Combination Therapy of PPARγ Ligands and Inhibitors of Arachidonic Acid in Lung Cancer

Lung cancer is the leading cause of cancer death in the United States and five-year survival remains low. Numerous studies have shown that chronic inflammation may lead to progression of carcinogenesis. As a result of inflammatory stimulation, arachidonic acid (AA) metabolism produces proliferation mediators through complex and dynamic interactions of the products of the LOX/COX enzymes. One important mediator in the activation of the AA pathways is the nuclear protein PPARγ. Targeting LOX/COX enzymes and inducing activation of PPARγ have resulted in significant reduction of cell growth in lung cancer cell lines. However, specific COX-inhibitors have been correlated with an increased cardiovascular risk. Clinical applications are still being explored with a novel generation of dual LOX/COX inhibitors. PPARγ activation through synthetic ligands (TZDs) has revealed a great mechanistic complexity since effects are produced through PPARγ-dependent and -independent mechanisms. Furthermore, PPARγ could also be involved in regulation of COX-2. Overexpression of PPARγ has reported to play a role in control of invasion and differentiation. Exploring the function of PPARγ, in this new context, may provide a better mechanistic model of its role in cancer and give an opportunity to design a more efficient therapeutic approach in combination with LOX/COX inhibitors

Cytokines and Growth Factors Stimulate Hyaluronan Production: Role of Hyaluronan in Epithelial to Mesenchymal-Like Transition in Non-Small Cell Lung Cancer

In this study, we investigated the role of hyaluronan (HA) in non-small cell lung cancer (NSCLC) since close association between HA level and malignancy has been reported. HA is an abundant extracellular matrix component and its synthesis is regulated by growth factors and cytokines that include epidermal growth factor (EGF) and interleukin-1β (IL-1β). We showed that treatment with recombinant EGF and IL-1β, alone or in combination with TGF-β, was able to stimulate HA production in lung adenocarcinoma cell line A549. TGF-β/IL-1β treatment induced epithelial to mesenchymal-like phenotype transition (EMT), changing cell morphology and expression of vimentin and E-cadherin. We also overexpressed hyaluronan synthase-3 (HAS3) in epithelial lung adenocarcinoma cell line H358, resulting in induced HA expression, EMT phenotype, enhanced MMP9 and MMP2 activities and increased invasion. Furthermore, adding exogenous HA to A549 cells and inducing HA H358 cells resulted in increased resistance to epidermal growth factor receptor (EGFR) inhibitor, Iressa. Together, these results suggest that elevated HA production is able to induce EMT and increase resistance to Iressa in NSCLC. Therefore, regulation of HA level in NSCLC may be a new target for therapeutic intervention

Implementation of lung cancer screening in Europe:challenges and potential solutions: summary of a multidisciplinary roundtable discussion

Recent randomised trials on screening with low-dose CT have shown important reductions in lung cancer (LC) mortality and have triggered international efforts to implement LC screening. Detection rates of stage I LC with volume CT approaching 70% have been demonstrated. In April 2019 'ESMO Open - Cancer Horizons' convened a roundtable discussion on the challenges and potential solutions regarding the implementation of LC screening in Europe. The expert panel reviewed the current evidence for LC screening with low-dose CT and discussed the next steps, which are covered in this article. The panel concluded that national health policy groups in Europe should start to implement CT screening as adequate evidence is available. It was recognised that there are opportunities to improve the screening process through 'Implementation Research Programmes'

The Liverpool Statement 2005: Priorities for the European Union/United States Spiral Computed Tomography Collaborative Group

