Canonical NF-κB promotes lung epithelial cell tumour growth by downregulating the metastasis suppressor CD82 and enhancing epithelial-to-mesenchymal cell transition

Copyright: © 2021 by the authors. Background: The development of non-small cell lung cancer (NSCLC) involves the progressive accumulation of genetic and epigenetic changes. These include somatic oncogenic KRAS and EGFR mutations and inactivating TP53 tumour suppressor mutations, leading to activation of canonical NF-κB. However, the mechanism(s) by which canonical NF-κB contributes to NSCLC is still under investigation. Methods: Human NSCLC cells were used to knock-down RelA/p65 (RelA/p65KD) and investigate its impact on cell growth, and its mechanism of action by employing RNA-seq analysis, qPCR, immunoblotting, immunohistochemistry, immunofluorescence and functional assays. Results: RelA/p65KD reduced the proliferation and tumour growth of human NSCLC cells grown in vivo as xenografts in immune-compromised mice. RNA-seq analysis identified canonical NF-κB targets mediating its tumour promoting function. RelA/p65KD resulted in the upregulation of the metastasis suppressor CD82/KAI1/TSPAN27 and downregulation of the proto-oncogene ROS1, and LGR6 involved in Wnt/β-catenin signalling. Immunohistochemical and bioinformatics analysis of human NSCLC samples showed that CD82 loss correlated with malignancy. RelA/p65KD suppressed cell migration and epithelial-to-mesenchymal cell transition (EMT), mediated, in part, by CD82/KAI1, through integrin-mediated signalling involving the mitogenic ERK, Akt1 and Rac1 proteins. Conclusions: Canonical NF-κB signalling promotes NSCLC, in part, by downregulating the metastasis suppressor CD82/KAI1 which inhibits cell migration, EMT and tumour growth.Institutional Program Grant for the Development of Research Institutes “Advanced research activities in biomedical and agro-alimentary technologies, ARABAT (BITAD)” (MIS5002469) of the operational program “Competitiveness, Entrepreneurship and Innovation” (NSRF2014-20, EU-ERDF); research grant in Biomedical Sciences from FONDATION SANTÉ; STAVROS NIARCHOS Foundation-FORTH Fellowship for PhD candidates of the program ARCHERS: Advancing young researchers’ human capital in cutting edge technologies in the preservation of cultural heritage and the tackling of societal challenges; Biomedical Research Division, IMBB-FORTH; University of Ioannina Research Committee

Cell Therapy for Idiopathic Pulmonary Fibrosis: Rationale and Progress to Date

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by progressive lung scarring due to unknown injurious stimuli ultimately leading to respiratory failure. Diagnosis is complex and requires a combination of clinical, laboratory, radiological, and histological investigations, along with exclusion of known causes of lung fibrosis. The current understanding of the disease etiology suggests an interaction between genetic factors and epigenetic alterations in susceptible, older individuals. Prognosis is dismal and current treatment options include anti-fibrotic agents that only slow down disease progression and carry considerable side effects that hamper patients’ quality of life. Therefore, the need for new, more effective treatments, alone or in combination with existing pharmacotherapy, is sorely needed. Regenerative medicine, the potential use of cell therapies to treat destructive diseases that cause architectural distortion to the target organ, has also emerged as an alternative therapeutic for lung diseases with unfavorable prognosis such as IPF. Mesenchymal stem cells (MSCs) and type II alveolar epithelial cells (AEC2s) have been used and their safety has been demonstrated. In the case of MSCs, both homogenic and allogeneic sources have been used and both are considered viable options without immunosuppressive therapy, taking into consideration the absence of immunogenicity and HLA response. AEC2s have been used in one trial with promising results but their use requires a deceased donor and immunosuppressive pre-treatment. In this review, we briefly summarize the current state of knowledge regarding the pathogenesis of IPF, and the background and rationale for using MSCs or AEC2s as potential treatment options. We list and describe the clinical trials completed to date and provide a comparison of their methods and results as well as a possible way forward. © 2020, Springer Nature Switzerland AG

Non-specific pleuritis: pathological patterns in benign pleuritis

A pleural biopsy without granulomatous inflammation or tumour cells is interpreted as 'non-specific pleuritis' (NSP), a diagnosis without any specificity, often frustrating for physicians. However, varying histological features are found in NSPs with unknown significance. The aim of this study was to describe the detailed microscopic features of NSP and correlate them with the underlying aetiology. One hundred patients diagnosed with NSP after pleural biopsy were retrospectively evaluated. A benign cause of pleural effusion was attributed. Histological features evaluated were inflammation, fibrosis, vascular proliferation, haemorrhage, fibrin, oedema and mesothelial hyperplasia. A semi-quantitative scoring was applied. Bacterial-caused and autoimmune disease-associated NSPs showed a higher score followed by viral and drug-induced conditions, while pneumothorax and cardiac-induced NSPs showed a lower score (p<0.0001). The degree of fibrosis was higher in bacterial NSP, and the type of fibrosis was cellular in this group (p=0.006). Vascular proliferation differed between groups (p<0.0001), and was higher in bacterial NSP. Histological findings differ significantly between the varying aetiologies of NSP, and this may be used to suggest the cause of the effusion

Non-specific pleuritis: pathological patterns in benign pleuritis

A pleural biopsy without granulomatous inflammation or tumour cells is interpreted as 'non-specific pleuritis' (NSP), a diagnosis without any specificity, often frustrating for physicians. However, varying histological features are found in NSPs with unknown significance. The aim of this study was to describe the detailed microscopic features of NSP and correlate them with the underlying aetiology. One hundred patients diagnosed with NSP after pleural biopsy were retrospectively evaluated. A benign cause of pleural effusion was attributed. Histological features evaluated were inflammation, fibrosis, vascular proliferation, haemorrhage, fibrin, oedema and mesothelial hyperplasia. A semi-quantitative scoring was applied. Bacterial-caused and autoimmune disease-associated NSPs showed a higher score followed by viral and drug-induced conditions, while pneumothorax and cardiac-induced NSPs showed a lower score (p<0.0001). The degree of fibrosis was higher in bacterial NSP, and the type of fibrosis was cellular in this group (p=0.006). Vascular proliferation differed between groups (p<0.0001), and was higher in bacterial NSP. Histological findings differ significantly between the varying aetiologies of NSP, and this may be used to suggest the cause of the effusion