Novel expression of kallikreins, kallikrein-related peptidases and kinin receptors in human pleural mesothelioma

2007 ◽  
Vol 388 (11) ◽  
pp. 1235-1242 ◽  
Author(s):  
Jessica Chee ◽  
Jasmine Singh ◽  
Anupam Naran ◽  
Neil L. Misso ◽  
Philip J. Thompson ◽  
...  
Keyword(s):  
Serine Proteases ◽  
Normal Tissue ◽  
Functional Role ◽  
Pleural Mesothelioma ◽  
Malignant Cells ◽  
Kinin Receptors ◽  
Aggressive Cancer ◽  
Nuclear Labelling ◽  
Immunofluorescence Labelling ◽  
Potential Biomarkers

Abstract Malignant mesothelioma is an aggressive cancer of the pleura that is causally related to exposure to asbestos fibres. The kallikrein serine proteases [tissue (hK1) and plasma (hKB1) kallikreins, and kallikrein-related peptidases (KRP/hK2–15)] and the mitogenic kinin peptides may have a role in tumourigenesis. However, it is not known whether hK1, hKB1, KRP/hK proteins or kinin receptors are expressed in pleural mesotheliomas. The expression of hK1, hKB1, KRP/hK2, 5, 6, 7, 8 and 9, and kinin B1 and B2 receptors was assessed in archived selected normal tissue and mesothelioma tumour sections by immunoperoxidase and immunofluorescence labelling. hK1, hKB1 and kinin B1 and B2 receptors were expressed in malignant cells of the epithelioid and sarcomatoid components of biphasic mesothelioma tumour cells. The percentage of cells with cytoplasmic and nuclear labelling and the intensity of labelling were similar for hK1, hKB1 and the kinin receptors. KRP/hK2, 6, 8 and 9 were also expressed in the cytoplasm and nuclei of mesothelioma cells, whereas KRP/hK5 and hK7 showed predominantly cytoplasmic localisation. This is a first report, but further studies are required to determine whether these proteins have a functional role in the pathogenesis of mesothelioma and/or may be potential biomarkers for pleural mesothelioma.

Expression of tissue and plasma kallikreins and kinin B1 and B2 receptors in lung cancer

2008 ◽  
Vol 389 (9) ◽  
Author(s):  
Jessica Chee ◽  
Anupam Naran ◽  
Neil L. Misso ◽  
Philip J. Thompson ◽  
Kanti D. Bhoola
Keyword(s):  
Lung Cancer ◽  
Serine Proteases ◽  
Large Cell ◽  
Small Cell ◽  
Biologically Active ◽  
Normal Lung ◽  
Receptor Proteins ◽  
Kinin Receptors ◽  
Immunofluorescence Labelling ◽  
B2 Receptors

AbstractTissue kallikrein (hK1) and plasma kallikrein (PK, hKB1) are serine proteases that produce biologically active kinin peptides from endogenous kininogen substrates. There is evidence linking the kallikreins and the mitogenic kinin peptides to carcinogenesis. The aim of this study was to investigate the expression of tissue prokallikrein (pro-hK1), plasma prekallikrein (PPK, pre-hKB1) and kinin B1and B2receptor proteins in different subtypes of lung cancer. Immunohistochemistry, using specific antibodies, was performed on archived normal lung sections and sections from adenocarcinomas, squamous cell carcinomas, large cell carcinomas, small cell carcinomas and carcinoid tumours of the lung. Immunoperoxidase labelling was visualised by brightfield microscopy and immunofluorescence labelling by confocal microscopy. Extensive cytoplasmic expression of pro-hK1 and PPK was observed, which was similar in small cell and non-small cell tumours. However, nuclear labelling for the kallikreins was absent or limited. The kinin B1and B2receptors were highly expressed in the cytoplasm of all tumour types and in the nuclei of non-small cell tumours. Further studies are required to assess the functional significance of the expression of hK1, PK and kinin receptors in lung tumours, and whether any of these proteins may be potential biomarkers for specific subtypes of lung carcinoma.

scholarly journals Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3932
Author(s):  
Dannel Yeo ◽  
Laura Castelletti ◽  
Nico van Zandwijk ◽  
John E. J. Rasko
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Treatment Options ◽  
Survival Rates ◽  
Treatment Strategies ◽  
Pleural Mesothelioma ◽  
Normal Tissues ◽  
Drug Conjugates ◽  
Aggressive Cancer ◽  
Immunotherapy Target ◽  
Bull's Eye