The Liverpool Statement 2005 was developed at the Fourth International Lung Cancer Molecular Biomarkers Workshop in Liverpool (October 27-29, 2005) and focused on the priorities for the European Union/United States (EU-US) Spiral Computed Tomography (CT) Collaborative Group. The application of spiral CT technology for early lung cancer screening has gained enormous momentum in the past 5 years. The EU-US Spiral CT Collaboration was initiated in 2001 in Liverpool, and subsequent meetings throughout Europe have resulted in the development of collaborative protocols and minimal data sets that provide a mechanism for the different trial groups to work together, with the ultimate aim to pool results. Considerable progress has been made with major national screening trials in the U.S. and Europe, which include IELCAP, NLST, and NELSON. The major objective of this international collaboration is the planned cross-analysis of the individual studies after they are reported. The EU-US researchers have agreed to a number of long-term objectives and to explore strategic areas for harmonization of complementary investigations

Expression of heterogeneous nuclear ribonucleoprotein A2/B1 changes with critical stages of mammalian lung development

Recent reports have demostrated a link between expression of members of the family of heterogeneous nuclear ribonucleoproteins (hnRNPs) and cancer. Overexpression of hnRNP A2/B1 correlated with the eventual development of lung cancer in three different clinical cohorts. We have studied the expression of hnRNP A2/B1 messenger RNA (mRNA) and protein during mammalian development. The expression of hnRNP A2/B1 mRNA and protein are parallel but change dynamically during critical periods in mouse pulmonary development. hnRNP A2/B1 is first detected in the lung in the early pseudoglandular period, peaks at the beginning of the canalicular period, and remains high during the saccular (alveolar) period. In mouse and rat, hnRNP A2/B1 expression is first evident in the earliest lung buds. As lung development progresses, the cuboidal epithelial cells of the distal primitive alveoli show high levels of the ribonucleoprotein, which is almost undetectable in the proximal conducting airways. The expression of hnRNP A2/ B1 is restricted in mature lung. Similar dynamic pattern of expression through lung development was also found in rat and human lung. Upregulated expression of hnRNP A2/B1 at critical periods of lung development was comparable to the level of expression found in lung cancers and preneoplastic lesions and is consistent with hnRNP A2/B1 overexpression playing an oncodevelopmental role

Implementation of lung cancer screening in Europe: Challenges and potential solutions: Summary of a multidisciplinary roundtable discussion

Recent randomised trials on screening with low-dose CT have shown important reductions in lung cancer (LC) mortality and have triggered international efforts to implement LC screening. Detection rates of stage I LC with volume CT approaching 70% have been demonstrated. In April 2019 'ESMO Open-Cancer Horizons' convened a roundtable discussion on the challenges and potential solutions regarding the implementation of LC screening in Europe. The expert panel reviewed the current evidence for LC screening with low-dose CT and discussed the next steps, which are covered in this article. The panel concluded that national health policy groups in Europe should start to implement CT screening as adequate evidence is available. It was recognised that there are opportunities to improve the screening process through 'Implementation Research Programmes'

The PROgnostic Value of unrequested Information in Diagnostic Imaging (PROVIDI) Study: rationale and design

We describe the rationale for a new study examining the prognostic value of unrequested findings in diagnostic imaging. The deployment of more advanced imaging modalities in routine care means that such findings are being detected with increasing frequency. However, as the prognostic significance of many types of unrequested findings is unknown, the optimal response to such findings remains uncertain and in many cases an overly defensive approach is adopted, to the detriment of patient-care. Additionally, novel and promising image findings that are newly available on many routine scans cannot be used to improve patient care until their prognostic value is properly determined. The PROVIDI study seeks to address these issues using an innovative multi-center case-cohort study design. PROVIDI is to consist of a series of studies investigating specific, selected disease entities and clusters. Computed Tomography images from the participating hospitals are reviewed for unrequested findings. Subsequently, this data is pooled with outcome data from a central population registry. Study populations consist of patients with endpoints relevant to the (group of) disease(s) under study along with a random control sample from the cohort. This innovative design allows PROVIDI to evaluate selected unrequested image findings for their true prognostic value in a series of manageable studies. By incorporating unrequested image findings and outcomes data relevant to patients, truly meaningful conclusions about the prognostic value of unrequested and emerging image findings can be reached and used to improve patient-care