TRAIL produced from multiple myeloma cells is associated with osteolytic markers

Department of Hematology, Kumamoto University School of Medicine, and Department of Surgical Pathology, Kumamoto University Hospital, Kumamoto, Japan.
Oncology Reports (Impact Factor: 2.3). 01/2012; 27(1):39-44. DOI: 10.3892/or.2011.1491
Source: PubMed


Skeletal complications represent major clinical problems in multiple myeloma (MM). MM cells are known to induce differentiation of osteoclasts and inhibit osteoblasts. Receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) are key molecules for osteoclastogenesis. Although OPG interacts with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), the contribution of TRAIL to skeletal-related events (SRE) remains a matter of debate. In the present study, we examined the role of TRAIL in MM bone lesions. Myeloma cells were purified from 56 MM patients by CD138-immunomagnetic beads. TRAIL, DKK-1 and MIP1α RNA expression in purified MM cells was analyzed by real-time PCR. Immunohistochemistry of TRAIL was performed on paraffin-embedded plasmacytoma tissue sections. The concentration of TRAIL in the serum and bone marrow plasma from MM patients was analyzed by ELISA. TRAIL expression was significantly higher in MM cells than in plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS). TRAIL staining was detected in the cytoplasm of myeloma cells. TRAIL expression in MM cells correlated with bone marrow plasma TRAIL concentration. TRAIL expression had a positive correlation with osteolytic markers, such as serum calcium and urinary deoxypyridinoline. These results suggest that TRAIL, produced from myeloma cells, may play an important role in bone resorption of MM patients. Inhibition of this pathway may lead to development of a new therapeutic approach preventing bone resorption in MM.

Download full-text


Available from: Yutaka Okuno
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Patients with locally advanced breast cancer treated with neoadjuvant chemotherapy are at risk of cancer treatment-induced bone loss and consequently of increased skeletal morbidity. In addition, this situation could be worsened by the fact that only a minority of patients with breast cancer have sufficient vitamin D. A comprehensive evaluation of bone homeostasis is critical in this context. We retrospectively evaluated the serum levels of calcium, vitamin D, TRAIL, RANK ligand (RANKL), Osteoprotegerin (OPG), Bone TRAP, CrossLaps and DKK1 in 77 patients (median age: 50 years; range 25-74), with locally advanced breast cancer treated in our institute with anthracyclines-taxane neoadjuvant chemotherapy (7 cycles of 21 days/each) between March 2007 and August 2008. Serum samples were collected before the first (baseline) and the last treatment cycle. Variations and correlations between biomarker levels were evaluated. At baseline, 79.5 % of patients had vitamin D insufficiency (<30 ng/ml), increasing to 97.4 % at the end of the neoadjuvant chemotherapy (p < 0.0001). Calcium and RANKL serum concentrations were also significantly decreased, while OPG was significantly increased, resulting in lower RANKL/OPG ratio. Calcium and vitamin D, RANKL and vitamin D and RANKL and OPG levels were significantly correlated (Spearman's coefficient r = 0.2721, p = 0.0006; r = 0.1916, p = 0.002; and r = -0.179, p = 0.03, respectively). Nearly all included patients suffered from vitamin D insufficiency by the end of the neoadjuvant chemotherapy with changes in the calcium/RANKL/OPG axis that are evocative of deregulation of a functional regulatory mechanism. Further studies are needed to determine how drugs modulate this regulatory mechanism to preserve bone homeostasis in patients with breast cancer.
    Full-text · Article · May 2012 · Breast Cancer Research and Treatment
  • [Show abstract] [Hide abstract]
    ABSTRACT: The TNF-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) superfamily that has been recognized for its specific pro-apoptotic effect on cancer cells and has been therefore proposed as a treatment in cancer. Studies on animal models have shown that TRAIL could also have a beneficial effect in rheumatoid arthritis (RA). This includes reports suggesting that TRAIL could be used to control the synovial hyperplasia and hyperactivation of immune cells observed in RA, but recent reports suggest a disease promoting role of TRAIL in RA. Indeed, adverse effects and mechanism of resistance could counteract beneficial effect of TRAIL. This review focuses on the role of TRAIL in immune regulation, synovial hyperplasia and joint remodeling in RA. We will also discuss the potential use of TRAIL in RA treatment.
    No preview · Article · May 2013 · Cytokine
  • [Show abstract] [Hide abstract]
    ABSTRACT: B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL) and apoptosis inducing ligand (TRAIL) are members of the tumour necrosis factor (TNF) family. They are the main survival factors for immature, naive and activated B cells. We have analysed BAFF, APRIL and TRAIL serum concentrations in 52 patients with newly diagnosed IgG multiple myeloma and 20 healthy volunteers. The values were significantly higher in the studied patients and advanced diseases, decreasing after chemotherapy, compared to the control group. It was established that BAFF as APRIL (but not TRAIL) correlated with adverse prognostic factors such as IL-6 and lactate dehydrogenase. Furthermore, higher concentrations of APRIL and BAFF (but not TRAIL) predicted a shorter progression free survival, suggesting thereby an important prognostic marker and a possible therapeutic target in myeloma.
    No preview · Article · Jun 2013 · Leukemia research
Show more