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options and poor prognosis. MPM originates from the mesothelial lining of the pleura. Mesothelin (MSLN) is a glycoprotein expressed at low levels in normal tissues and at high levels in MPM. Many other solid cancers overexpress MSLN, and this is associated with worse survival rates. However, this association has not been found in MPM, and the exact biological role of MSLN in MPM requires further exploration. Here, we discuss the current research on the diagnostic and prognostic value of MSLN in MPM patients. Furthermore, MSLN has become an attractive immunotherapy target in MPM, where better treatment strategies are urgently needed. Several MSLN-targeted monoclonal antibodies, antibody–drug conjugates, immunotoxins, cancer vaccines, and cellular therapies have been tested in the clinical setting. The biological rationale underpinning MSLN-targeted immunotherapies and their potential to improve MPM patient outcomes are reviewed.

scholarly journals Identification of Redox-Sensitive Transcription Factors as Markers of Malignant Pleural Mesothelioma

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1138
Author(s):  
Martina Schiavello ◽  
Elena Gazzano ◽  
Loredana Bergandi ◽  
Francesca Silvagno ◽  
Roberta Libener ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
Malignant Pleural Mesothelioma ◽  
Antioxidant Defense ◽  
Asbestos Exposure ◽  
Predictive Biomarkers ◽  
Antioxidant Systems ◽  
Pleural Mesothelioma ◽  
Related Factor ◽  
Aggressive Cancer

Although asbestos has been banned in most countries around the world, malignant pleural mesothelioma (MPM) is a current problem. MPM is an aggressive tumor with a poor prognosis, so it is crucial to identify new markers in the preventive field. Asbestos exposure induces oxidative stress and its carcinogenesis has been linked to a strong oxidative damage, event counteracted by antioxidant systems at the pulmonary level. The present study has been focused on some redox-sensitive transcription factors that regulate cellular antioxidant defense and are overexpressed in many tumors, such as Nrf2 (Nuclear factor erythroid 2-related factor 2), Ref-1 (Redox effector factor 1), and FOXM1 (Forkhead box protein M1). The research was performed in human mesothelial and MPM cells. Our results have clearly demonstrated an overexpression of Nrf2, Ref-1, and FOXM1 in mesothelioma towards mesothelium, and a consequent activation of downstream genes controlled by these factors, which in turn regulates antioxidant defense. This event is mediated by oxidative free radicals produced when mesothelial cells are exposed to asbestos fibers. We observed an increased expression of Nrf2, Ref-1, and FOXM1 towards untreated cells, confirming asbestos as the mediator of oxidative stress evoked at the mesothelium level. These factors can therefore be considered predictive biomarkers of MPM and potential pharmacological targets in the treatment of this aggressive cancer.

Biomarkers for malignant pleural mesothelioma: a meta-analysis

2019 ◽  
Vol 40 (11) ◽  
pp. 1320-1331 ◽  
Author(s):  
Christina N Gillezeau ◽  
Maaike van Gerwen ◽  
Julio Ramos ◽  
Bian Liu ◽  
Raja Flores ◽  
...  
Keyword(s):  
Lung Disease ◽  
Malignant Pleural Mesothelioma ◽  
Meta Analysis ◽  
Pleural Mesothelioma ◽  
Control Groups ◽  
Aggressive Cancer ◽  
Comparison Groups ◽  
The Mean ◽  
Mean Differences ◽  
Healthy Participants

