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  • 1
    Keywords: GENE-EXPRESSION ; IN-SITU ; COMPARATIVE GENOMIC HYBRIDIZATION ; STEM-CELLS ; CARCINOMAS ; CHROMOSOMAL ALTERATIONS ; CLONAL EVOLUTION ; ADENOCARCINOMA PATIENTS ; CD117 IMMUNOREACTIVITY ; FREE DEFINED MEDIUM
    Abstract: BACKGROUND: Cell lines play an important role for studying tumor biology and novel therapeutic agents. Particularly in pulmonary squamous cell carcinoma (SCC) the availability of cell lines is limited and knowledge about their representativeness for corresponding tumor tissue is scanty. MATERIALS AND METHODS: We established three novel SCC cell lines from fresh tumor tissue of 28 donors, including 8 SCC. Two cell lines were derived from different localizations of the same donor, i.e. primary tumor and lymph node metastasis. This represents a so far unique combination in lung cancer. The genotypes, gene expression profiles and mutational status of epidermal growth factor receptor (EGF-R) and Kirsten rat sarcoma (k-ras) of the cell lines and their corresponding tumor tissue were analyzed and compared. Moreover, the molecular characteristics were related to functional properties of the cell lines. Those comprised proliferation, motility and chemosensitivity. The cell lines were authenticated by single tandem repeat DNA typing. Tumorigenicity was analyzed in a murine xenograft model. RESULTS: Comparative genomic hybridization and multiplex fluorescence in situ hybridization revealed essential genetic similarities between the cell lines and their corresponding tumor tissue, but indicated also some genetic evolution and clonal selection. EGF-R or k-ras mutations were not detected. Gene expression profiling showed various differences between tumor tissue and cell lines affecting gene clusters associated with immune response, adhesion, proliferation, differentiation and angiogenesis. However, there were also common gene expression patterns reflecting the relationship between cell lines and their corresponding tumor tissue. Moreover, the molecular characteristics of the tumor tissue and the descendent cell line were associated with functional properties of the latter. All cell lines showed a unique, heterozygous human DNA profile and one cell line displayed rapid tumor formation in mice. CONCLUSIONS: Here, we demonstrate that cell lines represent a useful in vitro system for studying basic mechanisms in lung cancer, but cover only distinct molecular characteristics of the original tumor. Moreover, we present three novel, comprehensively characterized SCC cell lines.
    Type of Publication: Journal article published
    PubMed ID: 21684623
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  • 2
    Keywords: CANCER ; SURVIVAL ; BIOMARKERS ; RECURRENCE ; SIGNATURES ; MICRORNA EXPRESSION PROFILES
    Abstract: The outcome of resectable non-small cell lung cancer (NSCLC) is critically determined by metastatic spread: About 30-50% of early-stage NSCLC patients encounter tumour recurrence within 5 years after surgery. A biomarker-driven stratification of early-stage lung cancer with a high risk of recurrence may improve therapy management and patient care. The aim of this study was to identify microRNAs (miRNAs) in serum of patients associated with early relapse in pulmonary adenocarcinoma. Serum samples were collected from 204 patients before surgery. miRNA screening was done using qRT-PCR based low-density arrays (664 miRNAs) comparing adenocarcinoma patients (n = 40) with and without recurrence 24 months after surgery. Selected miRNAs associated with disease recurrence were Validated in an independent patient cohort (n = 114). miRNAs were also measured in advanced adenocarcinoma patients (n = 29), and individuals with benign pulmonary diagnosis (n = 21). Circulating miR-142-3p (p = 0.005) and miR-29b (p = 0.01) were identified in the screening and confirmed in the validation cohort to be increased in sera of early-stage adenocarcinoma patients suffering from recurrence within 24 months. Elevated miRNA levels were exclusively observed in the group of high-risk patient diagnosed for operable adenocarcinoma compared with benign diagnosis or advanced tumour disease. The differentiation between pulmonary adenocarcinoma patients with low and high risk for recurrence was improved by accounting for both miR-142-3p levels and tumour stage (p = 0.007; AUC = 0.78). In conclusion, circulating miR-142-3p was found to be associated with a high risk of recurrence in early-stage lung adenocarcinoma patients, and a putative serum marker for risk assessment.
