scholarly journals ALCAM contributes to brain metastasis formation in non-small-cell lung cancer through interaction with the vascular endothelium

2020 ◽  
Vol 22 (7) ◽  
pp. 955-966 ◽  
Author(s):  
Justine Münsterberg ◽  
Desirée Loreth ◽  
Laura Brylka ◽  
Stefan Werner ◽  
Jana Karbanova ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Brain Metastasis ◽  
Vascular Endothelium ◽  
Poor Prognosis ◽  
Small Cell ◽  
Tumor Cell Dissemination ◽  
Brain Endothelial Cells ◽  
Small Cell Lung ◽  
Cell Dissemination

Abstract Background Brain metastasis (BM) in non-small-cell lung cancer (NSCLC) has a very poor prognosis. Recent studies have demonstrated the importance of cell adhesion molecules in tumor metastasis. The aim of our study was to investigate the role of activated leukocyte cell adhesion molecule (ALCAM) in BM formation in NSCLC. Methods Immunohistochemical analysis was performed on 143 NSCLC primary tumors and BM. A correlation between clinicopathological parameters and survival was developed. Biological properties of ALCAM were assessed in vitro by gene ablation using CRISPR/Cas9 technology in the NCI-H460 NSCLC cell line and in vivo by intracranial and intracardial cell injection of NCI-H460 cells in NMRI-Foxn1nu/nu mice. Results ALCAM expression was significantly upregulated in NSCLC brain metastasis (P = 0.023) with a de novo expression of ALCAM in 31.2% of BM. Moderate/strong ALCAM expression in both primary NSCLC and brain metastasis was associated with shortened survival. Functional analysis of an ALCAM knock-out (KO) cell line showed a significantly decreased cell adhesion capacity to human brain endothelial cells by 38% (P = 0.045). In vivo studies showed significantly lower tumor cell dissemination in mice injected with ALCAM-KO cells in both mouse models, and both the number and size of BM were significantly diminished in ALCAM depleted tumors. Conclusions Our findings suggest that elevated levels of ALCAM expression promote BM formation in NSCLC through increased tumor cell dissemination and interaction with the brain endothelial cells. Therefore, ALCAM could be targeted to reduce the occurrence of BM. Key Points 1. ALCAM expression associates with poor prognosis and brain metastasis in NSCLC. 2. ALCAM mediates interaction of NSCLC tumor cells with brain vascular endothelium. 3. ALCAM might represent a novel preventive target to reduce the occurrence of BM in NSCLC.

scholarly journals Upregulation of IL-11, an IL-6 Family Cytokine, Promotes Tumor Progression and Correlates with Poor Prognosis in Non-Small Cell Lung Cancer

2018 ◽  
Vol 45 (6) ◽  
pp. 2213-2224 ◽  
Author(s):  
Meng Zhao ◽  
Yahui Liu ◽  
Ran Liu ◽  
Jin Qi ◽  
Yongwang Hou ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Poor Prognosis ◽  
Epithelial Mesenchymal Transition ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mesenchymal Transition

Background/Aims: Cytokines are key players in tumorigenesis and are potential targets in cancer treatment. Although IL-6 has attracted considerable attention, interleukin 11 (IL-11), another member of the IL-6 family, has long been overlooked, and little is known regarding its specific function in non-small cell lung cancer (NSCLC). In this study, we explored IL-11’s role in NSCLC and the detailed mechanism behind it. Methods: Cell proliferation in response to IL-11 was determined by colony formation, BrdU incorporation and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Cell motility was measured by Transwell and wound healing assays. NSCLC xenograft models were used to confirm oncogenic function of IL-11 in vivo. Immunohistochemical staining and western blot assay were performed to detect epithelial–mesenchymal transition (EMT) markers and cell signaling pathway alterations. Eighteen NSCLC patients and 5 normal lung samples were collected together with data from an online database to determine the link between IL-11 expression and malignant progression. Results: We observed that IL-11 was upregulated in NSCLC samples compared with normal tissue samples and correlated with poor prognosis. Data from in vitro and in vivo models indicated that IL-11 promotes cell proliferation and tumorigenesis. Cell migration and invasion were also enhanced by IL-11. Epithelial–mesenchymal transition (EMT) was also observed after IL-11 incubation. Furthermore, IL-11 activated AKT and STAT3 in our experimental models. In addition, we observed that hypoxia induced IL-11 expression in NSCLC cells. Deferoxamine (DFX) or dimethyloxalylglycine (DMOG) induced hypoxia-inducible factor 1-alpha (HIF1α) upregulation, which enhanced IL-11 expression in NSCLC cells. Conclusions: Taken together, our results indicate that IL-11 is an oncogene in NSCLC, and elucidating the mechanism behind it may provide insights for NSCLC treatment.