Abstract Malignant pleural mesothelioma (MPM) is a rare but aggressive cancer, and early detection is associated with better survival. Mesothelin, fibulin-3 and osteopontin have been suggested as screening biomarkers. The study conducted a meta-analysis of the mean differences of mesothelin, osteopontin and fibulin-3 in blood and pleural samples. PubMed searches were conducted for studies that measured levels of mesothelin, osteopontin and fibulin-3 in participants with MPM compared with malignancy, benign lung disease or healthy participants. Thirty-two studies with mesothelin levels, 12 studies with osteopontin levels and 9 studies with fibulin-3 levels were included in the meta-analysis. Statistically significant mean differences were seen between MPM patients and all other comparison groups for mesothelin blood and pleural levels. Statistically significant differences in blood osteopontin levels were seen between participants with benign lung disease and healthy participants compared with participants with MPM, but not when comparing participants with cancer with MPM participants. There were not enough studies that reported osteopontin levels in pleural fluid to complete a meta-analysis. Statistically significant differences were seen in both blood and pleural levels of fibulin-3 in MPM patients compared with all other groups. On the basis of these results, mesothelin and fibulin-3 levels appear to be significantly lower in all control groups compared with those with MPM, making them good candidates for screening biomarkers. Osteopontin may be a useful biomarker for screening healthy individuals or those with benign lung disease but would not be useful for screening patients with malignancies.

scholarly journals Patient-derived malignant pleural mesothelioma cell cultures: a tool to advance biomarker-driven treatments

Thorax ◽  
2020 ◽  
Vol 75 (11) ◽  
pp. 1004-1008 ◽  
Author(s):  
Nikolaos I Kanellakis ◽  
Rachelle Asciak ◽  
Megat Abd Hamid ◽  
Xuan Yao ◽  
Mark McCole ◽  
...  
Keyword(s):  
Cell Cultures ◽  
Malignant Pleural Mesothelioma ◽  
Poor Prognosis ◽  
Ex Vivo ◽  
Cytotoxic T Cells ◽  
Pleural Mesothelioma ◽  
Ex Vivo Model ◽  
High Throughput Drug Screening ◽  
Aggressive Cancer ◽  
Malignant Pleural Mesothelioma Cell

Malignant pleural mesothelioma (MPM) is an aggressive cancer, associated with poor prognosis. We assessed the feasibility of patient-derived cell cultures to serve as an ex vivo model of MPM. Patient-derived MPM cell cultures (n=16) exhibited stemness features and reflected intratumour and interpatient heterogeneity. A subset of the cells were subjected to high-throughput drug screening and coculture assays with cancer-specific cytotoxic T cells and showed diverse responses. Some of the biphasic MPM cells were capable of processing and presenting the neoantigen SSX-2 endogenously. In conclusion, patient-derived MPM cell cultures are a promising and faithful ex vivo model of MPM.

ENDOGENOUS STEROID LEVELS IN THE HUMAN PROSTATE FROM BIRTH TO OLD AGE: A COMPARISON OF NORMAL AND DISEASED TISSUES

1978 ◽  
Vol 78 (1) ◽  
pp. 7-19 ◽  
Author(s):  
G. L. HAMMOND
Keyword(s):  
Solvent Extraction ◽  
Normal Tissue ◽  
Functional Role ◽  
Tissue Sample ◽  
Benign Prostatic Hypertrophy ◽  
Normal Adult ◽  
Adult Tissue ◽  
Oestrogen Treatment ◽  
Variable Extent ◽  
Endogenous Steroid

The levels of steroids in prostatic tissues were determined by radioimmunoassay after solvent extraction of a single (300–600 mg wet tissue) sample and chromatography of extracts on hydroxyalkoxypropyl Sephadex microcolumns. In normal adult prostates (n = 18) the concentrations of steroids (mean±s.e.m. ng/g wet tissue) were: testosterone, 0·25 ± 0·04; androstenedione, 0·13 ± 0·03; 5α-androstane-3, 17-dione (5α-androstanedione), 1·31 ± 17β-hydroxy-5α-androstan-3-one (5α-dihydrotestosterone, DHT), 1·22± 0·14; 5α-androstane-3α, 17β-diol (3α-androstanediol), 4·32 ± 0·49; androsterone, 4·15± 1·07; progesterone, 0·39 ± 0·07; 17α-hydroxyprogesterone, 0·42 ± 0·06. Concentrations of steroids in tissues from outer-gland regions were within the ranges found in the periurethral regions. In the prostates of newborn boys, the concentrations of all steroids were high, including progesterone and 17α-hydroxyprogesterone. Apart from 3α-androstanediol, the levels of which tend to increase after this age, the concentrations of all steroids were lower in the infant and pubertal prostates, but most were re-established to a variable extent in the adult tissues. This was particularly evident with respect to 5α-androstanedione and androsterone, and it is suggested that these two androgens may have a functional role in the mature prostate. The concentrations of testosterone, androstenedione, 5α-androstanedione, progesterone and 17α-hydroxyprogesterone in tissues taken from ten patients with benign prostatic hypertrophy (BPH) were similar to those in normal adult tissue. The concentration of DHT was markedly raised (5·33 ± 0·46 ng/g) and the levels of 3α-androstanediol and androsterone were reduced (1·40 ± 0·12 and 0·80 ± 0·12 ng/g respectively) in adenomatous compared with normal tissue. The concentrations of various androgens displayed remarkable inter-relationships which characterize normal and BPH tissues. The concentrations of testosterone, androstenedione, DHT and 3α-androstanediol were particularly high in the untreated prostatic carcinomatous tissue sample investigated, whereas the concentrations of 5α-androstanedione and androsterone were very low. After oestrogen treatment, testosterone and androstenedione virtually disappeared, while reduced but significant concentrations of their metabolites remained in similar proportions to those observed in the untreated carcinomatous tissue. Under the conditions of therapy, oestrogens are suggested to influence the uptake of androgens.

