Decline in serum soluble E-cadherin and low baseline matrix metalloproteinase-9 are associated with response to combination celecoxib and erlotinib therapy in advanced non-small cell lung cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7640-7640
Author(s):  
K. L. Reckamp ◽  
B. K. Gardner ◽  
R. A. Figlin ◽  
D. Elashoff ◽  
K. Krysan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Combination Therapy ◽  
Matrix Metalloproteinase ◽  
Epithelial To Mesenchymal Transition ◽  
Advanced Nsclc ◽  
Mesenchymal Transition ◽  
Best Response ◽  
Cox 2 ◽  
E Cadherin

7640 Background: Cyclooxygenase-2 (COX-2) overexpression may mediate resistance to EGFR TK inhibition through prostaglandin E2 (PGE2)-dependent promotion of epithelial to mesenchymal transition (EMT). Thomson, et al. reported that the suppression of epithelial markers such as E-cadherin led to resistance to erlotinib (Cancer Res 2005;65:9455). In addition, PGE2 downregulates E-cadherin expression by upregulating transcriptional repressors including ZEB1 and Snail, as described by Dohadwala et al (Cancer Res 2006;66:5338). These findings suggest that COX-2 inhibition may enhance the efficacy of EGFR TKI therapy in NSCLC. Methods: A phase I, dose escalation trial to was performed investigating the combination of celecoxib and erlotinib in pts with advanced NSCLC. Soluble E-cadherin (sEC) was evaluated by ELISA in pt serum at baseline and weeks 4 and 8 of treatment. Other markers of COX-2 gene expression were evaluated by ELISA, including matrix metalloproteinase (MMP)-9, MMP-2 and tissue inhibitor of MMP (TIMP1). Results: 22 pts were enrolled and 21 were evaluable for the determination of the optimal dose, toxicity assessment and response (reported in Clin Cancer Res 2006;12:3381). Here we report serum sEC and MMP-9 levels, which were analyzed according to best response (PR, SD or PD) in 21 pts. SEC was analyzed according to best response (PR, SD or PD). We found a significant decrease in sEC between baseline and week 8 in pts with PR when compared to those with SD or PD (p = 0.021). In pts who responded to the combination therapy, baseline MMP-9 was significantly lower compared to non-responders (p = 0.006). Conclusions: SEC, MMP-9 and other downstream markers of COX-2 gene expression may be useful for assessing response to combination celecoxib and erlotinib in pts with advanced NSCLC. A randomized Phase II trial is planned comparing erlotinib and celecoxib with erlotinib plus placebo in advanced NSCLC, to evaluate the efficacy of this combination therapy and to assess these and other biomarkers in both serum and tumor tissue. Supported by ASCO Young Investigator Award, UCLA Lung Cancer SPORE NCI P50 CA 90388 and GLAVAHS Career Development Award. No significant financial relationships to disclose.

scholarly journals ZEB1/NuRD complex suppresses TBC1D2b to stimulate E-cadherin internalization and promote metastasis in lung cancer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Roxsan Manshouri ◽  
Etienne Coyaud ◽  
Samrat T. Kundu ◽  
David H. Peng ◽  
Sabrina A. Stratton ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Nurd Complex ◽  
Gtpase Activating Protein ◽  
Invasion And Metastasis ◽  
Small Cell Lung ◽  
Mesenchymal Transition ◽  
Proposed Model ◽  
Complex Target ◽  
E Cadherin

Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, due in part to the propensity of lung cancer to metastasize. Aberrant epithelial-to-mesenchymal transition (EMT) is a proposed model for the initiation of metastasis. During EMT cell-cell adhesion is reduced allowing cells to dissociate and invade. Of the EMT-associated transcription factors, ZEB1 uniquely promotes NSCLC disease progression. Here we apply two independent screens, BioID and an Epigenome shRNA dropout screen, to define ZEB1 interactors that are critical to metastatic NSCLC. We identify the NuRD complex as a ZEB1 co-repressor and the Rab22 GTPase-activating protein TBC1D2b as a ZEB1/NuRD complex target. We find that TBC1D2b suppresses E-cadherin internalization, thus hindering cancer cell invasion and metastasis.

scholarly journals Sinomenine Inhibits Migration and Invasion of Human Lung Cancer Cell through Downregulating Expression of miR-21 and MMPs

2020 ◽  
Vol 21 (9) ◽  
pp. 3080 ◽  
Author(s):  
Kun-Hung Shen ◽  
Jui-Hsiang Hung ◽  
Yi-Ching Liao ◽  
Shu-Ting Tsai ◽  
Ming-Jiuan Wu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Matrix Metalloproteinase ◽  
Cell Invasion ◽  
Human Lung ◽  
Human Lung Cancer ◽  
Matrix Metalloproteinase 2 ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
E Cadherin

Sinomenine is an alkaloid derived from Sinomenium acutum. Recent studies have found that sinomenine can inhibit various cancers by inhibiting the proliferation, migration and invasion of tumors and inducing apoptosis. This study aims to investigate the effect and mechanism of sinomenine on inhibiting the migration and invasion of human lung adenocarcinoma cells in vitro. The results demonstrate that viabilities of A549 and H1299 cells were inhibited by sinomenine in a dose-dependent manner. When treated with sub-toxic doses of sinomenine, cell migration and invasion are markedly suppressed. Sinomenine decreases the mRNA level of matrix metalloproteinase-2 (MMP-2), MMP-9, and the extracellular inducer of matrix metalloproteinase (EMMPRIN/CD147), but elevates the expression of reversion-inducing cysteine-rich proteins with kazal motifs (RECK) and the tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2. In addition, sinomenine significantly increases the expression of the epithelial marker E-cadherin but concomitantly decreases the expression of the mesenchymal marker vimentin, suggesting that it suppresses epithelial–mesenchymal transition (EMT). Moreover, sinomenine downregulates oncogenic microRNA-21 (miR-21), which has been known to target RECK. The downregulation of miR-21 decreases cell invasion, while the upregulation of miR-21 increases cell invasion. Furthermore, the downregulation of miR-21 stimulates the expression of RECK, TIMP-1/-2, and E-cadherin, but reduces the expression of MMP-2/-9, EMMPRIN/CD147, and vimentin. Taken together, the results reveal that the inhibition of A549 cell invasion by sinomenine may, at least in part, be through the downregulating expression of MMPs and miR-21. These findings demonstrate an attractive therapeutic potential for sinomenine in lung cancer anti-metastatic therapy.

