Association of epithelial-to-mesenchymal transition circulating tumor cells in non-small cell lung cancer (NSCLC) molecular subgroups

Messaritakis, Ippokratis; Κotsakis, Athanasios; Georgoulias, Vassilis

doi:10.21037/jtd.2017.11.106

Cited by 5 publications

(4 citation statements)

References 26 publications

(26 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with previous reports, CTCs in the current study could be detected in up to 90% of NSCLC patients. In line with previous studies regarding EMT in NSCLC patients, we noticed (Figures 2a and 4a) that Cytokeratins were downregulated in CTCs [5,26]. Particularly, tumor cells with a complete absence of cytokeratin expression (CK−/TUB+/CD45−) were detected in 19.05% of the pretreated patients (Figure 3a).…”

Section: Discussionsupporting

confidence: 90%

“…The enumeration and characterization of Circulating Tumor Cells is an important prognostic marker for NSCLC patients [5,24]. It is also widely accepted that CTCs could undergo Epithelial to Mesenchymal Transition in many different types of cancers, such as breast, colon, NSCLC, SCLC, etc., [26][27][28][29][30][31][32]. Particularly, the expression of epithelial markers in CTCs derived from NSCLC patients is extremely low, thus their detection based on common epithelial antigen makes them invisible in the bloodstream [5,25].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Detyrosinated α-Tubulin, Vimentin and PD-L1 in Circulating Tumor Cells (CTCs) Isolated from Non-Small Cell Lung Cancer (NSCLC) Patients

Katsarou

Messaritakis

Voumvouraki

et al. 2022

JPM

Self Cite

View full text Add to dashboard Cite

Upregulation of Vimentin (VIM), alpha-Tubulin (TUB) and Detyrosinated tubulin (GLU) in circulating tumor cells (CTCs) derived from breast cancer patients is related to poor prognosis. In the current study we evaluated for the first time, these cytoskeletal proteins in sixty Non-Small Cell Lung Cancer (NSCLC) patients’ CTCs (33 treatment-naïve and 27 pre-treated). Samples were isolated using the ISET platform and stained with a pancytokeratin (CK)/CD45/TUB, CK/GLU/VIM and CK/programmed death ligand 1 (PD-L1) combination of antibodies. Subsequently, slides were analyzed using confocal laser scanning microscopy. CTCs were detected in 86.7% of the patients. CTCs with TUB expression were identified in 65.4% (34/52) of the CK (+)-patients. GLU, VIM and PD-L1 were also evaluated. The frequency of the observed phenotypes was as follow: (CK+/GLU−/VIM−): 35.2%, (CK+/GLU+/VIM+): 63.0%, (CK+/GLU+/VIM−): 16.7%, (CK+/GLU−/VIM+): 72.2%, (CK+/PD-L1−): 75% and (CK+/PD-L1+): 55%. The OS was significantly decreased in patients with high GLU (3.8 vs. 7.9 months; p = 0.018) and/or high VIM (3.2 vs. 7.1 months; p = 0.029) expression in their CTCs. PD-L1 was also related to OS (3.4 vs. 7.21 months; p = 0.035). Moreover, TUB-high and TUB-low expression in CTCs inversely influenced patients’ OS as independent prognostic factors (p = 0.041 and p = 0.009). The current study revealed that TUB, GLU, VIM and PD-L1 were overexpressed in CTCs from NSCLC patients. Furthermore, the presence of GLU, VIM-positive and PD-L1 in CTCs is potentially related to patients’ outcomes.

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Detyrosinated α-Tubulin, Vimentin and PD-L1 in Circulating Tumor Cells (CTCs) Isolated from Non-Small Cell Lung Cancer (NSCLC) Patients

Katsarou

Messaritakis

Voumvouraki

et al. 2022

JPM

Self Cite

View full text Add to dashboard Cite

show abstract

“…A study demonstrated EMT as a hallmark of cancer in the initiation of cancer cell migration and invasion (7). EMT is related to treatment failure in lung cancer (41), and suppressing the molecular mechanisms of EMT has been suggested as an anti-metastasis strategy (36,42). Certain integrins are emerging as pivotal factors in preventing cancer cell apoptosis during metastasis.…”

Section: Discussionmentioning

confidence: 99%

DS-1 Inhibits Migration and Invasion of Non-small-cell Lung Cancer Cells Through Suppression of Epithelial to Mesenchymal Transition and Integrin β1/FAK Signaling