scholarly journals A Novel Panel of Serum Biomarkers for MPM Diagnosis

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
A. Bonotti ◽  
R. Foddis ◽  
S. Landi ◽  
O. Melaiu ◽  
C. De Santi ◽  
...  
Keyword(s):  
Early Detection ◽  
Healthy Subjects ◽  
Serum Markers ◽  
Serum Biomarkers ◽  
Clinical Approach ◽  
Pleural Mesothelioma ◽  
Strong Impact ◽  
Combined Approach ◽  
Aggressive Cancer ◽  
Genomics And Proteomics

Exposure to asbestos is the main cause of malignant pleural mesothelioma (MPM), a highly aggressive cancer of the pleura. Since the only tools for early detection are based on radiological tests, some authors focused on serum markers (i.e., mesothelin). The aim of this study was the evaluation of new serum biomarkers to be used individually or in combination, in order to improve the outcome of patients whose disease would be diagnosed at an earlier stage. Serum and plasma were available from 43 subjects previously exposed to asbestos and 27 MPM patients, all being epithelioid type. All the new markers found differentially expressed in MPM and healthy subjects, by proteomic and genomic approaches, have been validated in the serum by the use of specific ELISA. The combined approach, using tools of genomics and proteomics, is found to be highly innovative for this type of disease and led to the identification of new serum markers in the diagnosis of MPM. These results, if confirmed in a larger series, may have a strong impact in this area, because early detection of this cancer in people at high risk could significantly improve the course of the disease and the clinical approach to an individualized therapy.

scholarly journals Metabolic Rewiring in Radiation Oncology Toward Improving the Therapeutic Ratio

2021 ◽  
Vol 11 ◽  
Author(s):  
Marike W. van Gisbergen ◽  
Emma Zwilling ◽  
Ludwig J. Dubois
Keyword(s):  
Normal Tissue ◽  
Hypoxia Inducible Factor ◽  
Cellular Metabolism ◽  
Redox Balance ◽  
Metastatic Lesion ◽  
Proliferative Potential ◽  
Malignant Cells ◽  
Therapeutic Ratio ◽  
Current State ◽  
Lesion Treatment

To meet the anabolic demands of the proliferative potential of tumor cells, malignant cells tend to rewire their metabolic pathways. Although different types of malignant cells share this phenomenon, there is a large intracellular variability how these metabolic patterns are altered. Fortunately, differences in metabolic patterns between normal tissue and malignant cells can be exploited to increase the therapeutic ratio. Modulation of cellular metabolism to improve treatment outcome is an emerging field proposing a variety of promising strategies in primary tumor and metastatic lesion treatment. These strategies, capable of either sensitizing or protecting tissues, target either tumor or normal tissue and are often focused on modulating of tissue oxygenation, hypoxia-inducible factor (HIF) stabilization, glucose metabolism, mitochondrial function and the redox balance. Several compounds or therapies are still in under (pre-)clinical development, while others are already used in clinical practice. Here, we describe different strategies from bench to bedside to optimize the therapeutic ratio through modulation of the cellular metabolism. This review gives an overview of the current state on development and the mechanism of action of modulators affecting cellular metabolism with the aim to improve the radiotherapy response on tumors or to protect the normal tissue and therefore contribute to an improved therapeutic ratio.

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