Michihiro Hirama

Osteopontin overproduced by tumor cells acts as a potent angiogenic factor contributing to tumor growth

Angiogenesis, which is essential for tumor growth, is regulated by various angiogenic factors. Osteopontin (OPN) is expressed in various human tumors and is postulated to be involved in tumor progression. We have recently reported that culture medium with murine neuroblastoma C1300 cells transfected with OPN gene significantly stimulates human umbilical vein endothelial cell migration and induces neovascularization in mice by dorsal air sac assay. However, the effect of OPN on tumorigenesis as an angiogenic factor remains to be clarified. In this study, we injected the OPN-transfected C1300 cells and control cells into the nude mice subcutaneously. OPN-overexpressing C1300 cells significantly formed rapidly growing tumor as compared to the control cells in mice, although in vitro and in vivo cell growth rates were similar. In vivo tumorigenecity of these cells correlated with the amount of secreted OPN protein. In addition, neovascularization of OPN-transfected tumor was significantly increased in comparison with those of control cells by immunohistochemistry for CD31. In vitro chemoinvasiveness and gene expression of proteases including uPA, MMP2, 9, MT1-MMP, and cathepsin B, D, L, were not different between OPN-transfected and control cells determined with matrigel invasion assay and cDNA expression macroarray, respectively. Conclusively, these results strongly imply that OPN plays an important role in tumor growth through the enhancement of angiogenesis in vivo.

Osteopontin is involved in the formation of malignant pleural effusion in lung cancer

Malignant pleural effusion (MPE) is associated with advanced-stage lung cancer and is a poor prognostic sign for these patients. Osteopontin (OPN) is a multifunctional cytokine that is involved in the tumor progression and angiogenesis of lung cancer cells. The purpose of this study is to investigate and provide evidence for the role of OPN in the formation of MPE associated with lung cancer. In this study, we established an OPN knockdown murine lung cancer cell line, 3LL cells, utilizing the small interfering RNA (siRNA) technique. To reveal the effect of OPN on the formation of MPE associated with lung cancer, we directly injected OPN knockdown 3LL cells, 3LL/OPN siRNA, or control cells, 3LL/control siRNA, into the pleural space of C57BL/6 mice. OPN knockdown significantly reduced the formation of MPE, but did not inhibit in vivo tumor growth of 3LL cells in mice. Vascular endothelial growth factor (VEGF) concentration in MPE was markedly decreased in the 3LL/OPN siRNA in comparison with that of the 3LL/control siRNA. In vitro, recombinant OPN protein enhanced VEGF secretion from human umbilical vein endothelial cell (HUVEC) or human mesothelial cell line, Met5A cells, in a concentration-dependent manner. These results suggest that OPN is positively involved in the formation of MPE of lung cancer presumably by promoting VEGF secretion from vascular endothelial cells or mesothelial cells. OPN could be an effective target molecule for reducing MPE in lung cancer patients.

Restoration of CD44S in non-small cell lung cancer cells enhanced their susceptibility to the macrophage cytotoxicity

CD44 is a cell surface receptor for osteopontin (OPN) and hyaluronate. Transformation of normal tissue to a variety of cancers has been demonstrated to be associated with alterations of CD44 isoform expression. However, few reports have paid attention on differences in CD44S expression between non-small cell lung cancer (NSCLC) and adjacent normal lung tissue. In this study, we demonstrate that CD44S expression is down-regulated in NSCLC tissue when compared with paired normal lung tissue. To investigate the role of CD44S down-regulation in NSCLC cells, we reintroduced the CD44S back into the NSCLC cell line, H322 cells, which originally lack CD44S expression. The cytotoxicity by activated macrophage (RAW264.7 cells stimulated with lipopolysaccharide and interferon-gamma) against the H322 cells transfected with the CD44S gene (H322DeltaS) is more prominent than that against the H322 control transfectants (H322Deltaneo). The enhanced susceptibility of H322DeltaS cells to the activated macrophage cytotoxicity appears to be mediated by the interaction between CD44S expression on H322DeltaS cells and OPN produced by activated macrophages since it is completely blocked by either anti-OPN or anti-CD44 antibody. Moreover, H322DeltaS cells are attracted toward OPN produced by activated RAW264.7 cells to a much greater extent than H322Deltaneo cells. These findings suggest that CD44S down-regulation in NSCLC cells may confer a protective advantage of allowing escape from tumoricidal effector cells including activated macrophages of the host.

