scholarly journals Air Pollution Particles Hijack Peroxidasin to Disrupt Immunosurveillance and Promote Lung Cancer

2021 ◽  
Author(s):  
Zhenzhen Wang ◽  
Ziyu Zhai ◽  
Chunyu Chen ◽  
Xuejiao Tian ◽  
Zhen Xing ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Tissue ◽  
Lung Tumor ◽  
Fine Particulate Matter ◽  
Immune Surveillance ◽  
Dense Matrix ◽  
Lung Tumorigenesis ◽  
Promoting Effect ◽  
Type Iv ◽  
Global Threat

Although fine particulate matter (FPM) in air pollutants and tobacco smoke is recognized as a strong carcinogen and global threat to public health, its biological mechanism for inducing lung cancer remains unclear. Here, by investigating FPM's bioactivities in lung carcinoma mice models, we discover that these particles promote lung tumor progression by inducing aberrant thickening of tissue matrix and hampering migration of anti-tumor immunocytes. Upon inhalation into lung tissue, these FPM particles abundantly adsorb peroxidasin (PXDN)- an enzyme mediating type IV collagen (Col IV) crosslinking - onto their surface. The adsorbed PXDN exerts abnormally high activity to crosslink Col IV via increasing the formation of sulfilimine bonds at the NC1 domain, leading to an overly dense matrix in the lung tissue. This disordered structure decreases the mobility of cytotoxic CD8+ T lymphocytes into the lung and consequently impairs the local immune surveillance, enabling the flourish of nascent tumor cells. Meanwhile, inhibiting the activity of PXDN effectively abolishes the tumor-promoting effect of FPM, indicating the key impact of aberrant PXDN activity on tumorigenic process. In summary, our finding elucidates a new mechanism for FPM-induced lung tumorigenesis and identifies PXDN as a potential target for treatment or prevention of the FPM-relevant biological risks.

scholarly journals The ERBB network facilitates KRAS-driven lung tumorigenesis

2018 ◽  
Author(s):  
Björn Kruspig ◽  
Tiziana Monteverde ◽  
Sarah Neidler ◽  
Andreas Hock ◽  
Emma Kerr ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Tumor ◽  
Tumor Development ◽  
Treatment Strategies ◽  
Invasive Disease ◽  
Therapeutic Benefit ◽  
Lung Tumors ◽  
Network Activity ◽  
Lung Tumorigenesis

AbstractKRAS is the most frequently mutated driver oncogene in human adenocarcinoma of the lung. There are presently no clinically proven strategies for treatment of KRAS-driven lung cancer. Activating mutations in KRAS are thought to confer independence from upstream signaling, however recent data suggest that this independence may not be absolute. Here we show that initiation and progression of KRAS-driven lung tumors requires input from ERBB family RTKs: Multiple ERBB RTKs are expressed and active from the earliest stages of KRAS driven lung tumor development, and treatment with a multi-ERBB inhibitor suppresses formation of KRasG12D-driven lung tumors. We present evidence that ERBB activity amplifies signaling through the core RAS pathway, supporting proliferation of KRAS mutant tumor cells in culture and progression to invasive disease in vivo. Importantly, brief pharmacological inhibition of the ERBB network significantly enhances the therapeutic benefit of MEK inhibition in an autochthonous tumor setting. Our data suggest that lung cancer patients with KRAS-driven disease may benefit from inclusion of multi-ERBB inhibitors in rationally designed treatment strategies.One Sentence SummaryG12 Mutant KRAS requires tonic ERBB network activity for initiation and maintenance of lung cancer

scholarly journals Toll-like receptor 2 orchestrates a potent anti-tumor response in non-small cell lung cancer

2021 ◽  
Author(s):  
Fraser R Millar ◽  
Adam Pennycuick ◽  
Morwenna Muir ◽  
Andrea Quintanilla ◽  
Priya Hari ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Therapeutic Potential ◽  
Lung Tumor ◽  
Early Stage ◽  
Immune Surveillance ◽  
Genetically Engineered ◽  
Toll Like Receptor ◽  
Early Stage Lung Cancer ◽  
Toll Like Receptor 2 ◽  
Stage Lung Cancer

Targeting early-stage lung cancer is vital to improve overall survival. We previously identified Toll-like receptor 2 (TLR2) as a regulator of oncogene-induced senescence (OIS) and the senescence-associated secretory phenotype (SASP), both key for tumor suppression. Here, we demonstrate that TLR2 is widely expressed in human lung tumor epithelium where it correlates with improved survival and clinical regression. Using genetically engineered mouse models of lung cancer we have shown that Tlr2 is a tumor suppressor in lung cancer initiation via regulation of proliferation and the SASP. The SASP is integral in the regulation of immune surveillance of premalignant cells, and we observe impaired myeloid derived immune surveillance following Tlr2 loss. Lastly, we show that administration of a synthetic Tlr2 agonist significantly reduces preinvasive lung tumor growth. Our data highlight an unexpected tumor surveillance pathway in early-stage lung cancer with therapeutic potential.

