8743

TNFSF10

tumor necrosis factor (ligand) superfamily, member 10;TNFSF10;tumor necrosis factor (ligand) superfamily, member 10

Apo-2 ligand|TNF-related apoptosis inducing ligand TRAIL|chemokine tumor necrosis factor ligand superfamily member 10|tumor necrosis factor (ligand) family, member 10|tumor necrosis factor apoptosis-inducing ligand splice variant delta|tumor necrosis fact

3q26

protein-coding

PURPOSE: metastatic breast cancer is a deadly disease which requires new therapeutic strategies. Endogenous TNF-related apoptosis-inducing ligand (TRAIL) functions as a metastasis suppressor by activating proapoptotic TRAIL receptors (TRAIL-R1/DR4 and/or TRAIL-R2/DR5) in transformed cells, making it an attractive pathway for antimetastatic therapies. However, it is unclear whether TRAIL-R1 or TRAIL-R2 is a better therapeutic target in metastatic breast cancer. EXPERIMENTAL DESIGN: Several metastatic, triple (estrogen receptor, progesterone receptor, and HER2)-negative cancer cell lines were treated with human agonistic monoclonal antibodies targeting TRAIL-R1 (mapatumumab) or TRAIL-R2 (lexatumumab). The effects on cell viability, apoptosis, and caspase-8 activation were determined. An orthotopic model of triple-negative breast cancer in which fluorescently labeled breast cancer cells metastasize from the mammary gland to lymph nodes and lung was utilized to evaluate the effects of mapatumumab, lexatumumab, or doxorubicin on primary and metastatic tumor burden in vivo. RESULTS: Lexatumumab was more effective than mapatumumab in activating caspase-8, inducing apoptosis and inhibiting long-term survival of metastatic cancer cells, which expressed both TRAIL-R1 and TRAIL-R2. Human mammary epithelial cells transformed by oncogenic Ras were more sensitive to lexatumumab than nontransformed cells. Lexatumumab inhibited lymph node and lung metastases more robustly than mapatumumab in an orthotopic model of triple-negative breast cancer; both agents inhibited mammary tumor growth. In addition, lexatumumab was more effective than doxorubicin at suppressing metastases at doses of doxorubicin that were associated with toxicity, even though doxorubicin reduced primary tumor burden more robustly than lexatumumab. CONCLUSION: Targeting TRAIL-R2 receptor may be an effective therapeutic strategy for metastatic breast cancer.

BACKGROUND: Colorectal cancer is the third most common human cancer and the third leading cause of cancer related death. BevacizumAb is a humanized monoclonal antibody developed against vascular endothelial growth factor (VEGF) for the treatment of metastatic cancers. Our goal was to evaluate the possibility of using serum sTRAIL and IL8 as markers of treatment efficacy and prognosis in patients with metastatic colon cancer. METHODS: The study was conducted in Denizli between November 10, 2009 and September 20, 2010. 25 patients (6 female, 19 male) with metastatic colon cancer whose mean age was 58.7 years, were selected and included in the study. All patients received therapy with BevacizumAb. All patients were followed in the Oncology Clinic of Denizli State Hospital and were evaluated by clinical status, sTRAIL and IL8 levels were measured by ELISA in the sera of 25 BevacizumAb treated metastatic colon cancer patients and 20 healthy age-gender matched controls. Measurements were taken before and after treatment. RESULTS: The serum sTRAIL concentrations in patients before therapy were similar to those of healthy age-gender matched controls, namely 1.23 +/- 0.06 ng/mL and 1.21 +/- 0.04 ng/mL, respectively. After BevacizumAb treatment, sTRAIL ratios were increased significantly in 11 of 25 patients. 14 patients showed progressive disease with median overall survival of only 8.1 +/- 0.4 months. These 14 patients were the same ones who showed no increase in sTRAIL levels after BevacizumAb treatment. We explored evidence for a correlation between sTRAIL levels and overall survival rates and observed that elevated sTRAIL levels after the BevacizumAb treatment were significantly associated with increased median overall survival up to 22.6 months. Serum IL8 levels were decreased in all patients who received BevacizumAb therapy. CONCLUSIONS: In BevacizumAb therapy, serum IL8 levels were decreased in all patients, and thus, changes in such levels were not correlated with disease outcome. Our data suggest measurement of changes in sTRAIL following BevacizumAb treatment may have prognostic value in metastatic colon cancer patients.

cancer is a leading cause of mortality throughout the world and new treatments are urgently needed. Recent studies suggest that bone marrow-derived mesenchymal stem cells (MSC) home to and incorporate within tumor tissue. We hypothesized that MSCs engineered to produce and deliver tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a transmembrane protein that causes selective apoptosis of tumor cells, would home to and kill cancer cells in a lung metastatic cancer model. Human MSCs were transduced with TRAIL and the IRES-eGFP reporter gene under the control of a tetracycline promoter using a lentiviral vector. Transduced and activated MSCs caused lung (A549), breast (MDAMB231), squamous (H357), and cervical (Hela) cancer cell apoptosis and death in coculture experiments. Subcutaneous xenograft experiments confirmed that directly delivered TRAIL-expressing MSCs were able to significantly reduce tumor growth [0.12 cm(3) (0.04-0.21) versus 0.66 cm(3) (0.21-1.11); P < 0.001]. We then found, using a pulmonary metastasis model, systemically delivered MSCs localized to lung metastases and the controlled local delivery of TRAIL completely cleared the metastatic disease in 38% of mice compared with 0% of controls (P < 0.05). This is the first study to show a significant reduction in metastatic tumor burden with frequent eradication of metastases using inducible TRAIL-expressing MSCs. This has a wide potential therapeutic role, which includes the treatment of both primary tumors and their metastases, possibly as an adjuvant therapy in clearing micrometastatic disease following primary tumor resection.