Senescence-associated secretory phenotype in a mouse model of bleomycin-induced lung injury.

Bleomycin produces DNA damage, apoptosis and senescence, all of which play crucial roles in the development of pulmonary fibrosis. Recently, close attention has been paid to a DNA damage-induced phenotypic change (senescence-associated secretory phenotype; SASP) as a trigger for the secretion of various mediators which modify the processes of tissue injury, inflammation, repair and fibrosis. We characterized the SASP in a murine model of bleomycin-induced lung injury. Mice were intratracheally administered bleomycin or control saline, and the lungs were obtained on days 7, 14 and 21. The occurrence of DNA damage and the SASP in the lungs was examined by immunostaining. γH2AX immunostaining of the bleomycin-treated lungs revealed double-strand breaks (DSBs), largely within E-cadherin-positive, ß4-integirn-positive alveolar epithelial cells. The DSBs were associated with phosphorylation of ATM/ATR, a central signal transducer mediating the DNA damage response, and upregulation of the cyclin-dependent kinase inhibitor p21(CIP1). The DSBs persisted for at least 21 days after the bleomycin exposure, although it began to wane after 7 days. A subpopulation of the γH2AX-positive, DNA-damaged cells exhibited the SASP, characterized by overexpression of IL-6, TNFα, MMP-2 and MMP-9, in association with the phosphorylation of IKKα/ß and p38 MAPK. Persistent DNA damage and the SASP are induced in the process of bleomycin-induced lung injury and repair, suggesting that these events play an important role in the regulation of inflammation and tissue remodeling in bleomycin-induced pneumopathy.

Isolated pineal region metastasis from lung adenocarcinoma with obstructive hydrocephalus: a case report.

INTRODUCTION: Although the brain is a common site of metastasis from lung cancer, pineal region metastasis from lung adenocarcinoma is rare. Most cases of pineal metastases are asymptomatic, and are diagnosed by autopsy. Therefore, the management of pineal region tumors remains controversial. Here, we present a rare case of lung carcinoma presenting with pineal region metastasis and obstructive hydrocephalus as the first manifestation of the lung adenocarcinoma. CASE PRESENTATION: A 63-year-old Japanese woman was referred to our hospital for treatment of a tumor of the pineal region associated with hydrocephalus. On admission, she was found to have a mass in her right lung on a chest radiograph. During the preoperative investigation, the patient began to show a progressively worsening level of altered consciousness. Therefore, neuroendoscopic surgery was performed as an emergency procedure, which resulted in improvement of the hydrocephalus and diagnosis of adenocarcinoma. A systematic investigation revealed adenocarcinoma of her right lung as the primary lesion. She was treated by a platinum-based chemotherapy regime. Stereotactic radiation to the pineal region was undertaken concurrently. After completion of the chemotherapy, the primary lesion and pineal region metastasis showed good partial response. CONCLUSION: The prognosis of pineal region metastasis is extremely poor, and only three patients with metastatic pineal region metastasis from lung cancer who were treated by chemotherapy have been reported. We performed neuroendoscopic surgery to obtain resolution of the obstructive hydrocephalus and the definite histological diagnosis. This resulted in improvement of the general condition of the patient, and the patient could be treated by chemotherapy and radiotherapy. We strongly believe that neuroendoscopic surgery was a good option in this case. This case report suggests that in the presence of an isolated pineal region tumor, metastasis should be considered a possible diagnosis, and careful examination for systemic malignant disease will be needed.

[A case of posterior mediastinal mature teratoma].

The chest radiograph of a 57-year-old man, complaining of paroxysmal dyspnea, suggested the probably of a tumor. Chest CT showed a tumor containing calcification, behind the left crus of the diaphragm. Chest MRI suggested lipid components and a cystic lesion within the tumor. Their findings were clinically compatible with posterior mediastinal teratoma. The pathological diagnosis of the surgically resected tumor was mature teratoma with neither malignant components nor thymic tissue. Study of past case reports suggests that posterior mediastinal teratomas should have less malignant characteristics than anterior mediastainal teratomas. Our case is the fifteenth case report in the Japanese literature, and accumulation of more cases is required.

Correlation between liver metastasis of the colocalization of actin-related protein 2 and 3 complex and WAVE2 in colorectal carcinoma.

Directed movement of normal cells occurs when actin-related protein 2 and 3 complex (Arp2/3 complex) triggers the actin polymerization that forms lamellipodia immediately after binding to WAVE2. In order to determine whether the same mechanism correlates with liver metastasis from colorectal cancer, paired mirror sections of 154 cancer specimens (29 cases with liver metastasis and 125 cases without liver metastasis in which T factor, gender, primary tumor site, and age at operation were matched) were examined immunohistochemically for the localization of Arp2 and WAVE2. Expression of both Arp2 and WAVE2 was detected in the same cancer cells in 55 (35.7%) of the 154 cases, but not detected in the normal colonic epithelial cells. Univariate analysis showed that the colocalization was significantly predictive of liver metastasis (risk ratio [RR] 8.760. Likewise, histological grade (RR 2.46), lymphatic invasion (RR 9.95), and tumor budding (RR 4.00) were significant predictors. Among these, colocalization and lymphatic invasion were shown to be independent risk factors by multivariate analysis. Another 59 colorectal specimens were examined for mRNA expression of Arp2 by real time polymerase chain reaction. High mRNA levels of Arp2, that in situ hybridization revealed to be expressed by the cancer cells, were significantly associated with liver metastasis. However, its effect was absorbed by the influence of risk of the colocalization that is closely related to high expression of Arp2. These results indicate that the colocalization of Arp2 and WAVE2 is an independent risk factor for liver metastasis of colorectal carcinoma.

Coexpression of actin-related protein 2 and Wiskott-Aldrich syndrome family verproline-homologous protein 2 in adenocarcinoma of the lung.

PURPOSE: Highly invasive and metastatic cancer cells, such as adenocarcinoma of the lung cells, form irregular protrusions by assembling a branched network of actin filaments. In mammalian cells, the actin-related protein 2 and 3 (Arp2/3) complex initiates actin assembly to form lamellipodial protrusions by binding to Wiskott-Aldrich syndrome (WASP)/WASP family verproline-homologous protein 2 (WAVE2). In this study, colocalization of Arp2 and WAVE2 in adenocarcinoma of the lung was investigated to elucidate its prognostic value. EXPERIMENTAL DESIGN: Immunohistochemical staining of Arp2 and WAVE2 was done on mirror sections of 115 adenocarcinomas of the lung from pathologic stage IA to IIIA classes. Kaplan-Meier disease-free survival and overall survival curves were analyzed to determine the prognostic significance of the coexpression of Arp2 and WAVE2. RESULTS: Immunoreactivity for both Arp2 and WAVE2 was detected in the same cancer cells in 78 (67.8%) of the 115 lung cancer specimens. The proportion of cancer cells expressing both Arp2 and WAVE2 was significantly higher in cases with lymph-node metastasis (P = 0.0046), and significantly lower in bronchioloalveolar carcinomas (P < 0.0001). The patients whose cancer cells coexpressed them had a shorter disease-free survival time (P < 0.0001) and overall survival time (P < 0.0001). Multivariate Cox regression analysis revealed that coexpression of Arp2 and WAVE2 is an independent risk factor for tumor recurrence. CONCLUSIONS: Coexpression of Arp2 and WAVE2 is correlated with poorer patient outcome, and may be involved in the mechanism of cancer metastasis.