 months study in the Department of Pathology, TUTH. Squamous cell carcinoma (22 cases or 73.3%) was the commonest followed by Oat cell carcinoma (5 cases or 16.7%). Lung cancer was found more in the old age group, that is 23 cases (7.7%) in over 50 yrs old, 6 cases (20%) in 40-50 yrs group and only one case (3%) in 25 yrs male. The average age for the lung cancer in this study is 58.2 yrs. Lung cancer is more common in male than in female (5:1). All nine patients with bronchogenic carcinoma in whom the history of smoking habit was taken, were heavy smoker for a long time (more than 15 yrs) & 89 (8 out of 9 pts) have Squamous cell carcinoma. In 17 cases of lung cancers 12 (70%) were founf in right lung and 5 ( 30%) in the left lung.

scholarly journals Chemical exhaustion of RPA in cancer treatment

2020 ◽  
Author(s):  
Pamela S. VanderVere-Carozza ◽  
Katherine S. Pawelczak ◽  
Navnath S. Gavande ◽  
Shadia I. Jalal ◽  
Karen E. Pollok ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Anticancer Activity ◽  
Cellular Response ◽  
Threshold Model ◽  
Single Agent ◽  
Cancer Therapeutics ◽  
Genotoxic Stress ◽  
Lung Cancers ◽  
Response To Chemotherapy

AbstractReplication protein A (RPA) plays essential roles in DNA replication, repair, recombination and the DNA-damage response (DDR). We have developed second generation RPA inhibitors (RPAi’s) that block the RPA-DNA interaction. These DNA-binding inhibitors (DBi’s) can elicit a state of cellular RPA exhaustion resulting in single agent in vitro anticancer activity across a broad spectrum of cancers and in vivo activity in two non-small cell lung cancer models. The cellular response to RPAi treatment suggests a threshold exists before RPA inhibition induces cell death. Chemical RPA exhaustion potentiates the anticancer activity of other DDR inhibitors as well as traditional DNA damaging cancer therapeutics. Consistent with the chemical RPA exhaustion model, we demonstrate that the effects of RPAi on replication fork dynamics and DNA damage signaling are similar to other known DDR inhibitors. In accordance with the RPA threshold model, retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. These data demonstrate a unique mechanism of action of RPAi’s eliciting a state of RPA exhaustion that impacts the DDR and may provide an effective therapeutic option for difficult to treat lung cancers.Graphical Abstract

scholarly journals TP53 Mutations in Nonsmall Cell Lung Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Akira Mogi ◽  
Hiroyuki Kuwano
Keyword(s):  
Lung Cancer ◽  
Cell Lung Cancer ◽  
Survival Rates ◽  
Deep Understanding ◽  
Nonsmall Cell Lung Cancer ◽  
Lung Epithelial Cells ◽  
Clinical Approach ◽  
Lung Carcinogenesis ◽  
Lung Cancers

The tumor suppressor gene TP53 is frequently mutated in human cancers. Abnormality of the TP53 gene is one of the most significant events in lung cancers and plays an important role in the tumorigenesis of lung epithelial cells. Human lung cancers are classified into two major types, small cell lung cancer (SCLC) and nonsmall cell lung cancer (NSCLC). The latter accounts for approximately 80% of all primary lung cancers, and the incidence of NSCLC is increasing yearly. Most clinical studies suggest that NSCLC with TP53 alterations carries a worse prognosis and may be relatively more resistant to chemotherapy and radiation. A deep understanding of the role of TP53 in lung carcinogenesis may lead to a more reasonably targeted clinical approach, which should be exploited to enhance the survival rates of patients with lung cancer. This paper will focus on the role of TP53 in the molecular pathogenesis, epidemiology, and therapeutic strategies of TP53 mutation in NSCLC.

