Current Molecular Medicine - Volume 14, Issue 4, 2014

Multiple myeloma (MM) is a clonal neoplasm characterized by expansion of malignant plasma cells in the bone marrow causing various complications including osteolytic lesions and impaired immune function. It has recently been reported that human myeloma cells express multiple Toll-like receptors (TLRs), and their activation-induced functional responses show heterogeneity among cell lines and patient samples. TLRs are critical germ-line encoded molecules expressed in immune cells as well as in a variety of cancer cells. In multiple myeloma, they may induce cell growth and proliferation or promote cell death. In fact, our current knowledge of Toll-like receptor function has gone beyond their main function as triggers of innate and adaptive immune responses. Considering the essential role of bone marrow microenvironment components in myeloma tumor expansion, survival, invasion and drug resistance, TLR triggering may contribute to adhesion-induced or de novo drug resistance of MM cells. Future preclinical and clinical studies are needed to address if TLRs can be exploited as novel therapeutic targets for MM.

The TP73 gene is a member of the TP53 family with high structural homology to p53 and capable of transactivating p53 target genes. The TP73 gene locus which is highly conserved and complex, encodes for two classes of isoforms TAp73 (tumor suppressor isoforms containing the transactivation domain) and ΔNp73 (oncogenic isoforms, truncated and lacking the transactivation domain) with opposing effects. The balance between TAp73 and ΔNp73 isoforms and their harmony with other members of the TP73 family regulate various cellular responses such as apoptosis, autophagy, proliferation, and differentiation. The transcriptionally active isoforms of p73 are capable of inducing apoptosis in cancer cells independent of p53 status. Unlike p53, p73 is rarely mutated in cancers, however, the ratio of ΔNp73:TAp73 is frequently up-regulated in many carcinomas and is indicative of poor prognosis. Moreover, p73 is an important determinant of chemosensitivity and radiosensitivity, the two major treatment modalities for lymphoma. In the current review, we will provide an overview of recent progress discussing the role of TP73 in cancer, specifically addressing its relevance to lymphomagenesis, progression, therapy resistance, and its potential as a novel therapeutic target.

Interest in biomarkers in the field of thoracic oncology is focused on the search for new robust tests for diagnosis (in particular for screening), prognosis and theragnosis. These biomarkers can be detected in tissues and/or cells, but also in biological fluids, mainly the blood. In this context, there is growing interest in the detection of circulating tumor cells (CTCs) in the blood of lung cancer patients since CTC identification, enumeration and characterization may have a direct impact on diagnosis, prognosis and theragnosis in the daily clinical practice. Many direct and indirect methods have been developed to detect and characterize CTCs in lung cancer patients. However, these different approaches still hold limitations and many of them have demonstrated unequal sensitivity and specificity. Indeed, these methods hold advantages but also certain disadvantages. Therefore, despite the promises, it is currently difficult and premature to apply this methodology to the routine care of lung cancer patients. This situation is the consequence of the analysis of the methodological approaches for the detection and characterization of CTCs and of the results published to date. Finally, the advent of targeted cancer therapies in thoracic oncology has stimulated considerable interest in non-invasive detection of genomic alterations in tumors over time through the analysis of CTCs, an approach that may help clinicians to optimize therapeutic strategies for lung cancer patients. We describe here the main methods for CTC detection, the advantages and limitations of these different approaches and the potential usefulness and value of CTC characterization in the field of thoracic oncology.

Rather being an inert barrier between vessel lumen and surrounding tissues, vascular endothelium plays a key role in the maintenance of cardiovascular homeostasis. The de-endothelialization of blood vessels is regarded as the early event that results in the onset of severe vascular disorders, including atherosclerosis, acute myocardial infarction, brain stroke, and aortic aneurysm. Restoration of the endothelial lining may be accomplished by the activation of neighbouring endothelial cells (ECs) freed by contact inhibition and by circulating endothelial progenitor cells (EPCs). Intracellular Ca2+ signalling is essential to promote wound healing: however, the molecular underpinnings of the Ca2+ response to injury are yet to be fully elucidated. Similarly, the components of the Ca2+ toolkit that drive EPC incorporation into denuded vessels are far from being fully elucidated. The present review will survey the current knowledge on the role of Ca2+ signalling in endothelial repair and in EPC activation. We propose that endothelial regeneration might be boosted by intraluminal release of specific Ca2+ channel agonists or by gene transfer strategies aiming to enhance the expression of the most suitable Ca2+ channels at the wound site. In this view, connexin (Cx) channels/hemichannels and store-operated Ca2+ entry (SOCE) stand amid the most proper routes to therapeutically induce the regrowth of denuded vessels. Cx stimulation might trigger the proliferative and migratory behaviour of ECs facing the lesion site, whereas activation of SOCE is likely to favour EPC homing to the wounded vessel.

