Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options

Yousefi, Meysam; Bahrami, Tayyeb; Salmaninejad, Arash; Nosrati, Rahim; Ghaffari, Parisa

doi:10.1007/s13402-017-0345-5

Cited by 120 publications

(80 citation statements)

References 226 publications

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“…Several recent studies have identified brain-derived factors, including secreted proteins and exosomes, that alter the brain microenvironment to promote the survival and outgrowth of brain metastasis (35,36). In the current study, we discovered that the release of exosomes from HBMECs was mainly responsible for the elevation of S100A16 in the recipient SCLC cells.…”

Section: Discussionmentioning

confidence: 51%

Brain microvascular endothelial cell exosome–mediated S100A16 up‐regulation confers small‐cell lung cancer cell survival in brain

Miao

Jiang

et al. 2018

FASEB j.

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Small cell lung cancer (SCLC) is the most aggressive histologic subtype of lung cancer, with a strong predilection for early brain metastases. Despite efforts and advances in new therapeutics for SCLC, the prognosis of patients with SCLC with brain metastases is consistently poor. Therefore, a better understanding of the mechanisms of SCLC brain metastasis is important in improving current treatments. In this study, elevated S100A16 levels were associated with SCLC brain metastases, which was a possible secondary event arising from the brain metastatic microenvironment. Using an in vitro cell coculture system, we found that the coculturing of SCLC cells with human brain microvascular endothelial cells (HBMECs) led to an increased expression of S100A16 in SCLC cells. Conversely, treatment of HBMECs with GW4869, an inhibitor of exosome release, significantly blocked this effect in the cocultured SCLC cells. Alternatively, the results from Western blot analyses and immunofluorescence indicated that the HBMEC exosomes purified by ultracentrifugation also induced the elevation and translocation from the cytoplasm to the nucleus of S100A16 in the recipient SCLC cells. The inhibition experiments demonstrated that elevated S100A16 contributed a benefit of HBMEC exosomes for the survival of the recipient SCLC cells under stress. Moreover, the elevation of S100A16 in SCLC cells prevented the loss of mitochondrial membrane potential (Δψm) and enhanced resistance to apoptosis under stressful conditions, which were determined by Annexin V/propidium iodide and JC-1 assay. Further results showed that the S100A16-mediated protective effect was caused by the presence of an important element in Δψm, prohibitin (PHB)-1, a protein in the mitochondrial inner membrane. Conversely, the delivery of PHB-1 siRNAs into S100A16 overexpressing SCLC cells weakened these protective effects. Our findings suggest that elevated S100A16 plays an active role in facilitating the survival of SCLC cells through modulating the mitochondrial function, identifying S100A16 as an important potential target in SCLC brain metastasis.-Xu, Z.-H., Miao, Z.-W., Jiang, Q.-Z., Gan, D.-X., Wei, X.-G., Xue, X.-Z., Li, J.-Q., Zheng, F., Qin, X.-X., Fang, W.-G., Chen, Y.-H., Li. B. Brain microvascular endothelial cell exosome-mediated S100A16 up-regulation confers small cell lung cancer cell survival in brain.

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Section: Discussionmentioning

confidence: 51%

Brain microvascular endothelial cell exosome–mediated S100A16 up‐regulation confers small‐cell lung cancer cell survival in brain

Miao

Jiang

et al. 2018

FASEB j.

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“…miR‐577 affects cell expression by regulating the Wnt signaling pathway, which subsequently affects cell growth and cell viability. Wang et al, to our knowledge, there are currently no reports relating miR‐1911, miR‐4732, or miR‐5682 to lung squamous cell malignancies. Therefore, more research is needed to investigate the function of these miRNAs in LUSC, and with the exponential increase of important findings in this area, we believe this could give exciting new insights.…”

Section: Discussionmentioning

confidence: 95%

MicroRNAs associated with lung squamous cell carcinoma: New prognostic biomarkers and therapeutic targets