Histology determination of lung cancers: A report on genomic profiling of lung cancer of mixing histology.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8570-8570 ◽  
Author(s):  
Ming Tang ◽  
Neda Kalhor ◽  
Maheshwari Ramineni ◽  
Junya Fujimoto ◽  
Jianhua Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Critical Role ◽  
Gene Mutations ◽  
Large Cell ◽  
Small Cell ◽  
Published Data ◽  
Lung Cancers ◽  
Whole Exome ◽  
Genomic Aberrations

8570 Background: Histopathology, largely determined by morphology, plays a critical role in choosing appropriate treatment for lung cancer. The understanding of molecular determination of lung cancer histology is rudimentary. Our recently published data (Zhang, Science, 2014 and Liu, Nature Communications, 2016) have demonstrated that within the same patients with identical genetic background and identical exposure, tumor regions with different morphologic appearances may have very similar genomic profiles while tumors with the same morphology may have distinct genomic landscape. Methods: We collected 12 lung cancers of mixing histology with 2 to 4 histologic components within each tumor. In total, 26 tumor regions including 9 adenocarcinomas, 6 large-cell neuroendocrine carcinoma, 6 small cell carcinomas and 4 squamous cell carcinomas and one poorly differentiated lung carcinoma were microdissected and subjected to whole exome sequencing. Results: A substantial number of identical mutations were shared between different histologic components within the same tumor in all 12 patients. However, the proportion of shared mutations varies in different patients ranging from as little as 4% to as much as 99%. Mutation spectrum is also similar between different histologic components within the same tumors suggesting similar mutational process in place. Identical canonical cancer gene mutations including TP53, KRAS, PIK3CA, SOS1 and STK11 are generally shared between different histologic components within the same tumors. Canonical mutations in FBXW7 and MTHFR were detected in squamous component, but not small-cell component in one patient. Conclusions: Different histologic components of lung cancers of mixing histology are likely derived from the same progenitor cells, but the molecular timing of branch separation of subclones giving rise to different histologic components varies in different tumors. Although genomic aberrations may play a role in a subset of tumors, histologic features may not be determined at genomic level for most lung cancers. Gene expression and methylation analyses from these tumors are underway.

scholarly journals Relationships and Qualitative Evaluation between Diffusion-Weighted Imaging and Pathologic Findings of Resected Lung Cancers

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1194
Author(s):  
Katsuo Usuda ◽  
Shun Iwai ◽  
Aika Yamagata ◽  
Atsushi Sekimura ◽  
Nozomu Motono ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Mucinous Adenocarcinoma ◽  
Cell Types ◽  
Adc Value ◽  
Lung Cancers ◽  
Diffusion Weighted ◽  
Pathologic Findings

For detecting malignant tumors, diffusion-weighted magnetic resonance imaging (DWI) as well as fluoro-2-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) are available. It is not definitive how DWI correlates the pathological findings of lung cancer. The aim of this study is to evaluate the relationships between DWI findings and pathologic findings. In this study, 226 patients with resected lung cancers were enrolled. DWI was performed on each patient before surgery. There were 167 patients with adenocarcinoma, 44 patients with squamous cell carcinoma, and 15 patients with other cell types. Relationships between the apparent diffusion coefficient (ADC) of DWI and the pathology were analyzed. When the optimal cutoff value (OCV) of ADC for diagnosing malignancy was 1.70 × 10−3 mm2/s, the sensitivity of DWI was 92.0% (208/226). The sensitivity was 33.3% (3/9) in mucinous adenocarcinoma. The ADC value (1.31 ± 0.32 × 10−3 mm2/s) of adenocarcinoma was significantly higher than that (1.17 ± 0.29 × 10−3 mm2/s) of squamous cell carcinoma (p = 0.012), or (0.93 ± 0.14 × 10−3 mm2/s) of small cell carcinoma (p = 0.0095). The ADC value (1.91 ± 0.36 × 10−3 mm2/s) of mucinous adenocarcinoma was significantly higher than that (1.25 ± 0.25 × 10−3 mm2/s) of adenocarcinoma with mucin and that (1.24 ± 0.30 × 10−3 mm2/s) of other cell types. The ADC (1.11 ± 0.26 × 10−3 mm2/s) of lung cancer with necrosis was significantly lower than that (1.32 ± 0.33 × 10−3 mm2/s) of lung cancer without necrosis. The ADC of mucinous adenocarcinoma was significantly higher than those of adenocarcinoma of other cell types. The ADC of lung cancer was likely to decrease according to cell differentiation decreasing. The sensitivity of DWI for lung cancer was 92% and this result shows that DWI is valuable for the evaluation of lung cancer. Lung cancer could be evaluated qualitatively using DWI.

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