Signalling pathways in vasculogenic mimicry

Solid tumour growth is dependent on the development of an adequate blood supply. For years, sprouting angiogenesis has been considered an exclusive mechanism of tumour vascularization. However, over the last years, several other mechanisms have been identified, including vessel-co-option, intussusception, recruitment of endothelial precursor cells (EPCs) and even mechanisms that do not involve endothelial cells, a process called vasculogenic mimicry (VM). The latter describes a mechanism by which highly aggressive tumour cells can form vessel-like structures themselves, by virtue of their high plasticity. VM has been observed in several tumour types and its occurrence is strongly associated with a poor prognosis. This review will focus on signalling molecules and cascades involved in VM. In addition, we will discuss the presence of VM in relation to ongoing cancer research. Finally, we describe the clinical significance of VM regarding anti-angiogenesis treatment modalities.     

Diversity and Complexity of Ceramide Signalling in Apoptosis

Sphingolipid ceramide has emerged as a lipid messenger of cell functions including differentiation and apoptosis. Diverse kinds of stresses (ultraviolet, irradiation, heat shock and hypoxia) and biological factors (TNF-, IFN-γ and Fas antibody) require ceramide generation to execute apoptosis. The review summarises the diversity and complexity of up- and downstream of ceramide signalling in apoptosis and clinical implications of ceramide-induced apoptosis.     

Signalling through the platelet glycoprotein Ib-V-IX complex

The glycoprotein Ib-V–IX is one of the major adhesive receptors expressed on the surface of circulating platelets. It is composed of four different polypeptides—GPIb, GPIbβ, GPIX, and GPV—and represents a multifunctional receptor able to interact with a number of ligands, including the adhesive protein von Willebrand factor, the coagulation factors thrombin, factors XI and XII, and the membrane glycoproteins P-selectin and Mac-1. Interaction of GPIb-V–IX with the subendothelial von Willebrand factor is essential for primary haemostasis, as it initiates platelet adhesion to the subendothelial matrix at the sites of vascular injury even under high flow conditions. Upon interaction with von Willebrand factor, GPIb-V–IX initiates transmembrane signalling events for platelet activation, which eventually result in integrin _IIbβ₃ stimulation and platelet aggregation. The investigation of the biochemical mechanisms for platelet activation by GPIb-V–IX has attracted increasing attention during the last years. This review will describe and discuss recent findings that have provided new insights into the events underlying GPIb-V–IX transmembrane signalling. In particular, it will summarise basic concepts on the structure of this receptor, extracellular ligands, and intracellular interactors potentially involved in transmembrane signalling. The recently suggested role of membrane Fc receptors in GPIb-V–IX-initiated platelet activation will also be discussed, along with the involvement of lipid metabolising enzymes, tyrosine kinases, and the cytoskeleton in the crosstalk between GPIb-V–IX and integrin _IIbβ₃.     

Mouse biodiversity in the genomic era

Comparative genomics has developed by comparison of distantly related genomes, for which the link between the reported evolutionary changes and species development/physiology/ecology is not obvious. It is argued that the mouse (genus Mus) is an optimal model for microevolutionary genomics in vertebrates. This is because the mouse genome sequence, physical and genetic map have been completed, because mouse genetics, morpho-anatomy, pathology, behavior and ecology are well-studied, and because the Mus genus is a diverse, well- documented taxon, allowing comparative studies at the level of individual, population, subspecies, and species. The potential of the interaction between mouse genome and mouse biodiversity is illustrated by recent studies of speciation in the house mouse Mus musculus, and studies about the evolution of isochores, the peculiar pattern of GC-content variation across mammalian genomes.     

Managing peptidases in the genomic era

The enzymes that hydrolyse peptide bonds, called peptidases or proteases, are very important to mankind and are also very numerous. The many scientists working on these enzymes are rapidly acquiring new data, and they need good methods to store it and retrieve it. The storage and retrieval require effective systems of classification and nomenclature, and it is the design and implementation of these that we mean by 'managing' peptidases. Ten years ago Rawlings and Barrett proposed the first comprehensive system for the classification of peptidases, which included a set of simple names for the families. In the present article we describe how the system has developed since then. The peptidase classification has now been adopted for use by many other databases, and provides the structure around which the MEROPS protease database (http://merops.sanger.ac.uk) is built.     

