Current Molecular Medicine - Volume 8, Issue 6, 2008

CMYC has long been known to be among the most frequently de-regulated oncogenes in human cancer. Only recently, however has a clear understanding begun to emerge of how it promotes transformation. Through its role as a transcription factor, c-Myc alters the expression of hundreds of target genes, many of which are themselves oncogenes or tumor suppressors. The deregulation of c-Myc is both necessary and sufficient for the “acute” type of rapid in vitro transformation that occurs in certain established rodent cell lines. Transformation of primary rodent cells in vitro is also rapid but requires the contribution of at least one additional cooperating oncogene such as Ras. In contrast, the “chronic” form of in vivo transformation by c-Myc is a rare event that requires the acquisition of multiple mutations in other genes affecting cell cycle, senescence, and apoptosis. By greatly accelerating the intrinsic mutation rate at several levels, c-Myc increases the likelihood that these additional mutational “hits” will occur. Among the types of genomic instability mediated by c- Myc are single nucleotide substitutions and double-stranded breaks arising via the induction of reactive oxygen species, gene amplification and the generation of extrachromosomal elements, and numerical chromosomal defects resulting from aberrant DNA synthesis and defects in the mitotic spindle checkpoint. These nonmutually exclusive activities ensure a constant and varied source of genotoxic insults and suggest that c-Myc over-expression imposes a “mutator phenotpye”. This may be an early and necessary requirement for the initial steps in chronic transformation as well as for subsequent evolutionary changes that produce important tumor behaviors such as invasiveness, metastasis, and acquisition of chemotherapy resistance.

This review summarizes the emerging roles of NHERF1/EBP50 adaptor protein in tumorigenesis. NHERF1/EBP50 (Na+/H+ exchanger regulating factor 1; ezrin-radixin-moesin (ERM) binding phosphoprotein of 50 kDa) is a PDZ domain-containing protein with physiological localization at the plasma membrane. We discuss in this review the functions of NHERF1/EBP50 as a linker between membrane proteins and the cytoskeleton network, as well as its involvement in different types of cancer, such as breast and liver cancers. Recent evidence obtained from our laboratory and from other groups shows that NHERF1/EBP50 is an important player in cancer progression. It appears that, depending on its subcellular distribution, NHERF1/EBP50 may behave either as a tumor suppressor, when it is localized at the plasma membrane, or as an oncogenic protein, when it is shifted to the cytoplasm. We provide here an overview of the mechanisms by which this adaptor protein controls cell transformation, and propose a model suggesting a dual role of NHERF1/EBP50 in cancer.

Ovarian cancer is the leading cause of death from gynecological cancers in North America and Europe. Despite its clinical significance, the factors that regulate the development and progression of ovarian cancer are among the least understood of all major human malignancies. A growth factor with pleiotropic effects, which has attracted increasing attention in recent years, is the hepatocyte growth factor (HGF) and its receptor MET. While deregulated HGF/MET signaling is observed in many tumors, the consequences of MET activation are complex and context dependent. Recent observations have demonstrated a cross-talk of other signaling pathways with MET signaling. This review summarizes the key findings and recent advances in our understanding of HGF and MET in the transformation and progression of ovarian cancer. We will begin with a brief discussion on the role of HGF and MET in the physiology of normal ovarian surface epithelium (OSE) and ovarian cancer development. In particular, the coexpression of HGF and MET in OSE of women with hereditary ovarian cancer syndromes emphasizes their importance in neoplastic transformation of OSE. The involvement of HGF in other aspects of tumor progression, such as invasion and metastasis, and novel downstream target genes activated by HGF is summarized next. The therapeutic potential of HGF to treat ovarian cancer and to improve response to conventional chemotherapy is also described. Finally, the most recent progress in drug development and future areas of research in terms of their potential clinical implications are discussed.

Erythropoietin (EPO) has long been recognized as the major hematopoietic cytokine regulating normal erythropoiesis. Moreover, there is a growing interest in the non-erythropoietic, tissue-protective effects of EPO. Because of its potential to correct anemia, EPO has been increasingly prescribed to cancer patients. However, although recombinant human Epo (rHuEPO) significantly reduces the risk for red blood cell transfusions in cancer patients, recent clinical studies have reported decreased survival and disease control following rHuEPO treatment in patients with different cancer types. The issue of EPOR expression in tumor cells is critical in this respect. The expression of EPOR in tumor cells raises the possibility that exogenous rHuEPO may directly influence tumor growth or sensitivity to chemo-radiation therapy. In addition, EPOR expression in endothelial cells suggests what potential effects EPO may have on tumor capillaries, such as the stimulation of angiogenesis. However, as experimental studies reveal, the overall direct effect of EPO-EPOR signaling on cancer progression and therapy is not a straightforward one. The current paper provides an update on the biology of EPO, and discusses its utility in the treatment of cancer patients.