scholarly journals Detachment-induced E-cadherin expression promotes 3D tumor spheroid formation but inhibits tumor formation and metastasis of lung cancer cells

2017 ◽  
Vol 313 (5) ◽  
pp. C556-C566 ◽  
Author(s):  
Phattrakorn Powan ◽  
Sudjit Luanpitpong ◽  
Xiaoqing He ◽  
Yon Rojanasakul ◽  
Pithi Chanvorachote
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Tumor Formation ◽  
Lung Cancer Cells ◽  
Tumor Spheroid ◽  
Mesenchymal Transition ◽  
E Cadherin

The epithelial-to-mesenchymal transition is proposed to be a key mechanism responsible for metastasis-related deaths. Similarly, cancer stem cells (CSCs) have been proposed to be a key driver of tumor metastasis. However, the link between the two events and their control mechanisms is unclear. We used a three-dimensional (3D) tumor spheroid assay and other CSC-indicating assays to investigate the role of E-cadherin in CSC regulation and its association to epithelial-to-mesenchymal transition in lung cancer cells. Ectopic overexpression and knockdown of E-cadherin were found to promote and retard, respectively, the formation of tumor spheroids in vitro but had opposite effects on tumor formation and metastasis in vivo in a xenograft mouse model. We explored the discrepancy between the in vitro and in vivo results and demonstrated, for the first time, that E-cadherin is required as a component of a major survival pathway under detachment conditions. Downregulation of E-cadherin increased the stemness of lung cancer cells but had an adverse effect on their survival, particularly on non-CSCs. Such downregulation also promoted anoikis resistance and invasiveness of lung cancer cells. These results suggest that anoikis assay could be used as an alternative method for in vitro assessment of CSCs that involves dysregulated adhesion proteins. Our data also suggest that agents that restore E-cadherin expression may be used as therapeutic agents for metastatic cancers.

Randomized phase II trial of erlotinib (E) plus high-dose celecoxib (HD-C) or placebo (P) in advanced non-small cell lung cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7518-7518
Author(s):  
Karen L. Reckamp ◽  
Marianna Koczywas ◽  
Mihaela C. Cristea ◽  
Jonathan Dowell ◽  
Brian Gardner ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Kinase Inhibitor ◽  
Smoking Status ◽  
High Dose ◽  
Primary Resistance ◽  
Mesenchymal Transition ◽  
Egfr Inhibition ◽  
Cox 2 ◽  
Egfr Tki ◽  
E Cadherin

7518 Background: Cyclooxygenase-2 (COX-2)-dependent signalling represents a potential mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in NSCLC. This is mediated in part through an EGFR-independent activation of MAPK/Erk by the COX-2 metabolite PGE2. In addition, PGE2 promotes downregulation of E-cadherin and epithelial to mesenchymal transition. We hypothesize that EGFR and COX-2 inhibition with E and HD-C will augment EGFR TKI efficacy by increasing tumor E-cadherin expression and blocking PGE2-mediated resistance to EGFR inhibition. Methods: Pts with stage IIIB/IV NSCLC who progressed following at least one line of therapy or refused standard chemotherapy were randomized to E (150mg/day)/HD-C (600mg/2x day) vs E/P in a 28-day cycle. Pts were stratified by smoking status and ECOG PS. The primary endpoint was PFS with 80% power to detect a 50% improvement; assessments were performed every 2 cycles. Secondary endpoints included response rate, OS and evaluation of molecular markers in tissue and serum to assess targeting COX-2-related pathways and evaluate EGFR TKI-resistance. All pts were required to have pre-treatment tissue available. Results: 107 pts were enrolled with comparable baseline characteristics in both arms. Disease control rate (DCR) was similar in both arms, and a trend toward improved PFS was seen in the E/HD-C arm with HR 0.81 (see Table). Analysis of those with EGFR wild type revealed a significantly increased PFS while those with EGFR mutation had similar PFS in both groups. Safety analysis showed similar toxicity in both arms. Additional biomarker correlations will be presented. Conclusions: The combination of E/C in metastatic NSCLC with HD-C is well tolerated and demonstrates significantly improved efficacy in EGFR wt population. This warrants further study into the COX-2-dependent mechanisms of primary resistance to EGFR TKI therapy. Supported by NIH 1P50 CA90388, K12 CA01727 and medical research funds from the Dept of Veterans’ Affairs. [Table: see text]

scholarly journals Krüppel-like Factor 4 Inhibits Epithelial-to-Mesenchymal Transition through Regulation of E-cadherin Gene Expression

2010 ◽  
Vol 285 (22) ◽  
pp. 16854-16863 ◽  
Author(s):  
Jennifer L. Yori ◽  
Emhonta Johnson ◽  
Guangjin Zhou ◽  
Mukesh K. Jain ◽  
Ruth A. Keri
Keyword(s):  
Gene Expression ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
E Cadherin
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