In vitro and in vivo evaluation of therapy targeting epithelial-cell adhesion-molecule aptamers for non-small cell lung cancer

2015 ◽  
Vol 209 ◽  
pp. 88-100 ◽  
Author(s):  
Mona Alibolandi ◽  
Mohammad Ramezani ◽  
Khalil Abnous ◽  
Fatemeh Sadeghi ◽  
Fatemeh Atyabi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Adhesion ◽  
Epithelial Cell ◽  
Cell Adhesion Molecule ◽  
Small Cell ◽  
Epithelial Cell Adhesion Molecule ◽  
Small Cell Lung ◽  
In Vivo Evaluation

scholarly journals FAIM2 Promotes Non-Small Cell Lung Cancer Cell Growth and Bone Metastasis by Activating the Wnt/β-Catenin Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Kelin She ◽  
Wensheng Yang ◽  
Mengna Li ◽  
Wei Xiong ◽  
Ming Zhou
Keyword(s):  
Lung Cancer ◽  
Bone Metastasis ◽  
Cell Growth ◽  
Small Cell Lung Cancer ◽  
Signaling Pathway ◽  
Poor Prognosis ◽  
Small Cell ◽  
Small Cell Lung ◽  
Adhesive Ability

AimBone metastasis is the major reason for the poor prognosis and high mortality rate of non-small cell lung cancer (NSCLC) patients. This study explored the function and underlying mechanism of Fas apoptotic inhibitory molecule 2 (FAIM2) in the bone metastasis of NSCLC.MethodsSamples of normal lung tissue and NSCLC tissue (with or without bone metastasis) were collected and analyzed for FAIM2 expression. HARA cells with FAIM2 overexpression and HARA-B4 cells with FAIM2 knockdown were tested for proliferation, migration, invasion, anoikis, and their ability to adhere to osteoblasts. Next, whether FAIM2 facilitates bone metastasis by regulating the epithelial mesenchymal transformation (EMT) process and Wnt/β-catenin signaling pathway were investigated. Finally, an in vivo model of NSCLC bone metastasis was established and used to further examine the influence of FAIM2 on bone metastasis.ResultsFAIM2 was highly expressed in NSCLC tissues and NSCLC tissues with bone metastasis. FAIM2 expression was positively associated with the tumor stage, lymph node metastasis, bone metastasis, and poor prognosis of NSCLC. FAIM2 upregulation promoted HARA cell proliferation, migration, and invasion, but inhibited cell apoptosis. FAIM2 knockdown in HARA-B4 cells produced the opposite effects. HARA-B4 cells showed a stronger adhesive ability to osteocytes than did HARA cells. FAIM2 was found to be related to the adhesive ability of HARA and HARA-B4 cells to osteocytes. FAIM2 facilitated bone metastasis by regulating the EMT process and Wnt/β-catenin signaling pathway. Finally, FAIM2 was found to participate in regulating NSCLC bone metastasis in vivo.ConclusionsFAIM2 promoted NSCLC cell growth and bone metastasis by regulating the EMT process and Wnt/β-catenin signaling pathway. FAIM2 might be useful for diagnosing and treating NSCLC bone metastases.

TMOD-01. AN IN VIVO FUNCTIONAL GENOMICS SCREEN TO IDENTIFY NOVEL DRIVERS OF LUNG-TO-BRAIN METASTASIS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi215-vi215
Author(s):  
Nikoo Aghaei ◽  
Fred C Lam ◽  
Ekkhard Kasper ◽  
Chitra Venugopal ◽  
Sheila K Singh
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Genome Wide ◽  
Crispr Activation

Abstract INTRODUCTION Brain metastases, the most common tumors of the central nervous system, occur in approximately 20% of primary adult cancers. In particular, 40% of patients with non-small cell lung cancer develop brain metastasis. As systemic therapies for the treatment of non-small cell lung cancer become increasingly effective at controlling primary disease, patients are ironically succumbing to their brain metastases. This highlights a large unmet need to develop novel targeted therapies for the treatment of lung-to-brain metastases (LBM). We hypothesize that an in vivo functional genomic screen can identify novel genes that drive LBM. METHODS To do this, we developed a patient-derived xenograft (PDX) mouse model of LBM using patient lung cancer cell lines. This PDX model of LBM enables the use of fluorescent and bioluminescent in vivo imaging to track the progression of lung tumor and brain metastases. RESULTS We have performed an in vivo genome-wide CRISPR activation screening to identify novel drivers of LBM. We will derive candidate genes through mouse brain and lung tissue sequencing after mice reach endpoint. EXPECTED AREA OF FINDINGS This platform will lead to potential therapeutic targets to prevent the formation of LBM and prolong the survival of patients with non-small cell lung cancer. LIMITATIONS There may be limitations in getting candidate hits that overlap in all mice in our first replicate. This can be remedied by conducting the in vivo screen in at least three biological replicates. CONCLUSION To the best of our knowledge, this is the first genome-wide in vivo CRISPR activation screen searching for drivers of LBM using a PDX animal model. This study can provide a framework to gain a deeper understanding of the regulators of BM formation which will hopefully lead to targeted drug discovery.