    Type of Publication: Journal article published
    PubMed ID: 23410826
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  • 3
    Abstract: The growth of a tumor depends to a certain extent on an increase in mitotic events. Key steps during mitosis are the regulated assembly of the spindle apparatus and the separation of the sister chromatids. The microtubule-associated protein Aurora kinase A phosphorylates DLGAP5 in order to correctly segregate the chromatids. Its activity and recruitment to the spindle apparatus is regulated by TPX2. KIF11 and CKAP5 control the correct arrangement of the microtubules and prevent their degradation. In the present study, we investigated the role of these five molecules in non-small cell lung cancer (NSCLC). We analyzed the expression of the five genes in a large cohort of NSCLC patients (n=362) by quantitative real-time PCR. Each of the genes was highly overexpressed in the tumor tissues compared to corresponding normal lung tissue. The correlation of the expression of the individual genes depended on the histology. An increased expression of AURKA, DLGAP5, TPX2, KIF11 and CKAP5 was associated with poor overall survival (P=0.001-0.065). AURKA was a significant prognostic marker using multivariate analyses (P=0.006). Immunofluorescence studies demonstrated that the five mitosis-associated proteins co-localized with the spindle apparatus during cell division. Taken together, our data demonstrate that the expression of the mitosis-associated genes AURKA, DLGAP5, TPX2, KIF11 and CKAP5 is associated with the prognosis of NSCLC patients.
    Type of Publication: Journal article published
    PubMed ID: 28101582
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  • 4
    Keywords: APOPTOSIS ; TISSUE ; BONE-MARROW ; BREAST ; microenvironment ; STROMAL CELLS ; tumor stroma ; GENE-EXPRESSION SIGNATURE ; CARCINOMA-ASSOCIATED FIBROBLASTS ; FACTOR PATHWAY INHIBITOR-2
    Abstract: BACKGROUND: Cancer-associated fibroblasts (CAF) play a vital role in lung cancer initiation and progression. Although mesenchymal stem cells (MSC) are considered progenitor cells of fibroblasts and show cancer modulating abilities themselves, analyses on their presence and properties in lung cancer are lacking so far. METHODS: We performed a comparative molecular and functional analysis of MSC derived from non-small cell lung cancer (NSCLC) and corresponding normal lung tissue (NLT) of a total of 15 patients. MSC were identified and selected according to their mesenchymal multilineage differentiation capability and surface marker profile. RESULTS: Compared to NLT-MSC, NSCLC-MSC showed accelerated growth kinetics and reduced sensitivity to cisplatin. Karyotyping, comparative genomic hybridization and multiplex fluorescence in situ hybridization revealed no chromosomal aberrations. However, gene expression profiling of NSCLC- and NLT-MSC indicated variable expression of 62 genes involved in proliferation, DNA repair, apoptosis, extracellular matrix synthesis, tissue remodeling and angiogenesis. Differential expression of the selected candidate genes butyrylcholinesterase, clusterin and quiescin Q6 sulfhydryl oxidase 1 was validated by quantitative real-time PCR and, on protein level, by immunohistochemical analyses of original tumor tissue. Upon exposure to tumor cell-conditioned medium or transforming growth factor-beta, both, NSCLC-MSC and NLT-MSC acquired expression of alpha-smooth muscle actin (alpha-SMA), a major characteristics of CAF. CONCLUSIONS: This study indicates that NSCLC tissue contains MSC with specific molecular and functional properties. These cells might represent a progenitor reservoir for CAF and thus crucially contribute to lung cancer progression.
    Type of Publication: Journal article published
    PubMed ID: 23294501
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  • 5
    Keywords: EXPRESSION ; IN-VIVO ; EMPHYSEMA ; NF-KAPPA-B ; TRANSPORT ; PHENOTYPE ; OBSTRUCTIVE PULMONARY-DISEASE ; IL-1-BETA ; OVEREXPRESSING MICE ; TRANSMEMBRANE CONDUCTANCE REGULATOR
    Abstract: RATIONALE: In many organs, hypoxic cell death triggers sterile neutrophilic inflammation via IL-1R signaling. Although hypoxia is common in airways from patients with cystic fibrosis (CF), its role in neutrophilic inflammation remains unknown. We recently demonstrated that hypoxic epithelial necrosis caused by airway mucus obstruction precedes neutrophilic inflammation in Scnn1b-transgenic (Scnn1b-Tg) mice with CF-like lung disease. OBJECTIVES: To determine the role of epithelial necrosis and IL-1R signaling in the development of neutrophilic airway inflammation, mucus obstruction, and structural lung damage in CF lung disease. METHODS: We used genetic deletion and pharmacologic inhibition of IL-1R in Scnn1b-Tg mice and determined effects on airway epithelial necrosis; levels of IL-1alpha, keratinocyte chemoattractant, and neutrophils in bronchoalveolar lavage; and mortality, mucus obstruction, and structural lung damage. Furthermore, we analyzed lung tissues from 21 patients with CF and chronic obstructive pulmonary disease and 19 control subjects for the presence of epithelial necrosis. MEASUREMENTS AND MAIN RESULTS: Lack of IL-1R had no effect on epithelial necrosis and elevated IL-1alpha, but abrogated airway neutrophilia and reduced mortality, mucus obstruction, and emphysema in Scnn1b-Tg mice. Treatment of adult Scnn1b-Tg mice with the IL-1R antagonist anakinra had protective effects on neutrophilic inflammation and emphysema. Numbers of necrotic airway epithelial cells were elevated and correlated with mucus obstruction in patients with CF and chronic obstructive pulmonary disease. CONCLUSIONS: Our results support an important role of hypoxic epithelial necrosis in the pathogenesis of neutrophilic inflammation independent of bacterial infection and suggest IL-1R as a novel target for antiinflammatory therapy in CF and potentially other mucoobstructive airway diseases.
