Expression of cathepsins B, D and K in thymic epithelial tumours.

AIM: Cathepsins are proteases that regulate a wide range of physiological processes, including protein turnover, cell signalling and antigen presentation. Recent studies have shown that cathepsins are highly upregulated in many types of tumours. Of the 15 cathepsins in humans, cathepsins V and S are abundantly expressed in the thymus, and we previously showed that the immunostaining of these cathepsins could serve as diagnostic markers for thymic epithelial tumours. However, little is known about the expression of other cathepsins in thymic epithelial tumours. To determine the diagnostic implications of cathepsins, we performed immunohistochemical analysis of cathepsin B (CTB), cathepsin D (CTD) and cathepsin K (CTK), all of which have been reported to correlate with the progression of squamous cell carcinoma. METHODS: The association between cathepsin expression and clinicopathological features was evaluated in 122 cases of thymoma and thymic carcinoma. RESULTS: CTB and CTD were frequently expressed in type A and type AB thymomas. In contrast, CTB and CTD were significantly less common in type B thymomas than in type A or AB thymomas. In type AB thymomas, the expression of CTB correlated with histological features, and was found predominantly in the type A component. Notably, CTK was expressed most commonly in thymic carcinomas, and patients who died of the disease showed increased expression of CTK. CONCLUSIONS: The expression of CTB and CTD correlated with the histological subtype of thymoma. In addition, the expression of CTK appears to be useful for the diagnosis of thymic carcinomas and as a prognostic marker.

Expression of the immunoproteasome subunit ß5i in non-small cell lung carcinomas.

AIM: The immunoproteasome is a specific proteasome isoform whose proteolytic activity enhances the generation of antigenic peptides to be presented by major histocompatibility complex class I molecules to CD8+ T cells. Physiologically, it is expressed abundantly in immune cells and is induced in somatic cells by cytokines, especially interferon-γ. Recently, variable expression of immunoproteasomes has been demonstrated in different types of cancers. However, the clinical significance of immunoproteasome expression in malignant tumours is poorly understood. In this study, we performed clinicopathological evaluation of immunoproteasome subunit ß5i in non-small cell lung carcinomas (NSCLCs). METHODS: Tumour tissues were collected from 155 patients with NSCLCs, and immunohistochemical analysis for ß5i was performed in relation to the prognosis of patients. RESULTS: High expression of ß5i was found in about 20% of all NSCLCs and was found significantly more frequently (40%) in the adenocarcinoma subset. High expression of ß5i was associated with a better 5-year relative survival rate in patients with pStage I to II adenocarcinoma and was also a significant and independent favourable prognostic factor in adenocarcinoma patients. In addition, when we performed in vitro analysis using NSCLC cell lines, combined treatment with the immunoproteasome-specific inhibitor ONX0914 and the proteasome inhibitor MG132 enhanced cell death in ß5i-expressing NSCLC cell lines. CONCLUSION: The expression of immunoproteasome can be explored as both a prognostic factor and a potential therapeutic target in NSCLCs. Since immunoproteasomes have crucial role in the antigen presentation, further studies may help to provide essential knowledge for therapeutic strategies in anticancer immunotherapy.

Expression of cathepsins V and S in thymic epithelial tumors.

Cathepsins are a group of proteolytic enzymes of the endosomal/lysosomal pathway involved in the thymic development of T cells restricted by major histocompatibility complex class II molecules. In the normal thymus, cathepsin V (CTV) and cathepsin S (CTS) are expressed in cortical and medullary epithelial cells, respectively. To investigate whether cathepsins could serve as a diagnostic marker, we performed immunohistochemical analysis for CTV and CTS in 77 cases of thymic epithelial tumors. Almost all cases (59/60) of thymoma expressed CTV, whereas 28 of 60 cases of thymoma expressed CTS. Notably, CTS was expressed in most cases of type A and type AB thymomas, but not in type B thymoma. The expression of cathepsins in type AB thymoma showed a clear correlation with histologic features; CTV was found predominantly in the type B component, and CTS was frequently expressed in the type A component. In thymic carcinoma, CTV was expressed in less than half cases (7/17), and the ratio of CTS-positive cases was equivalent to that of thymoma (8/17). Cases of CTV-negative thymic carcinoma tended to have a higher incidence of recurrence than did CTV-positive cases. Although further studies with a larger number of cases are required to confirm the utility of cathepsin immunostaining, CTV and CTS appear to serve as auxiliary diagnostic and/or prognostic markers in thymic epithelial tumors.

Decreased proteasomal function accelerates cigarette smoke-induced pulmonary emphysema in mice.