2021

View full text Add to dashboard Cite

Background/Aim: Epithelial to mesenchymal transition (EMT), and focal adhesion kinase (FAK) facilitate lung cancer cell motility and survival. We, therefore, investigated the antimigratory effect of 3,4-dihydroxy-5,4'-dimethoxybibenzyl (DS-1) on human lung cancer cells. Materials and Methods: Cell viability and proliferation were examined by the 3-[4,5dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide assay. Filopodia formation, migration, and anchorage-independent growth assays were performed to assess metastatic behaviors while EMT-related proteins, integrins, and FAK-RhoA pathway were evaluated by western blot analysis. Results: We found that DS-1 significantly inhibited the proliferation of lung cancer cells compared to the control. The aggressive behavior of cancer cells, including migration and invasion, was significantly reduced by DS-1. Anchorage-independent growth analysis provided evidence that DS-1 suppressed the growth and survival of cancer cells in detached conditions as indicated by the significant reduction in size and number of colonies. With regard to the mechanisms involved, we found that DS-1-suppressed EMT, as indicated by the reduction of EMT markers, namely Ncadherin, SNAIL and SLUG, and increased levels of the epithelial marker, E-cadherin. In addition, DS-1 was shown to reduce the level of integrin β1 protein and FAK activation. Conclusion: DS-1 suppressed lung cancer metastasis via suppressing EMT, integrin β1 expression and FAK-related signaling.Metastasis is the primary cause of cancer-related morbidity and mortality. Lung cancer is often diagnosed at a late stage with metastasis (1). Studies reported that 20-40% of advanced lung cancer patients develop brain metastases, which significantly reduces their quality of life (2, 3). Metastatic cancer cells resist therapy (4) and, due to their increased migration and invasion, actively spread, leading to the formation of secondary tumors (5).The change of cancer cell phenotype from epithelial into motile mesenchymal cells through the epithelial-mesenchymal transition (EMT) is essential for migration, invasion, and survival in detached conditions during metastasis (6, 7). The major hallmarks of this process are the loss of cell polarity, dissociation of cell-cell junctions, and restructuring of the extracellular matrix (8). Along with EMT progression, expression of motility-and adhesion-regulatory proteins is altered, including the switch from E-cadherin to N-cadherin (9, 10). N-Cadherin facilitates the interaction of cancer and stromal cells, facilitating cancer cell migration and invasion (8,11,12). Both E-cadherin and N-cadherin are adherens junction molecules (13). However, E-cadherin expression is exhibited in epithelial tissue and contributes to maintaining cell integrity and homeostasis. Expression of E-cadherin has been correlated with better prognosis and long-term overall survival in patients with lung cancer (11). In contrast, N-cadherin is mostly expressed in mesenchymal cells and is associated with cell motility (14). Thus, c...

show abstract

“…The mechanisms of DS-1 on NSCLC; DS-1 interacts with MDM2 resulting in accumulating p53 intracellular protein prevent p53 ubiquitination, as observer DS-1 reduces ubiquitin-p53 complex.For cancer metastasis, despite EMT phenomenon in such cellular biology taking place in many processes during the development of living cells, aberration EMT has been associated with metastasis and resistance evolvement in many types of cancer cells(Savagner 2010;Xiao and He 2010). A study has conclusively demonstrated EMT as cancer hallmark is purposed for the initiation of cancer cell migration and invasion, which is related to the risk of lung cancer in treatment failure(Messaritakis et al, 2017). Suppressing molecular mechanisms governing EMT has been considered an effective target for anticancer strategies in many preclinical and early-clinical study(Yang et al, 2019).…”

mentioning

confidence: 99%

3,4-dihydroxy-5,4-dimethoxybibenzyl sensitizes non-small cell lung cancer cells to cisplatin-induced apoptosis via p53 upregulation