The role of S100A4 in tumor progression and metastasis is well documented in numerous research articles and summarized in several reviews [1-3]. Currently S100A4 is categorized as an essential metastasispromoting factor whose production and secretion from “activated” stromal cells (fibroblasts, immunocytes and vascular cells) is initiated and stimulated by signals derived in tumor cells (cytokines, growth factors and others). However recent data gained from experimental and clinical studies significantly extend our knowledge on S100A4. Implications of S100A4 in various non-malignant pathological conditions have been demonstrated by number of research groups. In the mini-review we attempted to highlight the role of S100A4 in other than cancer important human pathologies, such as autoimmune inflammation (RA) and disorders in cardio-vascular, nervous and pulmonary systems. We suggest that diverse human diseases might have common molecular components and pathway(s). Possibly, inflammatory machinery and S100A4 as its intrinsic constituent could contribute to the pathogenesis of various disorders. Therefore, we presume that facts on S100A4 performance could be attractive for broad range of researchers and clinicians.

The cholesterol-dependent cytolysins are pore-forming toxins. Pneumolysin is the cytolysin produced by Streptococcus pneumoniae and is a key virulence factor. The protein contains 471 amino acids and four structural domains. Binding to cholesterol is followed by oligomerization and membrane pore formation. Pneumolysin also activates the classical pathway of complement. Mutational analysis of the toxin and knowledge of sequence variation in outbreak strains suggests that additional activities of biologic importance exist. Pneumolysin activates a large number of genes, some by epigenetic modification, in eukaryotic cells and multiple signal transduction pathways. Cytolytic effects contribute to lung injury and neuronal damage while proinflammatory effects compound tissue damage. Nevertheless pneumolysin is a focal point of the immune response to pneumococci. Toll-like receptor 4-mediated recognition, osmosensing and T-cell responses to pneumolysin have been identified. In some animal models mutants that lack pneumolysin are associated with impaired bacterial clearance. Pneumolysin, which itself may induce apoptosis in neurones and other cells can activate host-mediated apoptosis in macrophages enhancing clearance. Disease pathogenesis, which has traditionally focused on the harmful effects of the toxin, increasingly recognises that a precarious balance between limited host responses to pneumolysin and either excessive immune responses or toxin-mediated subversion of host immunity exists.

Chagas heart disease (CHD), caused by the protozoan parasite Trypanosoma cruzi, is the leading cause of infectious myocarditis in the world. The etiology of CHD is unclear and multiple mechanisms have been proposed to explain the pathogenesis of the disease. This review describes the proposed mechanisms of CHD pathogenesis and evaluates the historical significance and evidence supporting each. Although the majority of CHD-related pathologies are currently attributed to parasite persistence in the myocardium and autoimmunity, there is strong evidence that CHD develops as a result of additive and even synergistic effects of several distinct mechanisms rather than one factor.

Type 2 diabetes is one of the fastest growing public health problems worldwide. Both environmental (e.g. physical activity, obesity, and diet) and genetic factors are involved in the development of type 2 diabetes. The associations between physical activity and diabetes risk have been assessed by a number of prospective studies and clinical trials. The results from these studies consistently indicate that the regular physical activity during occupation, commuting, leisure time or daily life reduces the risk of type 2 diabetes by 15-60%; and lifestyle intervention, including counselling for physical activity, nutrition, and body weight, can reduce the risk of type 2 diabetes by 40-60% among adults with impaired glucose tolerance and by about 20% among general individuals. In the past decade, studies using traditional linkage analysis and candidate-gene association approach have found dozens of genes harboring common variants that were related to the common-form type 2 diabetes. However, most reported associations are lack of reproducibility, except TCF7L2, PPARG, CAPN10, and KCNJ11. Since 2007, seven genome-wide association (GWA) studies emerged to generate a list of new diabetes genes. The genetic effects are largely of moderate size. These findings provide novel insight into the diabetes etiology and pave new avenue for predicting the disease risk using genetic information. In addition, data especially those from intervention trials display preliminary but promising evidence that the genetic variants might interact with physical activity in predisposing to type 2 diabetes. The gene-environment interactions merit extensive exploration in large, prospective studies.

Diabetic nephropathy, which represents a major form of chronic kidney disease (CKD), is a leading cause of end-stage renal disease worldwide, and is also a risk factor for cardiovascular disease (CVD). Patients with diabetes and CKD have poorer outcomes after myocardial infarction. The underlying pathogenic mechanism that links diabetic nephropathy to a high risk of CVD remains unclear. In addition to traditional risk factors, including hypertension, hyperglycemia, and dyslipidemia, identification of novel modifiable risk factors is important in preventing CVD in people with diabetes. Inflammation/oxidative stress are known to be associated with an increased risk for CVD in patients with diabetic nephropathy. Moreover, homocysteine, advanced glycation end products, asymmetric dimethylarginine, and anemia may play a role in the development and progression of atherosclerosis in patients with diabetic nephropathy. This review summarizes the epidemiologic evidence, molecular mechanisms responsible for the increased risk for CVD in patients with diabetic nephropathy, and therapeutic intervention for diabetic nephropathy as evidenced by large-scale clinical trials.