Lung Tumorigenesis Suppressing Effects of a Commercial Kava Extract and Its Selected Compounds in A/J Mice

2011 ◽  
Vol 39 (04) ◽  
pp. 727-742 ◽  
Author(s):  
Thomas E. Johnson ◽  
David Hermanson ◽  
Lei Wang ◽  
Fekadu Kassie ◽  
Pramod Upadhyaya ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Lung Tumor ◽  
Cancer Control ◽  
Liver Weight ◽  
Detectable Effect ◽  
Lung Tumorigenesis ◽  
Active Constituent ◽  
Treatment Regimens ◽  
Complementary Approach

Lung cancer is the most deadly malignancy in the US. Chemoprevention is potentially a complementary approach to smoking cessation for lung cancer control. Recently, we reported that a commercially available form of kava extract significantly inhibits 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(a)pyrene (BaP)-induced lung tumorigenesis in A/J mice at a dose of 10 mg per gram diet. In the present study, we examined the dose-dependent lung tumor inhibitory activities of kava and investigated potential active constituent(s). Mice treated with carcinogen alone contained 12.1±5.8 lung adenomas per mouse 22 weeks after final carcinogen administration. Mice that were fed diets containing kava at dosages of 1.25, 2.5, 5, and 10 mg/g of diet had 8.4±3.5, 6.6±3.5, 4.3±2.4, and 3.8±2.3 lung adenomas per mouse, respectively. This corresponds to a reduction of 31%, 46%, 65% and 69% in tumor multiplicity, which were all statistically significant (p < 0.05). Analyses of lung adenoma tissues derived from kava-treated animals revealed that kava significantly inhibited adenoma cell proliferation while it had no detectable effect on cell death, indicating that kava primarily suppressed lung tumorigenesis in A/J mice via inhibition of cell proliferation. Flavokawains A, B, and C, three chalcone-based components from kava, demonstrated greatly reduced chemopreventive efficacies even at concentrations much higher than their natural abundance, suggesting that they alone were unlikely to be responsible for kava's chemopreventive activity. Kava at all dosages and treatment regimens did not induce detectable adverse effects, particularly with respect to liver. Specifically, kava treatment showed no effect on liver integrity indicator enzymes or liver weight, indicating that kava may be potentially safe for long-term chemopreventive application.

scholarly journals Microbiota Biomarkers for Lung Cancer

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 407
Author(s):  
Qixin Leng ◽  
Van K. Holden ◽  
Janaki Deepak ◽  
Nevins W. Todd ◽  
Feng Jiang
Keyword(s):  
Lung Cancer ◽  
Early Detection ◽  
Lung Tumor ◽  
Lung Squamous Cell Carcinoma ◽  
Digital Pcr ◽  
Lung Tumorigenesis ◽  
Tumor Tissues ◽  
Diagnostic Values ◽  
Noninvasive Biomarkers ◽  
Nsclc Patients

Non-small cell lung cancer (NSCLC) is the number one cancer killer and its early detection can reduce mortality. Accumulating evidences suggest an etiopathogenic role of microorganisms in lung tumorigenesis. Certain bacteria are found to be associated with NSCLC. Herein we evaluated the potential use of microbiome as biomarkers for the early detection of NSCLC. We used droplet digital PCR to analyze 25 NSCLC-associated bacterial genera in 31 lung tumor and the paired noncancerous lung tissues and sputum of 17 NSCLC patients and ten cancer-free smokers. Of the bacterial genera, four had altered abundances in lung tumor tissues, while five were aberrantly abundant in sputum of NSCLC patients compared with their normal counterparts (all p < 0.05). Acidovorax and Veillonella were further developed as a panel of sputum biomarkers that could diagnose lung squamous cell carcinoma (SCC) with 80% sensitivity and 89% specificity. The use of Capnocytophaga as a sputum biomarker identified lung adenocarcinoma (AC) with 72% sensitivity and 85% specificity. The use of Acidovorax as a sputum biomarker had 63% sensitivity and 96% specificity for distinguishing between SCC and AC, the two major types of NSCLC. The sputum biomarkers were further validated for the diagnostic values in a different cohort of 69 NSCLC cases and 79 cancer-free controls. Sputum microbiome might provide noninvasive biomarkers for the early detection and classification of NSCLC.