    Type of Publication: Journal article published
    PubMed ID: 25607238
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  • 6
    Keywords: tomography ; MANAGEMENT ; HIGH-RISK PATIENTS ; CLINICAL-PRACTICE ; AMERICAN-COLLEGE ; CHEST PHYSICIANS
    Abstract: BACKGROUND: The best therapy for patients with stage I non-small cell lung cancer (NSCLC) who are medically unfit for lobectomy or prefer not to undergo surgery has not yet been demonstrated. OBJECTIVES: We analyzed data from our prospective database to evaluate the recurrence and survival rates and assess the extent to which the type of treatment explains outcome differences. METHODS: This study included 116 patients with histologically proven clinical stage I NSCLC who were treated with sublobar resection (SLR; n = 42), radiofrequency ablation (RFA; n = 25) or radiotherapy (RT; n = 49) between 2009 and 2013. The primary end point was the time to primary tumor recurrence (PR). Kaplan-Meier curves and Cox regression were used to compare the recurrence patterns and survivals after adjustments for potential confounders. RESULTS: The SLR patients were younger and exhibited better performance status. The RT patients had larger tumors. After adjusting for age and tumor size, there were differences between the different treatments in terms of the PR rate, but no differences were observed in overall (OS) or disease-free survival. The hazard ratio for PR comparing SLR versus RT adjusted for age and tumor size was 2.73 (95% confidence interval, CI, 0.72-10.27) and that for SLR versus RFA was 7.57 (95% CI 1.94-29.47). CONCLUSIONS: Our study suggests that SLR was associated with a higher primary tumor control rate compared to RFA or RT, although the OSs were not different. These results should be confirmed in prospective trials. (c) 2015 S. Karger AG, Basel.
    Type of Publication: Journal article published
    PubMed ID: 25968471
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  • 7
  • 8
    Keywords: CANCER ; CELLS ; tumor ; SYSTEM ; ASSOCIATION ; metastases ; RADIOFREQUENCY ABLATION ; lung neoplasms ; HISTOLOGY ; Local thermal therapy ; PULMONARY TUMORS
    Abstract: Objective: Radiofrequency ablation (RFA) has obtained increasing attention as an interventional approach for the local treatment of primary and secondary lung neoplasms. The local effect of the procedure is usually controlled by radiologic means. The objectives of this 'ablate and resect' study were to investigate the efficacy of bipolar and multipolar RFA by histologic evaluation and to compare the two techniques. Methods: In a total of 32 subjects with histologically proven non-small-cell lung cancer or pulmonary metastases from an extrathoracic primary tumor, bipolar, or multipolar RFA was performed during open thoracotomy. Curative resection (lobectomy or wedge resection including mediastinal lymph node dissection) was performed subsequently. The extent of cell death and early histologic findings following RFA were determined by histology and immunohistochemistry (nicotinamide adenine dinucleotide (NADH) and monoclonal anti-mitochondrial antibodies MAB 1273). Results: Intra-operative bipolar and multipolar RFA is a safe procedure, and there was no bleeding or thermal damage of the lung tissue. Routine histologic staining could not identify tumor cell death. However, immunohistochemistry was able to verify cell death in the ablated tumor tissue. Complete tumor cell necrosis was determined in 12 tumors (37.5%); and scattered vital tumor tissue was detected in 16 tumors (50%). Incomplete ablation with a ratio of 〉20% vital tumor tissue was found in four tumors (12.5%), particularly surrounding vascular structures within the tumor tissue or in marginal zones of the tumor tissue. The local efficacy of bipolar and multipolar RFA was comparable, and incomplete ablations were found only in adenocarcinoma. Conclusions: Bipolar and multipolar RFA in an open thoracotomy setting is a technically feasible and safe procedure. Early immunohistochemical findings after RFA showed complete tumor cell necrosis in 38% of cases. The high rate of viable tumor cells remaining after ablation casts doubt on RFA as a curative concept. This approach should be reserved for palliative indications. Patients fulfilling the criteria for curative resection should not be denied surgery.
    Type of Publication: Journal article published
    PubMed ID: 20961771
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