Isolated metastasis of an EGFR-L858R-mutated NSCLC of the meninges: the potential impact of CXCL12/CXCR4 axis in EGFRmut NSCLC in diagnosis, follow-up and treatment

Lüke, Florian; Blazquez, Raquel; Yamaci, Rezan Fahrioglu; Lü, Xin; Pregler, Benedikt; Hannus, Stefan; Menhart, Karin; Hellwig, Dirk; Wester, Hans‐Jürgen; Kropf, Saskia; Heudobler, Daniel; Grosse, Jirka; Moosbauer, J; Hutterer, Markus; Hau, Peter; Riemenschneider, Markus J.; Bayerlová, Michaela; Bleckmann, Annalen; Polzer, Bernhard; Beißbarth, Tim; Pukrop, Tobias

doi:10.18632/oncotarget.24787

Cited by 9 publications

(3 citation statements)

References 36 publications

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“…The L858R mutation and the exon 19 deletion are common EGFR mutations. It has been reported that the L858R mutation can promote cancer development through the CXCL12-CXCR4 pathway ( 71 ), but the molecular mechanisms in plasma exosomes remain unclear. Univariate analysis revealed that ITIH4, IGHM, and HPR expression were significantly different in patients with and without L858R mutation, however, no significant difference was detected in the multivariate analyses.…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of plasma exosomes in patients with non-small cell lung cancer

Bao¹,

Huang²,

Lang³

et al. 2022

Transl Lung Cancer Res

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Background: Currently, the prognosis of patients with non-small cell lung cancer (NSCLC) remains unsatisfactory. This current study evaluated the relationship between histology of NSCLC and protein expression of exosomes in the plasma from NSCLC patients, and furthermore investigate the impact of the exosome profile on the tumor, node, metastasis (TNM) classification.Methods: Plasma samples were collected from 26 NSCLC patients before surgery. The exosomes were extracted from the plasma and liquid chromatography-mass spectrometry (LC/MS) was used to evaluate the expression of the proteins in the exosomes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the Cytoscape 3.8.2 software. Multivariate logistic regression and receiver operating characteristic (ROC) curves were used to identify proteins which could effectively distinguish between lung adenocarcinoma and lung squamous cell carcinoma. The relationship between protein expression and the TNM stage was calculated using Spearman rank correlation. Results:The expression levels of ZSWIM9, FYB1, SERPINF1, C1orf68, MASP2, and IGHV3-72 were higher in patients with lung adenocarcinoma compared to patients with lung squamous cell carcinoma.MFGE8 was associated with the occurrence of squamous cell carcinoma. CORO1A was positively correlated with the TNM stage of the patients, and COL4A2 was negatively correlated with TNM stage. GO and KEGG analyses revealed that cholesterol metabolism was important in NSCLC development.Conclusions: Lung adenocarcinoma may be distinguished from squamous cell carcinoma by the molecular profile of exosomes in the plasma samples. And, proteomics analysis suggested that cholesterol metabolism may play an important role of cancer progress in NSCLC.

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Section: Discussionmentioning

confidence: 99%

Proteomic analysis of plasma exosomes in patients with non-small cell lung cancer

Bao¹,

Huang²,

Lang³

et al. 2022

Transl Lung Cancer Res

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“…The raw data from the GSE14108 and GSE10245 microarray datasets were downloaded from the Gene Expression Omnibus (GEO) () database. From the datasets, 19 LAD-BM samples (GSE14108) (19) and 40 LAD samples (GSE10245) (20) were used in the current study. The platform used for the detection of these microarray data was the GPL570 Human Genome U133 Plus 2.0 Array (Affymetrix; Thermo Fisher Scientific, Inc., Waltham, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

Identification of potential biomarkers of lung adenocarcinoma brain metastases via microarray analysis of cDNA expression profiles

