Current perspectives between metabolic syndrome and cancer.

Metabolic syndrome is a cluster of risk factors that lead to cardiovascular morbidity and mortality. Recent studies linked metabolic syndrome and several types of cancer. Although metabolic syndrome may not necessarily cause cancer, it is linked to poorer cancer outcomes including increased risk of recurrence and overall mortality.

HIF2α is involved in the expansion of CXCR4-positive cancer stem-like cells in renal cell carcinoma.

Background: Hypoxia and the subsequent activation of hypoxia-inducible factor-2α (HIF2α) contribute to the progression of a variety of cancers. However, their role in the generation of renal cell carcinoma-derived stem cells has not been fully addressed.

Methods: A sphere formation assay, cell proliferation, RT-PCR, western blot, FACS, immunohistochemistry and tumour xenograft were used to study the role of HIF2α.

Hyperglycemia promotes K-Ras-induced lung tumorigenesis through BASCs amplification.

Oncogenic K-Ras represents the most common molecular change in human lung adenocarcinomas, the major histologic subtype of non-small cell lung cancer (NSCLC). The presence of K-Ras mutation is associated with a poor prognosis, but no effective treatment strategies are available for K-Ras -mutant NSCLC. Epidemiological studies report higher lung cancer mortality rates in patients with type 2 diabetes.

Phase II escalation study of sorafenib in patients with metastatic renal cell carcinoma who have been previously treated with anti-angiogenic treatment.

Objective: To assess both clinical and biological efficacy and toxicity of sorafenib in patients with metastatic renal cell carcinoma (mRCC) previously treated with an anti-angiogenic vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor.

Methods: Sorafenib is an orally active multikinase inhibitor approved for the treatment of mRCC. Drug-focused translational research on tissues (i.

The neuroimmune semaphorin-3A reduces inflammation and progression of experimental autoimmune arthritis.

Semaphorin-3A (Sema3A), a member of a large family of conserved proteins originally implicated in axon guidance, is expressed by activated T cells and downmodulates T cell activation in vitro. This study examined the effect and mechanism of action of Sema3A overexpression in a mouse model of collagen-induced arthritis. Prophylactic i.

Metronomic administration of zoledronic acid and taxotere combination in castration resistant prostate cancer patients: phase I ZANTE trial.

Background: Docetaxel (DTX) and zoledronic acid (ZOL) are effective in patients with hormone resistant prostate cancer (HRPC) with bone metastases. A phase I clinical trial of metronomic administration of Zoledronic Acid AN d TaxoterE combination (ZANTE trial) in 2 different sequences was conducted in HRPC.

Results: The maximum tolerated dose was not achieved with sequence A.

Lipoxygenase inhibitors for cancer prevention: promises and risks.

It is well established that an increase of n-6 polyunsaturated (i.e. arachidonic and arachidonic-converted linoleic acids) fat dietary intake enhances carcinogenesis and promotes tumorigenesis through oxidative metabolism.

The plexin-A1 receptor activates vascular endothelial growth factor-receptor 2 and nuclear factor-kappaB to mediate survival and anchorage-independent growth of malignant mesothelioma cells.

The semaphorins and their receptors, the neuropilins and the plexins, are constituents of a complex regulatory system that controls axonal guidance. Moreover, many types of tumor cells express various members of semaphorins and receptors, but the biological activities within tumor mass and the signal transduction mechanism(s) they use are largely unknown. Here, we show that in asbestos-related malignant pleural mesothelioma (MPM), Semaphorin-6D (Sema6D) and its receptor plexin-A1 are frequently expressed and trigger a prosurvival program that promotes anchorage-independent growth of MPM cells.

Enhanced antitumor therapy by inhibition of p21waf1 in human malignant mesothelioma.

Purpose: The p21 cyclin-dependent kinase inhibitor was frequently expressed in human malignant pleural mesothelioma (MPM) tissues as well as cell lines. Recent data indicate that p21 keeps tumor cells alive after DNA damage, favoring a survival advantage. In this study, we assessed the possibility of p21 suppression as a therapeutic target for MPM.

Semaphorin3A signaling controls Fas (CD95)-mediated apoptosis by promoting Fas translocation into lipid rafts.

Semaphorins and their receptors (plexins) have pleiotropic biologic functions, including regulation of immune responses. However, the role of these molecules inside the immune system and the signal transduction mechanism(s) they use are largely unknown. Here, we show that Semaphorin3A (Sema3A) triggers a proapoptotic program that sensitizes leukemic T cells to Fas (CD95)-mediated apoptosis.

Integrin-mediated cell adhesion and spreading engage different sources of reactive oxygen species.

The tightly regulated production of intracellular reactive oxygen species (ROS) participates in several biologic processes such as cellular growth, programmed cell death, senescence, and adhesion. It is increasingly evident that the same enzymatic processes that were originally linked to ROS generation during host defence or apoptosis execution are also involved in redox-mediated signal transduction. We investigated in murine NIH3T3 fibroblasts the contribution of a variety of redox-dependent events during signal transduction initiated by integrin engagement due to fibronectin stimulation and report that a mitochondrial ROS release occurs, strictly confined to the early phase of extracellular matrix (ECM) contact (10 min).

Neuronal semaphorins regulate a primary immune response.

