Glutathione s-transferase omega in the lung and sputum supernatants of COPD patients

BACKGROUND: The major contribution to oxidant related lung damage in COPD is from the oxidant/antioxidant imbalance and possibly impaired antioxidant defence. Glutathione (GSH) is one of the most important antioxidants in human lung and lung secretions, but the mechanisms participating in its homeostasis are partly unclear. Glutathione-S-transferase omega (GSTO) is a recently characterized cysteine containing enzyme with the capability to bind and release GSH in vitro. GSTO has not been investigated in human lung or lung diseases. METHODS: GSTO1-1 was investigated by immunohistochemistry and Western blot analysis in 72 lung tissue specimens and 40 sputum specimens from non-smokers, smokers and COPD, in bronchoalveolar lavage fluid and in plasma from healthy non-smokers and smokers. It was also examined in human monocytes and bronchial epithelial cells and their culture mediums in vitro. RESULTS: GSTO1-1 was mainly expressed in alveolar macrophages, but it was also found in airway and alveolar epithelium and in extracellular fluids including sputum supernatants, bronchoalveolar lavage fluid, plasma and cell culture mediums. The levels of GSTO1-1 were significantly lower in the sputum supernatants (p = 0.023) and lung homogenates (p = 0.003) of COPD patients than in nonsmokers. CONCLUSION: GSTO1-1 is abundant in the alveolar macrophages, but it is also present in extracellular fluids and in airway secretions, the levels being decreased in COPD. The clinical significance of GSTO1-1 and its role in regulating GSH homeostasis in airway secretions, however, needs further investigations

Keuhkosyövän molekyylipatologinen diagnostiikka edellyttää perustietoja myös kliinikoilta

Teema : keuhkosyövän diagnostiikka ja hoito. English summaryPeer reviewe

CDKN2A copy number and p16 expression in malignant pleural mesothelioma in relation to asbestos exposure

BackgroundDeletion of the CDKN2A locus is centrally involved in the development of several malignancies. In malignant pleural mesothelioma (MPM), it is one of the most frequently reported genomic alteration. MPM is strongly associated with a patients' asbestos exposure. However, the status of CDKN2A and the expression of the corresponding protein, p16, in relation to MPM patient's asbestos exposure is poorly known. Copy number alterations in 2p16, 9q33.1 and 19p13 have earlier been shown to accumulate in lung cancer in relation to asbestos exposure but their status in MPM is unclear.MethodsWe studied DNA copy numbers for CDKN2A using fluorescence in situ hybridization (FISH) and p16 expression by immunohistochemistry (IHC) in 92 MPM patients, 75 of which with known asbestos exposure status. We also studied, in MPM, copy number alterations in 2p16, 9q33.1 and 19p13 by FISH.ResultsWe were unable to detect an association between p16 expression and pulmonary asbestos fiber count in MPM tumor cells. However, significantly more MPM patients with high pulmonary asbestos fiber count (>1 million fibers per gram [f/g]) had stromal p16 immunoreactivity than MPM of patients with low exposure ( 0.5 million f/g) (51.4% vs 16.7%; p=0.035, Chi-Square). We found that an abnormal copy number of CDKN2A in MPM tumor cells associated with a high pulmonary asbestos fiber count (p=0.044, Fisher's Exact test, two-tailed). In contrast to our earlier findings in asbestos associated lung cancer, DNA copy number changes in 2p16, 9q33 and 19p13 were not frequent in MPM although single cases with variable copy numbers on those regions were seen.ConclusionsWe found two instances where the gene locus CDKN2A or its corresponding protein expression, is associated with high asbestos exposure levels. This suggests that there may be biological differences between the mesotheliomas with high pulmonary asbestos fiber count and those with low fiber count.Peer reviewe

CDKN2A copy number and p16 expression in malignant pleural mesothelioma in relation to asbestos exposure

BackgroundDeletion of the CDKN2A locus is centrally involved in the development of several malignancies. In malignant pleural mesothelioma (MPM), it is one of the most frequently reported genomic alteration. MPM is strongly associated with a patients' asbestos exposure. However, the status of CDKN2A and the expression of the corresponding protein, p16, in relation to MPM patient's asbestos exposure is poorly known. Copy number alterations in 2p16, 9q33.1 and 19p13 have earlier been shown to accumulate in lung cancer in relation to asbestos exposure but their status in MPM is unclear.MethodsWe studied DNA copy numbers for CDKN2A using fluorescence in situ hybridization (FISH) and p16 expression by immunohistochemistry (IHC) in 92 MPM patients, 75 of which with known asbestos exposure status. We also studied, in MPM, copy number alterations in 2p16, 9q33.1 and 19p13 by FISH.ResultsWe were unable to detect an association between p16 expression and pulmonary asbestos fiber count in MPM tumor cells. However, significantly more MPM patients with high pulmonary asbestos fiber count (>1 million fibers per gram [f/g]) had stromal p16 immunoreactivity than MPM of patients with low exposure ( 0.5 million f/g) (51.4% vs 16.7%; p=0.035, Chi-Square). We found that an abnormal copy number of CDKN2A in MPM tumor cells associated with a high pulmonary asbestos fiber count (p=0.044, Fisher's Exact test, two-tailed). In contrast to our earlier findings in asbestos associated lung cancer, DNA copy number changes in 2p16, 9q33 and 19p13 were not frequent in MPM although single cases with variable copy numbers on those regions were seen.ConclusionsWe found two instances where the gene locus CDKN2A or its corresponding protein expression, is associated with high asbestos exposure levels. This suggests that there may be biological differences between the mesotheliomas with high pulmonary asbestos fiber count and those with low fiber count.Peer reviewe

