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E. Lang
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-026 - Activin A is Associated with Poor Prognosis and Promotes Metastatic Growth in Small Cell Lung Cancer (ID 5888)
14:30 - 14:30 | Author(s): E. Lang
- Abstract
Background:
Small cell lung cancer (SCLC) is a devastating malignancy characterized by resistance to therapy and poor clinical outcome. Therefore, identification of novel therapeutic strategies and non-invasive biomarkers that facilitate early detection and predict prognosis is urgently needed. Expression of the growth factor activin A (ActA), a member of the TGF beta superfamily, is deregulated in a number of malignancies. However, to date there is no data on the role of ActA in SCLC.
Methods:
In a cohort of SCLC patients (n=79) and in sex- and age-matched controls (n=66), plasma levels of ActA were measured by ELISA. The diagnostic value of plasma ActA was evaluated by ROC curve analysis. The mRNA and protein expression levels of ActA were analyzed in SCLC cell lines by qRT-PCR and by ELISA, respectively, and one of the cell lines with low baseline ActA expression was transfected with ActA and a control vector. The effect of ActA overexpression on the in vivo growth of SCLC cells was investigated in an orthotopic xenograft model.
Results:
Increased plasma ActA levels were found in patients with SCLC (vs. controls) and ActA levels were elevated in a TNM stage-dependent manner. Moreover, high ActA levels were associated with significantly shorter overall survival and multivariate analysis revealed that plasma ActA concentration is an independent negative prognostic factor in this patient cohort. With an area under the curve of 0.81 (95% CI: 0.74-0-0.88), circulating ActA was identified as a useful biomarker for the diagnosis of SCLC. Expression of ActA in SCLC cell lines was detected in vitro. Furthermore, ActA overexpression increased the metastatic capacity of SCLC cells in our xenograft model.
Conclusion:
Our findings suggest that the measurement of circulating ActA can support the diagnosis and staging of SCLC and, moreover, that it can help to predict the clinical outcome. We also conclude that ActA has a role in the aggressive behavior of this tumor type and that its potential therapeutic relevance needs to be further investigated.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-002 - Inducible Changes in Cell Morphology and Gene Expression Reflecting the Histological Subtypes of Mesothelioma (ID 5405)
14:30 - 14:30 | Author(s): E. Lang
- Abstract
Background:
Malignant pleural mesothelioma (MPM) represents an aggressive malignancy with dismal prognosis and limited therapeutic options. MPM occurs in three main histological subtypes: epithelioid, sarcomatoid and biphasic, which are characterized by differences in morphological growth pattern, aggressiveness and patient prognosis. However, the mechanisms and causes responsible for the different cell morphologies are poorly understood. Epithelial-mesenchymal transition (EMT) has been implicated in cancer progression and chemoresistance, but its role in MPM is not well understood. Fibroblast growth factor (FGF) signals promote cell growth, survival and aggressiveness in several tumors including mesothelioma. Aim of this study was to characterize growth factor-induced, EMT-like changes with respect to the MPM histological subtypes.
Methods:
Morphological and behavioral changes of treated cell models were analyzed by morphometry, immunoblotting and functional assays. Alterations in gene or microRNA expression were evaluated via qPCR and array hybridization. Pathway enrichment analysis was based on KEGG.
Results:
In several cell lines established from biphasic MPM, treatment with FGF2 and EGF induced morphological changes reminiscent of EMT and aggressive behavior such as scattering, increased migration, proliferation and invasiveness. Inhibition of the fibroblast growth factor receptors (FGFR) or the MAPK axis via small-molecule inhibitors could prevent these changes and, in cell lines with sarcomatoid-like shape, reverse scattering and induce a more epithelioid morphology. Comparable results were obtained using an engineered FGFR1 enabling contactless activation via blue light. Analyses of genes and microRNAs regulated by FGF2 or EGF showed an overlap with previously established EMT markers but also identified several novel potential markers such as MMP1, ESM1, ETV4, PDL1, ITGA6 or BDKRB2. Blocking the FGFR or MAPK pathways resulted in the opposite regulation of these genes. Inhibition of MMP1 via siRNAs or pharmacological inhibitors prevented FGF2-induced scattering and invasiveness. In unsupervised clustering, the gene expression profiles of solvent- or cytokine-treated cells were associated with those of epithelioid and sarcomatoid MPM, respectively. Immunohistochemistry showed an association of MMP1 as well as phospho-ERK with the sarcomatoid part of tissue specimens from biphasic tumors. Pathway enrichment analysis of differentially expressed genes as well as the targets of altered microRNAs after FGF2 treatment showed that the regulated genes are assigned to categories important for cell growth and aggressive behavior.
Conclusion:
Our data characterize FGFR-mediated signals as important players in MPM aggressiveness and the morphological and behavioral plasticity of mesothelioma cells, leading to a better understanding of the link between the MPM histological subtypes and their influence on patient outcome.