Putri

View full text Add to dashboard Cite

Lung cancer is a leading fatal malignancy with the highest number of cancer deaths. Targeting a specific protein regulating cancer progression and metastasis has been attracting much attention for the development of cancer therapy. Thus, this study was aimed to investigate the effect of 3,4-dihydroxy-5,4?-dimethoxybibenzyl (DS-1) in targeting MDM2-attenuating p53 function and inhibition EMT in lung cancer cells. The efficacy of DS-1 or combined with cisplatin in lung cancer cells was determined by MTT, nuclear staining, and Annexin V/PI assays. The expression of apoptosis- and EMT-related proteins was determined by western blot analysis. Metastatic behaviors were evaluated by cell shape�characterization, migration, invasion, and anchorage-independent cell growth assay. To investigate the role of DS-1 on stabilization and degradation of p53, cycloheximide chasing assay and immunoprecipitation were conducted, and the active form of p53 was investigated by immunofluorescent staining assay. To confirm and demonstrate the site interaction between DS-1 and MDM2 protein, the in silico computational analysis was performed. The results showed that DS-1 exhibited a cytotoxic effect and sensitized lung cancer cells to cisplatin-induced apoptosis. DS-1 caused a significant increase in cellular level of p53 protein, while the active form of p53 (phosphorylation at Ser15) was insignificant change. DS-1 combined with cisplatin could enhance p-p53 (Ser15) and p53 downstream signaling (Bax, Bcl-2, and Akt), leading to higher level of apoptosis. Immunoprecipitation analysis revealed that DS-1 decreased p53-ubiquitin complex, a prerequisite step of p53 proteasomal degradation. Molecular docking simulation further evidenced that DS-1 interacts with MDM2 within p53-binding domain by carbon-hydrogen bond interaction at Lys27, ?-Alkyl interactions at Ile37, and Leu30, and Van der Waals interactions at Ile75, Val51, Val69, Phe67, Met38, Tyr43, Gly34, Phe31, and Lys27. Treatment of DS-1 and cisplatin in patient-derived primary lung cancer cells showed the consistent effects of increasing cisplatin sensitivity. For cancer metastasis, DS-1 significantly inhibited the proliferation of lung cancer cells compared to the control group. The aggressive behavior of cancer cells including migration and invasion ability was significantly reduced in the DS-1-treated cells. Besides, anchorage-independent growth analysis provides evidence that DS-1 could suppress the growth of the cancer cell in detached condition indicated by the significant reduction in cell colony size and number. For mechanisms, we found that DS-1 suppressed EMT indicated by the reduction of EMT markers namely N-cadherin, Snail, and Slug, while increasing epithelial maker of E-cadherin. Also, DS-1 was shown to decrease the cellular levels of integrin ?1. Our findings provide evidence of DS-1 as an MDM2 inhibitor and metastasis prevention through integrin and FAK suppression, which may benefit the development of this compound for lung cancer treatment.

show abstract

Association of epithelial-to-mesenchymal transition circulating tumor cells in non-small cell lung cancer (NSCLC) molecular subgroups

Cited by 5 publications

References 26 publications

Detyrosinated α-Tubulin, Vimentin and PD-L1 in Circulating Tumor Cells (CTCs) Isolated from Non-Small Cell Lung Cancer (NSCLC) Patients

Detyrosinated α-Tubulin, Vimentin and PD-L1 in Circulating Tumor Cells (CTCs) Isolated from Non-Small Cell Lung Cancer (NSCLC) Patients

DS-1 Inhibits Migration and Invasion of Non-small-cell Lung Cancer Cells Through Suppression of Epithelial to Mesenchymal Transition and Integrin β1/FAK Signaling

3,4-dihydroxy-5,4-dimethoxybibenzyl sensitizes non-small cell lung cancer cells to cisplatin-induced apoptosis via p53 upregulation

Contact Info

Product

Resources

About

Association of epithelial-to-mesenchymal transition circulating tumor cells in non-small cell lung cancer (NSCLC) molecular subgroups

Cited by 5 publications

References 26 publications

Detyrosinated α-Tubulin, Vimentin and PD-L1 in Circulating Tumor Cells (CTCs) Isolated from Non-Small Cell Lung Cancer (NSCLC) Patients

Detyrosinated α-Tubulin, Vimentin and PD-L1 in Circulating Tumor Cells (CTCs) Isolated from Non-Small Cell Lung Cancer (NSCLC) Patients

DS-1 Inhibits Migration and Invasion of Non-small-cell Lung Cancer Cells Through Suppression of Epithelial to Mesenchymal Transition and Integrin β1/FAK Signaling

3,4-dihydroxy-5,4-dimethoxybibenzyl sensitizes non-small cell lung cancer cells to cisplatin-induced apoptosis via p53 upregulation

Contact Info

Product

Resources

About

3,4-dihydroxy-5,4-dimethoxybibenzyl sensitizes non-small cell lung cancer cells to cisplatin-induced apoptosis via p53 upregulation