The N-ERC index is a novel monitoring and prognostic marker for advanced malignant pleural mesothelioma

BACKGROUND Although N-ERC/mesothelin (N-ERC) is an attractive diagnostic and treatment monitoring biomarker for malignant pleural mesothelioma (MPM), its clinical utility for predicting the prognosis has not yet been clarified. The aim of this study is to investigate whether the serum N-ERC level can accurately predict the outcome in patients with MPM. METHODS Twenty-six patients with MPM were enrolled. Serum N-ERC level was measured before and after chemotherapy. The N-ERC index was determined by the logarithm of the division of the N-ERC level after two courses of chemotherapy by the prior level. RESULTS The median N-ERC index in the partial response (PR) group was significantly lower than that in patients with the stable disease (SD) plus the progressive disease (PD) group. The overall survival in the group whose median N-ERC index was lower than its median value was significantly longer than the group whose median N-ERC index was higher than its median value. CONCLUSIONS The N-ERC index is therefore considered to be a useful biomarker for predicting not only the chemotherapeutic response, but also the prognosis in patients with advanced MPM.

Malignant pericardial mesothelioma

A 72-year-old female, who had no asbestos exposure, felt chest pain. She was diagnosed with pericarditis. After 6 months, a follow-up chest computed tomography (CT) showed a thickened pericardium (Fig. 1(A) and (B)) and a positron emission tomography (PET) scan was positive along the pericardium (Fig. 1(C)). An open pericardial biopsy proved malignant pericardial mesothelioma (Fig. 2). www.elsevier.com/locate/ejcts European Journal of Cardio-thoracic Surgery 39 (2011) 420

A feasibility study of zoledronic acid combined with carboplatin/nedaplatin plus paclitaxel in patients with non-small cell lung cancer with bone metastases.

AIMS AND BACKGROUND Although zoledronic acid (ZOL) has been reported to inhibit bone metastasis from lung cancer, the optimum chemotherapy regimen in combination with ZOL has not yet been determined. METHODS AND STUDY DESIGN Eighteen patients having non-small cell lung cancer (NSCLC) with bone metastasis who received carboplatin/nedaplatin plus paclitaxel combined with ZOL (4 mg every 28 days) were enrolled to investigate the feasibility of this treatment. The efficacy was evaluated by the percentage of patients at 9 months who were receiving radiation therapy, the time to first radiation treatment, and quality of life. Adverse effects were also evaluated. RESULTS Only 3 among 18 patients received radiation therapy for bone metastases during the 9 months of the study. ZOL seems to prolong the median time to the first radiation treatment and maintain the quality of life regarding pain and activity status. No patients discontinued the treatment, although grade 3 or 4 treatment-related adverse effects occurred in 8 patients. CONCLUSIONS ZOL combined with carboplatin/nedaplatin plus paclitaxel is an effective and tolerable treatment for NSCLC with bone metastases.

Safety of Bronchoscopy for Patients Undergoing Hemodialysis

Yuuki Sandhu, Katsutoshi Ando, Hidenori Takekawa, Haruhi Takagi, Michihiro Hirama, Kenji Kido, Kazuhisa Takahashi Department of Respiratory Internal Medicine, Juntendo University Nerima Hospital, 3-1-10 Takanodai, Nerima-ku, Tokyo 177-8521, Japan Department of Internal Medicine, Division of Respiratory Medicine, Juntendo University Graduate School of Medicine, 21-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan