We previously established an osteolytic bone metastasis model with multiorgan dissemination in natural killer (NK) cell-depleted severe combined immunodeficient (SCID) mice using human small cell lung cancer cells (SBC-5), which highly express the parathyroid hormone-related protein (PTHrP). In our present study, we evaluated the role of PTHrP on bone metastasis by SBC-5 cells using anti-PTHrP neutralizing antibody (Ab). Anti-PTHrP Ab did not affect the proliferation or cytokine production of SBC-5 cells in vitro. Key words: PTHrP; bone metastasis; small cell lung cancerMore than 50,000 new cases of lung cancer are detected annually in Japan, and the mortality rate of nearly 90% makes it the leading cause of cancer-related death. More than 90% of deaths from lung cancer can be attributed to metastasis. 1 Lung cancer is histologically classified into 2 groups-small cell lung cancer (SCLC) and non small cell lung cancer (NSCLC)-based on their different clinical behaviors, such as the rate of tumor growth, the pattern of tumor progression and the sensitivity to chemotherapy and radiotherapy. 2 SCLC grows more rapidly and frequently develops metastasis to multiple organs, including the brain, lungs, liver, adrenal glands and bone. In particular, bone metastasis causes bone pain, hypercalcemia, nerve compression syndromes and even fractures. 3 These might be the main causes of the decrease in quality of life in patients with bone metastasis. Therefore, the prevention and treatment of osteolytic bone metastasis are clinically important.Parathyroid hormone-related protein (PTHrP) was originally identified as a 17-kDa PTH-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy (HHM). 4 -7 Interestingly, a variety of tumor cells, including mammary cancer, prostate cancer and lung cancer, overexpress PTHrP. 8 A highly bone metastatic lung squamous cell carcinoma cell line was found to overexpress PTHrP, and the treatment of nude mice with anti-PTHrP antibody (Ab) inhibited the formation of bone metastasis. 9 Visceral metastasis is frequently observed clinically along with bone metastasis. The development of visceral metastasis is also a serious problem, as well as that of bone metastasis. Several reports have indicated that the heterogeneity of the organ microenvironment is very important in metastasis formation of cancer cells and that it is markedly different from each organ. Therefore, it is possible that the efficacy of therapeutic agents is different among organs. As visceral metastasis was hardly developed in previously reported bone metastasis models, an appropriate model for simultaneous evaluation of the efficacy of therapeutic agents on not only bone metastasis but also visceral metastasis is required.Recently, we developed an osteolytic bone metastasis model with human SCLC cells (SBC-5) in natural killer (NK) celldepleted severe combined immunodeficient (SCID) mice. 10 As visceral metastasis was also reproducibly developed resembling the clinical characteri...

ung cancer is the major cause of malignancy-related death worldwide, and its incidence is rising in many countries. The high mortality of this disease is due to the difficulty of early diagnosis and its high potential to invade locally and metastasize to distant organs. Metastasis consists of several sequentially linked steps, such as growth with blood supply at the primary site, invasion, and release into blood vessels or lymphatics, arrest at a distant site, extravasation, and proliferation as a secondary colony with angiogenesis. 1) Each step is strictly regulated by complex interactions occurring between tumors and host stomal cells. 1,2) Recently, the mechanisms of metastasis were thought to be similar to those of inflammation, because many of the mediators involved are similar in both reactions. 3) In fact, it was reported that highly metastatic human lung cancer cell lines overexpressed proinflammatory cytokines and angiogenic chemotactic chemokines. 4) Interleukin-1 (IL-1) is the prototypic proinflammatory cytokine, which was discovered independently as endogenous pyrogen (EP), 5) leukocytic endogenous mediator (LEM), 6) lymphocyte activation factor (LAF), 7) and B cell-activating factor (BAF). 8) While IL-1 consists of two different molecules, IL-1α and IL-1β, both IL-1α and IL-1β are synthesized as precursors without leader sequences. The molecular weight of each precursor is 31 kD, and these precursors are processed by specific cellular proteases to mature forms of 17 kD. Homology of IL-1α and IL-1β is only 25% at the amino acid level. IL-1α exists as a cell-associated form and is primarily a regulator of intracellular events and a mediator of local reaction. On the other hand, IL-1β is a systemic, hormone-like mediator intended to be released from cells. However, once they bind to their receptors, they have similar biological activities. 9) IL-1 is produced by a wide variety of cells, including leukocytes, fibroblasts, and malignant cells, by various stimuli such as bacterial products and cytokines. 9) Receptors for IL-1 are also expressed on various types of cells including endothelial cells, smooth muscles, epithelial cells, hepatocytes, fibroblasts, keratinocytes, epidermal dendritic cells, T lymphocytes, and malignant cells. There are two types of IL-1 receptors (IL-1R); the type I receptor (IL-1RI) transduces a signal, whereas the type II receptor (IL-1RII) binds IL-1, but does not transduce a signal. 10) IL-1 has multiple functions and plays crucial roles in various biologically essential reactions including inflammation, hematopoiesis, and reactions in the immune system, endocrine system, and central nervous system. 9) Many studies have been carried out to explore the role of IL-1 in malignant diseases. However, the effects of IL-1 are still controversial. Several studies found that IL-1 increased the proliferation of certain malignant cells via induction of other growth factors, including tumor necrosis factor-α (TNF-α), IL-6, IL-8, and transforming growth factor-β (TGF-β). 9,11) In sharp con...

BackgroundNeutrophil elastase plays a crucial role in the development of acute lung injury (ALI) in patients with systemic inflammatory response syndrome (SIRS). The clinical efficacy of the neutrophil elastase inhibitor, sivelestat, for patients with ALI associated with SIRS has not been convincingly demonstrated. The aim of this study was to determine if there are clinical features of patients with this condition that affect the efficacy of sivelestat.MethodsThis was a retrospective study of 110 ALI patients with SIRS. Clinical information, including the etiology of ALI, the number of organs failing, scoring systems for assessing the severity of illness, and laboratory data, was collected at the time of diagnosis. Information on the number of ventilator-free days (VFDs) and changes in PaO2/FIO2 (ΔP/F) before and 7 days after the time of ALI diagnosis was also collected. The effect of sivelestat on ALI patients was also examined based on whether they had sepsis and whether their initial serum procalcitonin level was ≥0.5 ng/mL.ResultsThere were 70 patients who were treated with sivelestat and 40 control patients. VFDs and ΔP/F were significantly higher in the treated patients than in the control patients. However, there was no significant difference in the patient survival rate between the two groups. Sivelestat was more effective in ALI patients with a PaO2/FIO2 ratio ≥ 140 mmHg or sepsis. Sivelestat significantly prolonged survival and led to higher VFDs and increased ΔP/F in septic patients and patients with initial serum procalcitonin levels ≥ 0.5 ng/mL.ConclusionThe results may facilitate a future randomized controlled trial to determine whether sivelestat is beneficial for ALI patients with sepsis.

Epidermal growth factor receptor (EGFR) is commonly overexpressed in non-small cell lung cancer (NSCLC) and its tyrosine kinase phosphorylation is thought to be an ideal target in the treatment of patients with NSCLC. In the present study, we examined surgically obtained specimens from a series of 36 NSCLC patients for expression of EGFR, phosphorylated EGFR (p-EGFR), and HER2 by immunohistochemistry, and also examined the correlation with clinical characteristics. The positive rate of EGFR, p-EGFR, and HER2 was 97.2%, 44.4%, and 88.6%, respectively, and the overexpression rate was 80.6%, 0.0%, and 27.8%, respectively. EGFR overexpression and phosphorylation were seen at almost the same rate in each histological type of squamous and nonsquamous cell carcinoma (squamous vs. nonsquamous; 78.6% vs. 81.8% for EGFR, 35.7% vs. 50.0% for p-EGFR), while HER2 overexpression was seen less frequently in squamous cell carcinoma than in nonsquamous cell carcinoma (0.0% vs. 45.5%, P = 0.003). Univariate analysis revealed that EGFR overexpression was related to good performance status (P = 0.038) but not related to EGFR phosphorylation. EGFR phosphorylation was correlated to short time to progression (TTP) (P = 0.002) and poor prognosis (P = 0.002), although EGFR overexpression, HER2 overexpression, or EGFR-HER2 coexpression were not correlated to TTP or survival. Bivariate analysis showed EGFR phosphorylation was related to short TTP and poor prognosis both in early and advanced stages. Multivariate analyses confirmed that clinical stage, performance status, and p-EGFR expression were independently associated with increasing risk of short TTP and poor prognosis. These results suggest that phosphorylation, but not overexpression, of EGFR may be an important predictor for clinical outcome of NSCLCs.

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