Plasma levels of high density lipoprotein (HDL) cholesterol levels and of apolipoprotein A-I are inversely correlated with the incidence of coronary heart disease. According to the HDL hypothesis, raising HDL cholesterol is expected to lead to a decrease of coronary heart disease risk. The stringent requirement for proving or refuting this hypothesis is that the causal pathway between the therapeutic intervention and a hard clinical end-point obligatory passes through HDL. The lack of positive clinical results in several recent HDL trials should be interpreted in light of the poor HDL specificity of the drugs that were investigated in these trials. Nevertheless, the results of Mendelian randomization studies further raise the possibility that the epidemiological relationship between HDL cholesterol and coronary artery disease might reflect residual confounding HDL are circulating multimolecular platforms that exert divergent functions: reverse cholesterol transport, antiinflammatory effects, anti-oxidative effects, immunomodulatory effects, improved endothelial function, increased endothelial progenitor cell number and function, antithrombotic effects, and potentiation of insulin secretion and improvement of insulin sensitivity. Pleiotropic effects of HDL might be translated in clinically significant effects in strategically selected therapeutic areas that are not directly related to native coronary artery disease. In this review, four new therapeutic areas for HDL-targeted diseases are presented: critical illness, allograft vasculopathy and vein graft atherosclerosis, type 2 diabetes mellitus, and heart failure. The strategic selection of these therapeutic areas is not only based on specific functional properties of HDL but also on significant pre-clinical and clinical data that support this choice.

The Fgf family comprises 22 members with diverse functions in development, repair, metabolism, and neuronal activities. Fgf10 mediates biological responses by activating Fgf receptor 2b (Fgfr2b) with heparin/heparan sulfate in a paracrine manner. Fgf10 and Fgfr2b are expressed in mesenchymal and epithelial tissues, respectively. Fgf10 is an epithelial-mesenchymal signaling molecule. Fgf10 knockout mice show severe phenotypes with complete truncation of the fore- and hindlimbs and die shortly after birth due to impaired lung development, indicating that Fgf10 serves as an essential regulator of lung and limb formation. Fgf10 also has roles in the development of white adipose tissue, heart, liver, brain, kidney, cecum, ocular glands, thymus, inner ear, tongue, trachea, eye, stomach, prostate, salivary gland, mammary gland, and whiskers. The diverse phenotypes of Fgf10 knockout mice are closely related to those of Fgfr2 knockout mice, suggesting that Fgf10 acts as a major ligand for Fgfr2b in mouse multi-organ development. Aplasia of lacrimal and salivary glands and lacrimo-auriculo-dento-digital syndrome are caused by Fgf10 mutations in humans. Variants in Fgf10 may be involved in an increased risk for limb deficiencies and cleft lip and palate. Patients with Fgf10 haploinsufficiency have lung function parameters indicating chronic obstructive pulmonary disease. Fgf10 induces migration and invasion in pancreatic cancer cells. Fgf10 signaling may be involved in an increased risk for breast cancer. Fgf10 also induces the differentiation of embryonic stem cells into a gut-like structure, cardiomyocytes, and hepatocytes. These findings indicate the crucial roles of Fgf10 in development, disease, and regenerative medicine.

Several studies have provided clear evidence of the importance of Wnt signaling in the function of several tissues. Wnt signaling has been related to several cellular processes including pre-natal development, cell division, regeneration and stem cell generation. By contrast, deregulation of this pathway has been associated with several diseases such as cancer, Alzheimer's disease, diabetes and, in recent years, fibrotic diseases in tissues such as skeletal muscle and kidney. Fibrotic diseases are characterized by an increase in the production and accumulation of extracellular matrix (ECM) components leading to the loss of tissue architecture and function. In a classical view, several molecules are related to the establishment of the fibrotic condition, including angiotensin II, transforming growth factorβ(TGF-β) and the connective tissue growth factor (CTGF) and a crosstalk has been suggested between these signaling molecules and the Wnt pathway. Skeletal muscle fibrosis, the most common disease, is typical of muscle dystrophies, where deregulation of the regenerative process in postnatal muscle leads to fibrotic differentiation and eventually to the failure of skeletal muscle. The fibrotic condition is also present in kidney pathologies such as polycystic kidney disease (PKD), in which fibrosis leads to a loss of tubule architecture and to a loss of function, which in almost all cases requires kidney surgery. A new actor in the pro-fibrotic effect of Wnt signaling in the kidney has been described, the primary cilium, an organelle that plays an important role in the onset of fibrosis. The aim of this review is to discuss the pro-fibrotic effect of Wnt signaling in both skeletal muscle and kidney, and to try to understand how this pathway is associated with the TGF-β, CTGF and angiotensin II pro-fibrotic pathway.

The epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells plays a key role in proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR), which lead to the loss of vision. The Jagged/Notch pathway has been reported to be essential in EMT during embryonic development, fibrotic diseases and cancer metastasis. However, the function of Jagged/Notch signaling in EMT of RPE cells is unknown. Thus, we hypothesized that a crosstalk between Notch and transforming growth factor β2 (TGF-β2) signaling could induce EMT in RPE cells, which subsequently contributes to PVR and PDR. Here, we demonstrate that Jagged-1/Notch pathway is involved in the TGF-β2-mediated EMT of human RPE cells. Blockade of Notch pathway with DAPT (a specific inhibitor of Notch receptor cleavage) and knockdown of Jagged-1 expression inhibited TGF-β2-induced EMT through regulating the expression of Snail, Slug and ZEB1. Besides the canonical Smad signaling pathway, the noncanonical PI3K/Akt and MAPK pathway also contributed to TGF-β2-induced up-regulation of Jagged-1 in RPE cells. Overexpression of Jagged-1 could mimic TGF-β2 induce EMT. Our data suggest that the Jagged-1/Notch signaling pathway plays a critical role in TGF-β2-induced EMT in human RPE cells, and may contribute to the development of PVR and PDR. Inhibition of the Jagged/Notch signaling pathway, therefore, may have therapeutic value in the prevention and treatment of PVR and PDR.

Interleukin 37 has been found to play a significant regulatory role in the innate immune response. It is not yet known whether IL-37 has also been involved in the development of Behcet’s disease (BD), a chronic systemic inflammatory disease. To examine the role of IL-37 in the pathogenesis of BD, a number of experiments were performed. IL-37 expression in peripheral blood mononuclear cells (PBMCs) from BD patients and normal controls was measured by RT-PCR and flow cytometry. Monocyte-derived Dendritic Cells (DCs) were cultured with or without IL-37 and levels of cytokines in the culture supernatants were measured by ELISA. The DC surface markers, reactive oxygen species (ROS) production and mitogen-activated protein kinase (MAPK) activation were measured by flow cytometry. The effect of IL-37-treated DCs on the development of CD4+ T cells was measured by ELISA and flow cytometry. The results show that both IL-37 mRNA level and protein expression were significantly decreased in PBMCs from active BD patients compared to normal controls. DCs stimulated with rIL-37 showed a decreased expression of IL-6, IL-1β and TNF-α, and a higher production of IL-27. rIL-37 significantly inhibited the production of ROS by DCs and reduced the activation of ERK1/2, JNK and P38 MAPK in DCs. rIL-37-treated DCs remarkably inhibited Th17 and Th1 cell responses as compared to control DCs. rIL-37 did not affect the expression of DC surface markers (CD40, CD86, CD80 and HLA-DR) or IL-10 production by DCs. We conclude that a decreased IL-37 expression in active BD patients may trigger the production of pro-inflammatory cytokines and ROS in association with activation of Th1 and Th17 cells by DCs.

G protein-coupled receptor 124 (GPR124; also called tumor endothelial marker 5, TEM5) is highly expressed in tumor vasculature. While recent studies have revealed a role in vasculogenesis, evidence for GPR124 function in tumor angiogenesis is lacking. Here, we demonstrate that GPR124 is required for VEGFinduced tumor angiogenesis. GPR124 silencing in human endothelial cells inhibited mouse xenograft tumor angiogenic vessel formation and tumor growth. GPR124 regulated VEGF-induced tumor angiogenic processes in vitro including cell-cell interaction, permeability, migration, invasion, and tube formation. Therefore, GPR124 plays a key role in VEGF-induced tumor angiogenesis.

Objectives: Celastrol, a quinone methide triterpenoid, could induce apoptosis in pancreatic cancer cells. The purpose of this study is to determine whether there is protective autophagy after celastrol treatment in pancreatic cancer cells and the synergistic effects of celastrol and 3-MA in vitro and in vivo. Methods: The cells viability was measured using MTT assays. Degree of apoptosis and amount of autophagic vacuoles were measured by flow cytometry. Immunofluorescence was adapted to monitor the localization of autophagic protein LC3-II. Expression of LC3-II, cleaved caspase-3, Bax and bcl-2 was detected by immunoblot. Autophagosomes were observed by electron microscopy. The synergistic effect of celastrol and 3- MA in vivo was studied in the MiaPaCa-2 xenograft tumor model. Results: Celastrol increased the level of autophagy in pancreatic cancer cells. Furthermore in vitro, when inhibiting the autophagy with 3-MA, the level of celastrol-induced apoptosis elevated; after upgrading autophagy by starvation, the level of celastrol-induced apoptosis descended. 3-MA enhanced celastrol-induced apoptosis and inhibitory effect on tumor growth in vivo. Conclusions: In pancreatic cancer, celastrol treatment increased the level of autophagy to protect cancer cells against apoptosis. Autophagy inhibitor 3-MA could improve the therapeutic effect of celastrol in vitro and in vivo.