scholarly journals Impact of Cancer Stem Cells and Cancer Stem Cell-Driven Drug Resiliency in Lung Tumor: Options in Sight

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 267
Author(s):  
Lourdes Cortes-Dericks ◽  
Domenico Galetta
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Lung Tumor ◽  
Current Knowledge ◽  
Immune Surveillance ◽  
Treatment Strategies ◽  
Resistant Cell ◽  
New Treatment ◽  
Efficient Elimination

Causing a high mortality rate worldwide, lung cancer remains an incurable malignancy resistant to conventional therapy. Despite the discovery of specific molecular targets and new treatment strategies, there remains a pressing need to develop more efficient therapy to further improve the management of this disease. Cancer stem cells (CSCs) are considered the root of sustained tumor growth. This consensus corroborates the CSC model asserting that a distinct subpopulation of malignant cells within a tumor drives and maintains tumor progression with high heterogeneity. Besides being highly tumorigenic, CSCs are highly refractory to standard drugs; therefore, cancer treatment should be focused on eliminating these cells. Herein, we present the current knowledge of the existence of CSCs, CSC-associated mechanisms of chemoresistance, the ability of CSCs to evade immune surveillance, and potential CSC inhibitors in lung cancer, to provide a wider insight to drive a more efficient elimination of this pro-oncogenic and treatment-resistant cell fraction.

Effects of EDTA, Hyaluronidase and Collagenase on Epiphyseal Cartilage Matrix

1968 ◽  
Vol 26 ◽  
pp. 56-57
Author(s):  
H. Clarke Anderson ◽  
Priscilla R. Coulter
Keyword(s):  
Light And Electron Microscopy ◽  
Matrix Vesicles ◽  
Cartilage Matrix ◽  
Collagen Fibrils ◽  
Epiphyseal Cartilage ◽  
Dense Matrix ◽  
Type Iv ◽  
Bovine Testicular Hyaluronidase ◽  
The Matrix ◽  
Testicular Hyaluronidase

Epiphyseal cartilage matrix contains fibrils and particles of at least 5 different types: 1. Banded collagen fibrils, present throughout the matrix, but not seen in the lacunae. 2. Non-periodic fine fibrils <100Å in diameter (Fig. 1), which are most notable in the lacunae, and may represent immature collagen. 3. Electron dense matrix granules (Fig. 1) which are often attached to fine fibrils and collagen fibrils, and probably contain protein-polysaccharide although the possibility of a mineral content has not been excluded. 4. Matrix vesicles (Fig. 2) which show a selective distribution throughout the epiphysis, and may play a role in calcification. 5. Needle-like apatite crystals (Fig. 2).Blocks of formalin-fixed epiphysis from weanling mice were digested with the following agents in 0.1M phosphate buffer: a) 5% ethylenediaminetetraacetate (EDTA) at pH 8.3, b) 0.015% bovine testicular hyaluronidase (Sigma, type IV, 750 units/mg) at pH 5.5, and c) 0.1% collagenase (Worthington, chromatograhically pure, 200 units/mg) at pH 7.4. All digestions were carried out at 37°C overnight. Following digestion tissues were examined by light and electron microscopy to determine changes in the various fibrils and particles of the matrix.

Improved Therapeutic Efficacy of Topotecan Against A549 Lung Cancer Cells with Folate-targeted Topotecan Liposomes

2020 ◽  
Vol 21 (11) ◽  
pp. 902-909
Author(s):  
Jingxin Zhang ◽  
Weiyue Shi ◽  
Gangqiang Xue ◽  
Qiang Ma ◽  
Haixin Cui ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Delivery ◽  
Cancer Cells ◽  
Targeted Delivery ◽  
Therapeutic Efficacy ◽  
Drug Delivery Systems ◽  
Lung Tumor ◽  
A549 Cells ◽  
Delivery Systems ◽  
Lung Cancer Cells

