Involvement of CCR6/CCL20/IL-17 Axis in NSCLC Disease Progression

OBJECTIVES: Autocrine and paracrine chemokine/chemokine receptor-based interactions promote non-small-cell-lung-cancer (NSCLC) carcinogenesis. CCL20/CCR6 interactions are involved in prostatic and colonic malignancy pathogenesis. The expression and function of CCL20/CCR6 and its related Th-17 type immune response in NSCLC is not yet defined. We sought to characterize the role of the CCL20/CCR6/IL-17 axis in NSCLC tumor growth. METHODS: A specialized histopathologist blindly assessed CCL20/CCR6 expression levels in 49 tissue samples of NSCLC patients operated in our department. Results were correlated to disease progression. Colony assays, ERK signaling and chemokine production were measured to assess cancer cell responsiveness to CCL20 and IL-17 stimulation. RESULTS: CCL20 was highly expressed in the majority (38/49, 77.5%) of tumor samples. Only a minority of samples (8/49, 16.5%) showed high CCR6 expression. High CCR6 expression was associated with a shorter disease-free survival (P = 0.008) and conferred a disease stage-independent 4.87-fold increased risk for disease recurrence (P = 0.0076, CI 95% 1.52-15.563). Cancerous cell colony-forming capacity was increased by CCL20 stimulation; this effect was dependent in part on ERK phosphorylation and signaling. IL-17 expression was detected in NSCLC; IL-17 potentiated the production of CCL20 by cancerous cells. CONCLUSION: Our findings suggest that the CCL20/CCR6 axis promotes NSCLC disease progression. CCR6 is identified as a potential new prognostic marker and the CCL20/CCR6/IL-17 axis as a potential new therapeutic target. Larger scale studies are required to consolidate these observations

In the Hunt for Therapeutic Targets: Mimicking the Growth, Metastasis, and Stromal Associations of Early-Stage Lung Cancer Using a Novel Orthotopic Animal Model

BackgroundThe existing shortage of animal models that properly mimic the progression of early-stage human lung cancer from a solitary confined tumor to an invasive metastatic disease hinders accurate characterization of key interactions between lung cancer cells and their stroma. We herein describe a novel orthotopic animal model that addresses these concerns and consequently serves as an attractive platform to study tumor–stromal cell interactions under conditions that reflect early-stage lung cancer.MethodsUnlike previous methodologies, we directly injected small numbers of human or murine lung cancer cells into murine's left lung and longitudinally monitored disease progression. Next, we used green fluorescent protein-tagged tumor cells and immuno-fluorescent staining to determine the tumor's microanatomic distribution and to look for tumor-infiltrating immune cells and stromal cells. Finally, we compared chemokine gene expression patterns in the tumor and lung microenvironment.ResultsWe successfully generated a solitary pulmonary nodule surrounded by normal lung parenchyma that grew locally and spread distally over time. Notably, we found that both fibroblasts and leukocytes are recruited to the tumor's margins and that distinct myeloid cell attracting and CCR2-binding chemokines are specifically induced in the tumor microenvironment.ConclusionOur orthotopic lung cancer model closely mimics the pathologic sequence of events that characterizes early-stage human lung cancer propagation. It further introduces new means to monitor tumor–stromal cell interactions and offers unique opportunities to test therapeutic targets under conditions that reflect early-stage lung cancer. We argue that for such purposes our model is superior to lung cancer models that are based either on genetic induction of epithelial transformation or on ectopic transplantation of malignant cells

Massive empyema caused by Mycoplasma pneumoniae in an adult: A case report

BACKGROUND: Mycoplasma pneumoniae is responsible for more than 20% of community acquired pneumonia cases, and capable of causing upper respiratory illness as well. Complications of M.pneumoniae infections include CNS involvement but other as pericarditis were also reported. The lack of feasible culture methods and under appreciation of the pathogens ability to cause invasive disease leads to reduced number of diagnosed M.pneumoniae related complications. In contrast to many other respiratory pathogens causing pneumonia, M. pneumoniae related severe pleural complications were almost never reported. CASE PRESENTATION: We report a previously healthy 57 years old woman presented with indolent massive right pleural effusion, leukocytosis and elevated ESR. Extensive microbiological evaluation didn't reveal any pathogen in the pus even before antibiotic treatment was started. Surprisingly, M.pneumoniae DNA was detected in the pus from the empyema using PCR designed to detect M.pneumoniae. A serological assay (Serodia-Myco II) using convalescent serum was indeterminate with a titer of 1:80. The patient responded well to a treatment that included right thoracotomy with pleural decortication and a combination of antibiotics and anti-inflammatory medications. CONCLUSION: M.pneumoniae related empyema was never reported before in adult patients and was reported in only a few pediatric patients. In our patient there was no evidence to any common pathogens even before initiating antibiotic treatment. The only pathogen detected was M.pneumoniae. In this patient, serology was not helpful in establishing the diagnosis of M.pneumoniae related diseases, as was suggested before for older patients. We suggest that M.pneumoniae related empyema is probably under-diagnosed complication due to insensitivity of serology in older patients and under use of other diagnosis methods

Dexamethasone and Salbutamol Stimulate Human Lung Fibroblast Proliferation

Background Asthma is characterized by bronchial hyperreactivity and airway remodeling. Subepithelial fibrosis, a feature of remodeling, is accompanied by activation of fibroblasts to myofibroblasts, with excessive proliferation and increased collagen, extracellular matrix protein, and profibrogenic cytokine production. Mast cells are important in the development of asthma and its fibrotic changes.Objective In this study, we aimed to investigate the direct effect of the drugs most frequently used in asthma, that is, glucocorticosteroids (dexamethasone) and shortacting β2-agonists (salbutamol), on human lung fibroblast proliferation when unstimulated or activated by mast cells or eotaxin.Methods Subconfluent human fetal lung or bronchial fibroblasts were incubated with different concentrations of the drugs (24 h) 6 activators, and [3H]-Thymidine was added (24 h) to measure their proliferation. IL-6 production in the supernatants of confluent mono-layers cultured in the presence of the drugs or forskolin (24 h) was analyzed by enzyme-linked immunosorbent assay.Results Both drugs alone and in the presence of the activators enhanced fibroblast proliferation in a seemingly synergistic way for both fetal and bronchial fibroblasts. Dexamethasone was found to decrease IL-6 production, while salbutamol increased it.Conclusions These observations if corroborated by in vivo data may possibly account for the deleterious effect of long-term therapy with β2-bronchodilators and inhaled glucocorticosteroids on the natural history of asthma. Keywords: fibroblasts, lung, proliferation, dexamethasone, salbutamol, IL-