scholarly journals ALKBH4 promotes tumourigenesis with a poor prognosis in non-small-cell lung cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kentaro Jingushi ◽  
Masaya Aoki ◽  
Kazuhiro Ueda ◽  
Takahiro Kogaki ◽  
Masaya Tanimoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Poor Prognosis ◽  
Critical Role ◽  
Small Cell ◽  
Normal Lung ◽  
Small Cell Lung ◽  
And Function

AbstractThe human AlkB homolog family (ALKBH) of proteins play a critical role in some types of cancer. However, the expression and function of the lysine demethylase ALKBH4 in cancer are poorly understood. Here, we examined the expression and function of ALKBH4 in non-small-cell lung cancer (NSCLC) and found that ALKBH4 was highly expressed in NSCLC, as compared to that in adjacent normal lung tissues. ALKBH4 knockdown significantly induced the downregulation of NSCLC cell proliferation via cell cycle arrest at the G1 phase of in vivo tumour growth. ALKBH4 knockdown downregulated E2F transcription factor 1 (E2F1) and its target gene expression in NSCLC cells. ALKBH4 and E2F1 expression was significantly correlated in NSCLC clinical specimens. Moreover, patients with high ALKBH4 expression showed a poor prognosis, suggesting that ALKBH4 plays a pivotal tumour-promoting role in NSCLC.

scholarly journals BSCI-18. Identifying novel drivers of lung-to-brain metastasis through in vivo functional genomics

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii5-iii5
Author(s):  
Nikoo Aghaei ◽  
Fred C Lam ◽  
Ekkehard Kasper ◽  
Chitra Venugopal ◽  
Sheila Singh
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Genome Wide ◽  
Crispr Activation

Abstract Introduction Brain metastases, the most common tumors of the central nervous system, occur in approximately 20% of primary adult cancers. In particular, 40% of patients with non-small cell lung cancer develop brain metastasis. As systemic therapies for the treatment of non-small cell lung cancer become increasingly effective at controlling primary disease, patients are ironically succumbing to their brain metastases. This highlights a large unmet need to develop novel targeted therapies for the treatment of lung-to-brain metastases (LBM). We hypothesize that an in vivo functional genomic screen can identify novel genes that drive LBM. Methods To do this, we developed a patient-derived xenograft (PDX) mouse model of LBM using patient lung cancer cell lines. This PDX model of LBM enables the use of fluorescent and bioluminescent in vivo imaging to track the progression of lung tumor and brain metastases. Results We have performed an in vivo genome-wide CRISPR activation screening to identify novel drivers of LBM. We will derive candidate genes through mouse brain and lung tissue sequencing after mice reach endpoint. Expected Area of findings This platform will lead to potential therapeutic targets to prevent the formation of LBM and prolong the survival of patients with non-small cell lung cancer. Limitations There may be limitations in getting candidate hits that overlap in all mice in our first replicate. This can be remedied by conducting the in vivo screen in at least three biological replicates. Conclusion To the best of our knowledge, this is the first genome-wide in vivo CRISPR activation screen searching for drivers of LBM using a PDX animal model. This study can provide a framework to gain a deeper understanding of the regulators of BM formation which will hopefully lead to targeted drug discovery.

scholarly journals Bevacizumab suppresses the growth of established non-small-cell lung cancer brain metastases in a hematogenous brain metastasis model

2019 ◽  
Vol 37 (1) ◽  
pp. 199-207
Author(s):  
Chinami Masuda ◽  
Masamichi Sugimoto ◽  
Daiko Wakita ◽  
Makoto Monnai ◽  
Chisako Ishimaru ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Nsclc Cell Line ◽  
Small Cell Lung ◽  
The Brain

AbstractBrain metastases are common in patients with non-small-cell lung cancer (NSCLC). The efficacy of bevacizumab, an anti-vascular endothelial growth factor (VEGF) humanized antibody, has been demonstrated in patients with nonsquamous NSCLC. We established a transplantable NSCLC cell line (Nluc-H1915) that stably expresses NanoLuc® reporter and confirmed the correlation between total Nluc activity in tumor and tumor volume in vivo. SCID mice inoculated with these cells through the internal carotid artery formed reproducible brain metastases, in which human VEGF was detected. Next, after metastases were established in the model mice (15–17 days), they were intraperitoneally administered weekly doses of human immunoglobulin G (HuIgG) or bevacizumab. Nluc activity in the brain was significantly lower in bevacizumab-treated mice than in HuIgG-treated mice. Additionally, bevacizumab concentration in the brain was higher in mice with brain metastasis than in normal mice, and bevacizumab was primarily observed in brain metastasis lesions. The microvessel density in brain metastasis was lower in bevacizumab-treated mice than in HuIgG-treated mice. We believe bevacizumab’s anti-proliferative effect on brain metastasis is due to anti-angiogenic activity achieved by its penetration into brain metastases; this suggests that a bevacizumab-containing regimen may be a promising treatment option for patients with NSCLC brain metastasis.

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