Yang

Peng

et al. 2018

Oncol Lett

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Brain metastases originating from lung adenocarcinoma (LAD) occur frequently. The aim of the current study was to assess potential biomarkers for the prognosis of lung adenocarcinoma brain metastasis (LAD-BM) through the analysis of gene expression microarrays. The current study downloaded two gene expression datasets, GSE14108 and GSE10245, from the Gene Expression Omnibus database. From GSE14108 and GSE10245, 19 LAD-BM samples and 40 primary LAD samples were selected for analysis. To identify the differentially expressed genes (DEGs), the current study compared the two sample groups, using the limma R package. Subsequently, pathway enrichment analysis was conducted using the Cluster Profiler R package, and the construction of the protein-protein interaction (PPI) network was executed utilizing the Search Tool for the Retrieval of Interacting Genes database. The microRNA-target network was built using the TargetScore R package. Then, these networks were established and visualized using Cytoscape software. An array of 463 DEGs was identified in the LAD-BM samples, including 256 upregulated and 207 downregulated genes. Based on functional term enrichment analysis using the Gene Ontology database and signaling pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes database, it was identified that the overlapping DEGs were primarily involved in chemokine-associated signal transduction, which may mediate lung cancer cell metastasis to the brain. Chemokine ligand 2, lysozyme, matrix metalloproteinase-2 (MMP-2), lysyl oxidase (LOX) and granzyme B were identified as potential biomarkers according to a topological analysis of the PPI networks. Two notable nodes, MMP-2 and LOX, appeared in the PPI network and were key points in the microRNA-target network, as they were regulated by hsa-let-7d. Many DEGs and microRNAs were regarded as prognostic biomarkers for lung adenocarcinoma metastasis in the current study. These DEGs were primarily associated with chemokine-mediated signaling pathways. In addition, MMP-2 and LOX were predicted to be targets of hsa-let-7d.

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“…More recently, an intriguing report by Tsai et al has suggested that the EGFR-L858R mutation (which is a common driver of NSCLC) fosters the spread of lung adenocarcinoma cells to the pleural space via activation of the CXCL12/CXCR4 axis [ 44 ]. However, further attempts to replicate these findings by other groups have so far failed to validate this specific link between EGFR-L858R and CXCR4 [ 45 ]. With regard to ACKR3, studies have shown that over expression of ACKR3 promotes lung cancer growth and angiogenesis [ 34 , 46 ].…”

Section: Pathologic Role For Cxcl12/cxcr4/ackr3 In Nsclcmentioning

confidence: 99%

CXCR4 Based Therapeutics for Non-Small Cell Lung Cancer (NSCLC)

Wald

2018

JCM

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Lung cancer is the second most common malignancy. Unfortunately, despite advances in multimodality therapeutics for the disease, the overall five-year survival rate among newly diagnosed lung cancer patients remains in the range region of 15%. In addition, although immune checkpoint inhibitors are increasingly being incorporated into lung cancer treatment protocols, the proportion of patients that respond to these agents remains low and the duration of response is often short. Therefore, novel methodologies to enhance the efficacy of immunotherapy in lung cancer are highly desirable. Chemokines are small chemotactic cytokines that interact with their 7 transmembrane G-protein–coupled receptors, to guide immune cell trafficking in the body under both physiologic and pathologic conditions. Tumor cells highjack a small repertoire of the chemokine/chemokine receptor system and utilize it in a manner that benefits local tumor growth and distant spread. The chemokine receptor, CXCR4 is expressed in over 30 types of malignant tumors and, through interaction with its ligand CXCL12, was shown exert pleotropic pro-tumorigenic effects. In this review, the pathologic roles that CXCL12/CXCR4 play in lung cancer propagation are presented. Furthermore, the challenges and potential benefits of incorporating drugs that target CXCL12/CXCR4 into immune-based lung cancer therapeutic protocols are discussed.

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Isolated metastasis of an EGFR-L858R-mutated NSCLC of the meninges: the potential impact of CXCL12/CXCR4 axis in EGFRmut NSCLC in diagnosis, follow-up and treatment

Cited by 9 publications

References 36 publications

Proteomic analysis of plasma exosomes in patients with non-small cell lung cancer

Proteomic analysis of plasma exosomes in patients with non-small cell lung cancer

Identification of potential biomarkers of lung adenocarcinoma brain metastases via microarray analysis of cDNA expression profiles

CXCR4 Based Therapeutics for Non-Small Cell Lung Cancer (NSCLC)

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