Gao

Feng

et al. 2019

J of Cellular Biochemistry

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Background With the development in research, the importance of microRNAs (miRNAs) in the occurrence and metastasis, and prognosis of lung squamous cell carcinoma (LUSC) have received extensive attention. This study aims to identify new biomarkers and pivotal genes associated with LUSC prognosis through bioinformatics. Materials and methods We downloaded miRNA and messenger RNA samples related to LUSC from The Cancer Genome Atlas (TCGA) database. Following initial data screening and preprocessing, we utilized the R platform and a range of analysis tools (miRDB, TargetScanHuman7.2, DAVID, and Cytoscape_v3.5.1) to analyze the TCGA data and identify highly specific and sensitive biomarkers. Results We finally identified 12 miRNAs and six central genes closely related to the overall survival of patients with LUSC. We found that high expression of 7 miRNAs (miR‐301b, miR‐383, miR‐512, miR‐515, miR‐525, miR‐577, and miR‐5682) and low expression of five miRNAs (miR‐448, miR‐486, miR‐4732,miR‐4732, miR‐516, and miR‐1911) can significantly improve the overall survival rate of patients with LUSC. The six central genes DLGAP5, CENPA, CHEK1, LRRK2, CALB1, and TOP2A are directly or indirectly involved in the formation and metastasis of LUSC and could, therefore, be considered as target genes for drug therapy. Conclusion With the development in research, the importance of miRNAs in the occurrence and metastasis and prognosis of LUSC have received extensive attention. This study aims to identify new biomarkers and pivotal genes associated with LUSC prognosis through bioinformatics.

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“…These cytokines can activate a series of EMT‐inducing transcription factors and thus act pleiotropically to choreograph the complex EMT program which eventually leads to the disruption of cell‐cell adherent junctions and the cell‐ECM adhesions . It has been demonstrated that the EMT can endow cancer cells with the migratory and invasive capabilities associated with metastatic competence …”

Section: Introductionmentioning

confidence: 99%

“…4 It has been demonstrated that the EMT can endow cancer cells with the migratory and invasive capabilities associated with metastatic competence. [5][6][7][8] Chemokines are a superfamily of secreted proteins involved in inflammatory and immunoregulatory processes. Monocyte chemoattractant protein-1/CCL2 is one of the key chemokines that displays chemotactic activity for monocytes and basophils but not for neutrophils or eosinophils.…”

mentioning

confidence: 99%

CCL2 promotes cell migration by inducing epithelial‐mesenchymal transition in oral squamous cell carcinoma

Ling

Yang

Chen

et al. 2019

J Oral Pathology Medicine

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Background Although a few studies suggested that the chemokine CCL2 might be involved in the development of oral squamous cell carcinoma (OSCC), the exact mechanism remains unclear. In this study, we aimed to determine the resource of CCL2 in lesions and explored a potential mechanism that CCL2 promotes tumor progression. The study was an effort to provide new insights into the pathological role of CCL2 in OSCC. Methods Specimens of OSCC and normal oral mucosa were stained using immunohistochemistry (IHC) to assess the CCL2 expression. Enzyme‐linked immunosorbent assay (ELISA) was used to detect the difference of CCL2 between OSCC and normal oral mucosa cell lines. In addition, we treated OSCC cells with exogenous rCCL2 combined with or without CCL2 neutralizing antibody and then determined the changes of in epithelial‐mesenchymal transition (EMT) markers and cell migration capacity using immunofluorescence, Western blotting, transwell migration, and wound healing assays. Results We have found that CCL2 expression was upregulated significantly in both lesions and cell culture supernatant of OSCC compared with controls. IHC staining demonstrated that CCL2 expression was primarily located in the cytoplasm and cell membrane of cells. We have also found that rCCL2 could effectively induce EMT through upregulating Snail in OSCC cells, which was demonstrated by the decrease of E‐cadherin and the increase of vimentin. In addition, we have found that CCL2 neutralizing antibody could block EMT induced by CCL2 in OSCC. Conclusions CCL2 secreted by cancer cells can promote cell migration by inducing EMT via paracrine or autocrine in OSCC.

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Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options

Abstract: The identification of molecular mechanisms underlying lung cancer metastasis has opened up new avenues towards their eradication and provides interesting opportunities for future research aimed at the development of novel targeted therapies.

Cited by 120 publications

References 226 publications

Brain microvascular endothelial cell exosome–mediated S100A16 up‐regulation confers small‐cell lung cancer cell survival in brain

Brain microvascular endothelial cell exosome–mediated S100A16 up‐regulation confers small‐cell lung cancer cell survival in brain

MicroRNAs associated with lung squamous cell carcinoma: New prognostic biomarkers and therapeutic targets

CCL2 promotes cell migration by inducing epithelial‐mesenchymal transition in oral squamous cell carcinoma

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