PD-1 and PD-L1 expression in pulmonary carcinoid tumors and their association to tumor spread

Pulmonary carcinoid (PC) tumors are rare tumors that account for approximately 1% of all lung cancers. The primary treatment option is surgery, while there is no standard treatment for metastatic disease. As the number of PCs diagnosed yearly is increasing, there is a need to establish novel therapeutic options. This study aimed to investigate programmed death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) expression in PC tumors since blocking of the PD-1/PD-L1 pathway is a promising therapeutic option in various other malignancies. A total of 168 PC patients treated between 1990 and 2013 were collected from the Finnish biobanks. After re-evaluation of the tumors, 131 (78%) were classified as typical carcinoid (TC) and 37 (22%) as atypical carcinoid (AC) tumors. Primary tumor samples were immunohistochemically labeled for PD-1, PD-L1 and CD8. High PD-1 expression was detected in 16% of the tumors. PD-L1 expression was detected in 7% of TC tumors; all AC tumors were PD-L1 negative. PD-L1 expression was associated with mediastinal lymph-node metastasis at the time of diagnosis (P = 0.021) as well as overall metastatic potential of the tumor (P = 0.010). Neither PD-1 expression, PD-L1 expression nor CD8(+) T cell density was associated with survival. In conclusion, PD-1 and PD-L1 were expressed in a small proportion of PC tumors and PD-L1 expression was associated with metastatic disease. Targeting of the PD-1/PD-L1 pathway with immune checkpoint inhibitors may thus offer a treatment option for a subset of PC patients.Peer reviewe

Somatostatin Receptor Expression Is Associated With Metastasis and Patient Outcome in Pulmonary Carcinoid Tumors

Context: Pulmonary carcinoids (PCs) belong to neuroendocrine tumors that often overexpress somatostatin receptors (SSTRs). This overexpression provides a molecular basis for tumor imaging and treatment with somatostatin analogs. Objective: To evaluate SSTR1 to SSTR5 distribution in a large set of PC tumors and to investigate whether the expression is associated with clinicopathological and outcome data. Design, Setting, and Patients: This retrospective study was conducted at Helsinki University Hospital and University of Helsinki. It included 178 PC tumors coupled with patients' clinical data retrieved through Finnish biobanks. After histological reclassification, tissue specimens were processed into next-generation tissue microarray format and stained immunohistochemically with monoclonal SSTR1 to SSTR5 antibodies. Main Outcome Measure: SSTR1 to SSTR5 expression in PC tumors. Results: Expression of SSTR1 to SSTR5 was detected in 52%, 75%, 56%, 16%, and 32% of the tumors, respectively. Membrane-bound staining was observed for all receptors. SSTR2 negativity and SSTR4 positivity was associated with lymph node involvement at the time of surgery (P = 0.014 and P = 0.017, respectively) and with distant metastasis (P = 0.027 and P = 0.015, respectively). SSTR3 and SSTR4 expression was associated with increased risk of shorter survival [P = 0.046, hazard ratio (HR) 4.703, 95% CI 1.027 to 21.533; and P = 0.013, HR 6.64, 95% CI 1.48 to 29.64, respectively], whereas expression of SSTR1 and SSTR2 was associated with improved outcome (P = 0.021, HR 0.167, 95% CI 0.037 to 0.765; and P = 0.022, HR 0.08, 95% CI 0.01 to 0.70, respectively). Conclusion: SSTR1 to SSTR5 expression is observed in PCs. As SSTR expression is associated with the tumor's metastatic potential and patient outcome, these receptors may offer the possibility for individualized prognosis estimation.Peer reviewe

SOX9 has distinct roles in the formation and progression of different non-small cell lung cancer histotypes

The transcription factor SOX9 is a key regulator of multiple developmental processes and is frequently re-expressed in non-small cell lung cancer (NSCLC). Its precise role in the progression of NSCLC histotypes has, however, remained elusive. We show that SOX9 expression relates to poor overall survival and invasive histopathology in human non-mucinous adenocarcinoma and is absent in murine early minimally invasive and low in human in situ adenocarcinoma. Interestingly, despite wide SOX9 expression across advanced NSCLC histotypes, its genetic deletion in the murine Kras(G12D);Lkb1(fl/fl) model selectively disrupted only the growth of papillary NSCLC, without affecting the initiation of precursor lesions or growth of mucinous or squamous tissue. Spatial tissue phenotyping indicated a requirement of SOX9 expression for the progression of surfactant protein C-expressing progenitor cells, which gave rise to papillary tumours. Intriguingly, while SOX9 expression was dispensable for squamous tissue formation, its loss in fact led to enhanced squamous tumour metastasis, which was associated with altered collagen IV deposition in the basement membrane. Our work therefore demonstrates histopathology-selective roles for SOX9 in NSCLC progression, namely as a promoter for papillary adenocarcinoma progression, but an opposing metastasis-suppressing role in squamous histotype tissue. This attests to a pleiotropic SOX9 function, linked to the cell of origin and microenvironmental tissue contexts. (c) 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.Peer reviewe