Chronic obstructive pulmonary disease (COPD) is a disease common in elderly people, characterized by progressive destruction of lung parenchyma and chronic inflammation of the airways. The pathogenesis of COPD remains unclear, but recent studies suggest that oxidative stress-induced apoptosis in alveolar cells contributes to emphysematous lung destruction. The proteasome is a multicatalytic enzyme complex that plays a critical role in proteostasis by rapidly destroying misfolded and modified proteins generated by oxidative and other stresses. Proteasome activity decreases with aging in many organs including lungs, and an age-related decline in proteasomal function has been implicated in various age-related pathologies. However, the role of the proteasome system in the pathogenesis of COPD has not been investigated. Recently, we have established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity, showing age-related phenotypes. Using this model, we demonstrate here that decreased proteasomal function accelerates cigarette smoke (CS)-induced pulmonary emphysema. CS-exposed Tg mice showed remarkable airspace enlargement and increased foci of inflammation compared with wild-type controls. Importantly, apoptotic cells were found in the alveolar walls of the affected lungs. Impaired proteasomal activity also enhanced apoptosis in cigarette smoke extract (CSE)-exposed fibroblastic cells derived from mice and humans in vitro. Notably, aggresome formation and prominent nuclear translocation of apoptosis-inducing factor were observed in CSE-exposed fibroblastic cells isolated from Tg mice. Collective evidence suggests that CS exposure and impaired proteasomal activity coordinately enhance apoptotic cell death in the alveolar walls that may be involved in the development and progression of emphysema in susceptible individuals such as the elderly.

Expression of thymoproteasome subunit ß5t in type AB thymoma.

Type AB thymoma is a thymic epithelial tumour composed of lymphocyte-poor type A and lymphocyte-rich type B components. Although it is categorised as a single entity in the classification of WHO, it shows a broad range of morphology. To investigate whether the functional characteristic of neoplastic cells in type AB thymoma relates to morphological diversity, we performed immunohistochemical analysis using anti-ß5t antibody in 20 cases of type AB thymoma. ß5t is a recently discovered proteasomal ß subunit expressed exclusively in cortical thymic epithelial cells and tumour epithelial cells of thymomas with cortical differentiation. Consistent with our previous observation, ß5t was predominantly expressed in the type B component. When the type B component was divided into three groups morphologically, ß5t was expressed more frequently in cases with round to polygonal than spindle to oval tumour cells. Furthermore, the ratio of terminal deoxynucleotidyl transferase (TdT)-positive lymphocytes was increased in components with higher expression of ß5t. These results indicate that the histological diversity of type AB thymoma correlates with expression of a functional marker ß5t and abundance of TdT-positive lymphocytes.

Expression of proteasome subunit ß5t in thymic epithelial tumors.

Recently, a proteasome ß subunit expressed exclusively in thymic cortical epithelial cells was discovered in mice and humans. This subunit, designated ß5t, is a component of the thymoproteasome, a specialized type of proteasome implicated in thymic positive selection. To investigate whether ß5t could serve as a marker for the differential diagnosis of thymic epithelial tumors, we performed immunohistochemical analysis using anti-ß5t antibody in 54 cases of thymic epithelial tumors comprising 41 cases of thymomas and 13 cases of thymic carcinomas. ß5t was detected in the neoplastic epithelial cells of thymomas. Among the subtypes of thymoma, expression of ß5t was observed in most cases of type B thymoma (20 of 21) but not in type A thymomas (0 of 3). In type AB thymomas, ß5t expression was variable (6 of 17). Type B3 thymomas (4 cases) were positive for ß5t but negative for CD5, c-kit, and glucose transporter 1 (GLUT-1), which are known as diagnostic markers for thymic carcinomas. In contrast, thymic carcinomas were negative for ß5t (0 of 13) but expressed at least one and usually all of CD5, c-kit, and GLUT-1. Thus, ß5t and CD5/c-kit/GLUT-1 were differentially expressed in type B3 thymoma and thymic carcinoma. We tested ß5t expression in 39 cases of tumors arising from other organs, which showed the specific expression of ß5t in thymic epithelial tumors. This study demonstrates that ß5t is expressed in most type B and in some type AB thymomas and is a marker useful in differentiating type B3 thymomas from thymic carcinomas when used in combination with other diagnostic markers.

Unusual injuries on the right hand and forearm caused by unidentified wild animals.

An old man was found dead in a rice paddy with his face down in the water. His right forearm and hand were severely injured and the shapes of injuries were unusual. It was initially suspected that the injuries had been caused by a cultivator placed at the site. However, they proved to be postmortem injuries because vital reactions were not observed. The skin was widely torn away. Some edges of the injuries looked like a bite mark and other parts looked like scratches. There were many parallel injuries on the right forearm and hand and footmark-like injuries on the right hand. They were probably caused by wild animals. Judging from the sizes and shapes of the footprint, bite marks and scratches, we estimated that the animal which caused the injuries was weasels.