Background: Among all cancers, lung cancer has high mortality among patients in most of the countries in the world. Targeted delivery of anticancer drugs can significantly reduce the side effects and dramatically improve the effects of the treatment. Folate, a suitable ligand, can be modified to the surface of tumor-selective drug delivery systems because it can selectively bind to the folate receptor, which is highly expressed on the surface of lung tumor cells. Objective: This study aimed to construct a kind of folate-targeted topotecan liposomes for investigating their efficacy and mechanism of action in the treatment of lung cancer in preclinical models. Methods: We conjugated topotecan liposomes with folate, and the liposomes were characterized by particle size, entrapment efficiency, cytotoxicity to A549 cells and in vitro release profile. Technical evaluations were performed on lung cancer A549 cells and xenografted A549 cancer cells in female nude mice, and the pharmacokinetics of the drug were evaluated in female SD rats. Results: The folate-targeted topotecan liposomes were proven to show effectiveness in targeting lung tumors. The anti-tumor effects of these liposomes were demonstrated by the decreased tumor volume and improved therapeutic efficacy. The folate-targeted topotecan liposomes also lengthened the topotecan blood circulation time. Conclusion: The folate-targeted topotecan liposomes are effective drug delivery systems and can be easily modified with folate, enabling the targeted liposomes to deliver topotecan to lung cancer cells and kill them, which could be used as potential carriers for lung chemotherapy.

Recombinant adeno-associated virus 9-mediated expression of Kallistatin suppresses lung tumor growth in mice

2020 ◽  
Vol 20 ◽  
Author(s):  
Weihong Qu ◽  
Jianguo Zhao ◽  
Yaqing Wu ◽  
Ruian Xu ◽  
Shaowu Liu
Keyword(s):  
Lung Cancer ◽  
Gene Therapy ◽  
Tumor Growth ◽  
Lung Tumor ◽  
Control Group ◽  
High Dose ◽  
Blank Control Group ◽  
Adeno Associated Virus ◽  
Tumor Tissues ◽  
Subcutaneous Xenograft

Background:: Lung cancer remains the most common cause of cancer-related deaths in China and worldwide. Traditional surgery and chemotherapy do not offer an effective cure although gene therapy may be a promising future alter-native. Kallistatin (Kal) is an endogenous inhibitor of angiogenesis and tumorigenesis. Recombinant adeno-associated virus (rAAV) is considered the most promising vector for gene therapy of many diseases due to persistent and long-term transgen-ic expression. Objective:: The aim of this study was to investigate whether rAAV9-Kal inhibited NCI-H446 subcutaneous xenograft tumor growth in mice. Method:: The subcutaneous xenograft mode were induced by subcutaneous injection of 2×106 H446 cells into the dorsal skin of BALB/c nude mice. The mice were administered with ssrAAV9-Kal (single-stranded rAAV9) or dsrAAV9-Kal (double-stranded rAAV9）by intraperitoneal injection (I.P.). Tumor microvessel density (MVD) was examined by anti-CD34 stain-ing to evaluate tumor angiogenesis. Results:: Compared with the PBS (blank control) group, tumor growth in the high-dose ssrAAV9-Kal group was inhibited by 40% by day 49, and the MVD of tumor tissues was significantly decreased. Conclusion:: The results indicate that this therapeutic strategy is a promising approach for clinical cancer therapy and impli-cate rAAV9-Kal as a candidate for gene therapy of lung cancer.

scholarly journals FlowCell-enriched circulating tumor cells as a predictor of lung cancer metastasis

Human Cell ◽  
2021 ◽  
Author(s):  
Yan Lu ◽  
Yushuang Zheng ◽  
Yuhong Wang ◽  
Dongmei Gu ◽  
Jun Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Cancer Metastasis ◽  
Lung Tumor ◽  
Early Stage ◽  
High Rate ◽  
Early Stage Lung Cancer ◽  
Lung Cancer Metastasis ◽  
Number Of Patients

AbstractLung cancer is the most fetal malignancy due to the high rate of metastasis and recurrence after treatment. A considerable number of patients with early-stage lung cancer relapse due to overlooked distant metastasis. Circulating tumor cells (CTCs) are tumor cells in blood circulation that originated from primary or metastatic sites, and it has been shown that CTCs are critical for metastasis and prognosis in various type of cancers. Here, we employed novel method to capture, isolate and classify CTC with FlowCell system and analyzed the CTCs from a cohort of 302 individuals. Our results illustrated that FlowCell-enriched CTCs effectively differentiated benign and malignant lung tumor and the total CTC counts increased as the tumor developed. More importantly, we showed that CTCs displayed superior sensitivity and specificity to predict lung cancer metastasis in comparison to conventional circulating biomarkers. Taken together, our data suggested CTCs can be used to assist the diagnosis of lung cancer as well as predict lung cancer metastasis. These findings provide an alternative means to screen early-stage metastasis.

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