Cystinuria type I is an autosomal recessive disorder with an exclusively renal phenotype caused by inactivating mutations in SLC3A1. Recently 3 similar but distinct syndromes associated with cystinuria type I have been described: 2p21 deletion syndrome, Hypotonia-Cystinuria Syndrome (HCS) and atypical HCS. Genetic analysis indicated that these are recessive contiguous gene deletion syndromes which differ in the number of genes affected. Patients with HCS are missing both alleles of SLC3A1 and PREPL. In atypical HCS an additional gene (C2orf34) is deleted, and finally, in the 2p21 deletion syndrome the open reading frame of PPM1B is also disrupted. With the exception of SLC3A1, the gene products have not been fully characterized. The severity of the different syndromes reflects the number of genes which are deleted. HCS, a relatively mild syndrome, is characterised by cystinuria type I, generalised hypotonia at birth, growth retardation and minor facial dysmorphic features. On the other end of the spectrum is the 2p21 deletion syndrome, a severe syndrome with a number of additional features including a moderate to severe psychomotor retardation and a decrease in activity of the respiratory chain complexes I, III, IV and V. Finally, atypical HCS displays an intermediate phenotype comparable with classical HCS but associated with mild to moderate mental retardation and a decrease in activity of only the respiratory chain complex IV. “This review will focus on the phenotypic similarities and differences observed in these syndromes. Furthermore, we speculate on the function of the gene products, based on the available data.”

Susceptibility to autoimmune disorders results from the interaction of multiple genetic factors that regulate the threshold of autoreactivity. Genome-wide microsatellite screens and large-scale single nucleotide polymorphism (SNP) association studies have identified chromosomal loci that are associated with specific disorders including systemic lupus erythematosus, rheumatoid arthritis, juvenile arthritis, multiple sclerosis, and diabetes. Numerous candidate gene association studies have in turn investigated the association of specific genes within these chromosomal regions, with susceptibility to autoimmune diseases (e.g. FcgammaReceptors, TYK2 and systemic lupus). More recently, large-scale differential gene expression studies performed on selected tissues from patients with autoimmune disorders, have led to the identification of gene signatures associated with the activation of specific pathways in these diseases (e.g. interferon signature in lupus). In the future, integrated analyses of gene (and protein) expression together with SNP data will allow us to sketch an intelligible picture of the genesis of autoimmunity in humans. This review sets out to illustrate how the most recent advances in the field of systemic lupus erythematosus, rheumatoid arthritis and juvenile arthritis have led to a better understanding of these disorders.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands constitute important insulin sensitizers that have already been used for the treatment of human metabolic disorders, exerting also pleiotropic effects on inflammatory related diseases and cancer. Ischemia-reperfusion injury that is mainly associated with organ transplantation constitutes a serious complication with a great relevance in clinical practice. Accumulating experimental data have recently revealed that natural and synthetic PPAR-γ ligands exert beneficial effects against ischemia-reperfusion injury. The present review summarizes the available information on the role of PPAR-γ ligands in ischemia-reperfusion injury amongst the different organ systems. Taking into consideration the data so far, PPAR-γ ligands seem to represent potential therapeutic agents in the aim to reduce or even prevent injury associated with ischemia-reperfusion.

The ‘amyloid cascade hypothesis’ links amyloid β peptide (Aβ) with the pathological process of Alzheimer's disease (AD) and it still awaits universal acceptance. Amyloid precursor protein (APP), through the actions of the β-secretase complex, eventually becomes a different Aβ species. The various Aβ species have proven to be difficult to investigate under physiological conditions, and the species of Aβ responsible for neurotoxicity has yet to be unequivocally identified. The two important Aβ peptides involved are Aβ1-40 and Aβ1-42, and each has been ascribed both toxic and beneficial attributes. The ratio between the two species can be important in AD etiology. Additionally, shorter variants of Aβ peptides such as Aβ1-8, Aβ9-16 and Aβ16 have also been shown to be potential participants in AD pathology. Interestingly, a new 56-kDa Aβ peptide (Aβ*56) disrupts memory when injected into the brains of young rats. Transgenic mice models are complicated by the interplay between various human Aβ types and the mouse Aβ types in the mouse brains. However, the accumulation of Aβ1-42 in the brains of transgenic C. elegans worms and Drosophila is indeed detrimental. A less investigated aspect of AD is epigenetics, but in time the investigation of the role of epigenetics in AD may add to our understanding of the development of AD.

Recruitment of eosinophils has long been recognized as a hallmark of the inflammatory response in asthma. However, the functions of this population of cells in host defense remain poorly understood. Eosinophils play an important part in the inflammatory response and have key regulatory roles in the afferent arm of the immune response. More recently, eosinophils have been demonstrated to participate in host defense against respiratory viruses. The specific contributions of eosinophils to the pathophysiology of asthma remain controversial. However, the balance of evidence indicates that they have a significant role in the disease, suggesting that they may be appropriate targets for therapy. Towards this end, a novel intervention of considerable potential interest is the use of an antibody directed against the β-common chain of the receptor for interleukin- 3, interleukin-5 and granulocyte-macrophage colony-stimulating factor. However, eliminating eosinophils may not be a risk-free therapeutic strategy, as there is potentially an increased likelihood of respiratory viral infections. This may predispose to the development of acute exacerbations of asthma, an outcome that would have significant clinical implications.