Semaphorins are involved in a wide range of biological processes, including axon guidance, neuronal migration, angiogenesis, cardio- and osteo-genesis. Recently they have also been found to be important for immune response. Sema3A reduces the activation of T cells through its cell-surface receptors, including members of the neuropilin and plexin families.

Characterization of human malignant mesothelioma cell lines orthotopically implanted in the pleural cavity of immunodeficient mice for their ability to grow and form metastasis.

Background: Malignant pleural mesothelioma (MPM) is a tumor known to be resistant to conventional therapies. Thus, an in vivo model can represent an important tool for assessing the efficacy of novel approaches in the treatment of MPM.Presently, human MPM cells have been grown orthotopically in mice upon transplantation of tumor masses or tumor cell suspensions following surgery.

Semaphorin-3A is expressed by tumor cells and alters T-cell signal transduction and function.

An important aspect of tumor progression is the ability of cancer cells to escape detection and clearance by the immune system. Recent studies suggest that several tumors express soluble factors interfering with the immune response. Here, we show that semaphorin-3A (Sema-3A), a secreted member of the semaphorin family involved in axonal guidance, organogenesis, and angiogenesis, is highly expressed in several tumor cells.

5-Lipoxygenase regulates senescence-like growth arrest by promoting ROS-dependent p53 activation.

5-Lipoxygenase (5LO) is involved in the production of leukotrienes and reactive oxygen species (ROS) from arachidonic acid. Its strong activation has been associated with several diseases like cancer and neurodegeneration. Here we show that 5LO activity increases during senescence-like growth arrest induced by oncogenic ras or culture history in both human and mouse embryo fibroblasts.

5-lipoxygenase antagonizes genotoxic stress-induced apoptosis by altering p53 nuclear trafficking.

5-lipoxygenase (5-LO) promotes cancer cell proliferation and survival by unclear mechanisms. Here, we show that 5-LO expression and activity were induced by genotoxic agents in a p53-independent manner and antagonized p53- or genotoxic drug-induced apoptosis in a variety of cancer cells. 5-LO inhibited p53-governed transactivation of the pro-apoptotic genes bax and pig3 but not of p21(WAF1/CIP1) or mdm2.

Induction of stem cell factor/c-Kit/slug signal transduction in multidrug-resistant malignant mesothelioma cells.

Malignant mesothelioma (MM) is strongly resistant to conventional chemotherapy by unclear mechanisms. We and others have previously reported that cytokine- and growth factor-mediated signal transduction is involved in the growth and progression of MM. Here, we identified a pathway that involves stem cell factor (SCF)/c-Kit/Slug in mediating multidrug resistance of MM cells.

FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells.

Tumors have developed several forms of resistance to receptor-induced cell death. Here, we show that malignant mesothelial (MM) cell lines as well as primary MM cells and normal mesothelial (NM) cells express Fas and TNF-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5. We found that, although Fas expression levels are comparable, only MM cells are resistant to cell death.

Experimental therapy of malignant mesothelioma: new perspectives from anti-angiogenic treatments.

We reviewed the published literature of clinical studies in malignant mesothelioma (MM), including phase II as well as older single-agent and combination chemotherapy trials with more than 15 patients. While response rates exceeding 30% have been achieved with established cytotoxic drugs in MM therapy, novel chemotherapeutic agents and their combinations appear more promising. This applies especially to the anti-metabolites (i.

Preclinical evaluation of the nonsteroidal anti-inflammatory agent celecoxib on malignant mesothelioma chemoprevention.

Malignant mesothelioma (MM) remains the most lethal pleural, peritoneal and pericardial cancer. Here, we characterize the effects of nonsteroidal anti-inflammatory agents (NSAIDs) on in vitro and in vivo experimental MM models. Unlike primary normal mesothelial cells, the selective cyclooxygenase (COX)-2 inhibitor celecoxib reduced the in vitro proliferation of several MM cells derived from previously untreated MM patients.

Cross-talk between vascular endothelial growth factor and semaphorin-3A pathway in the regulation of normal and malignant mesothelial cell proliferation.

Vascular endothelial growth factor (VEGF) and semaphorin-3A (Sema-3A) play important roles in the transduction of promitotic and antimitotic signals, respectively. Here, we report that these conflicting signals are integrated via negative feedback between VEGF and Sema-3A pathways in several primary normal, but not malignant, mesothelial cells. Unlike malignant mesothelial (MM) cells, in which VEGF induces cell proliferation, normal mesothelial (NM) cell growth was repressed by VEGF.

Enhanced expression of vascular endothelial growth factor (VEGF) plays a critical role in the tumor progression potential induced by simian virus 40 large T antigen.

Vascular endothelial growth factor (VEGF), an important angiogenic factor, regulates cell proliferation, differentiation, and apoptosis through activation of its tyrosine-kinase receptors, such as Flt-1 and Flk-1/Kdr. Human malignant mesothelioma cells (HMC), which have wild-type p53, express VEGF and exhibit cell growth increased by VEGF. Here, we demonstrate that early transforming proteins of simian virus (SV) 40, large tumor antigen (Tag) and small tumor antigen (tag), which have been associated with mesotheliomas, enhanced HMC proliferation by inducing VEGF expression.