Rats in the genomic era.

The rat genome project and the resources that it has generated are transforming the translation of rat biology to human medicine. The rat genome was sequenced to a high quality "draft," the structure and location of the genes were predicted, and a global assessment was published (Gibbs RA et al., Nature 428: 493-521, 2004). Since that time, researchers have made use of the genome sequence and annotations and related resources. We take this opportunity to review the currently available rat genome resources and to discuss the progress and future plans for the rat genome.     

Molecular dating in the genomic era

The comparison of DNA and protein sequences of extant species might be informative for reconstructing the chronology of evolutionary events on Earth. A phylogenetic tree inferred from molecular data directly depicts the evolutionary affinities of species and indirectly allows estimating the age of their origin and diversification. Molecular dating is achieved by assuming the molecular clock hypothesis, i.e., that the rate of change of nucleotide and amino acid sequences is on average constant over geological time. If paleontological calibrations are available, then absolute divergence times of species can be estimated. However, three major difficulties potentially hamper molecular dating : (1) a limited sample of genes and organisms, (2) a limited number of fossil references, and (3) pervasive variations of molecular evolutionary rates among genomes and species. To circumvent these problems, different solutions have been recently proposed. Larger data sets are built with more genes and more species sampled through the mining of an increasing number of genomes. Moreover, independent key fossils are identified to calibrate molecular clocks, and the uncertainty on their age is integrated in subsequent analyses. Finally, models of molecular rate variations are constructed, and incorporated in the so-called relaxed molecular clock approaches. As an illustration of these improvements, we mention that the debated age of the animal (bilaterian metazoans) diversification may have occurred between 642-761 million years ago (Mya), roughly 100 Ma before the Cambrian explosion. Among mammals, the initial diversification of major placental groups may have taken place around 100 Mya, well before the Cretaceous/Tertiary boundary marking the extinction of dinosaurs.     

Evolution enters the genomic era

A report on the 18th Congress of the European Society for Evolutionary Biology (ESEB), Aarhus, Denmark, 20-25 August, 2001.     

Bacterial strain typing in the genomic era

Bacterial strain typing, or identifying bacteria at the strain level, is particularly important for diagnosis, treatment, and epidemiological surveillance of bacterial infections. This is especially the case for bacteria exhibiting high levels of antibiotic resistance or virulence, and those involved in nosocomial or pandemic infections. Strain typing also has applications in studying bacterial population dynamics. Over the last two decades, molecular methods have progressively replaced phenotypic assays to type bacterial strains. In this article, we review the current bacterial genotyping methods and classify them into three main categories: (1) DNA banding pattern-based methods, which classify bacteria according to the size of fragments generated by amplification and/or enzymatic digestion of genomic DNA, (2) DNA sequencing-based methods, which study the polymorphism of DNA sequences, and (3) DNA hybridization-based methods using nucleotidic probes. We described and compared the applications of genotyping methods to the study of bacterial strain diversity. We also discussed the selection of appropriate genotyping methods and the challenges of bacterial strain typing, described the current trends of genotyping methods, and investigated the progresses allowed by the availability of genomic sequences.     

Exploring prokaryotic diversity in the genomic era

Our understanding of prokaryote biology from study of pure cultures and genome sequencing has been limited by a pronounced sampling bias towards four bacterial phyla - Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes - out of 35 bacterial and 18 archaeal phylum-level lineages. This bias is beginning to be rectified by the use of phylogenetically directed isolation strategies and by directly accessing microbial genomes from environmental samples.     

Reconstructing human origins in the genomic era

Analyses of recently acquired genomic sequence data are leading to important insights into the early evolution of anatomically modern humans, as well as into the more recent demographic processes that accompanied the global radiation of Homo sapiens. Some of the new results contradict early, but still influential, conclusions that were based on analyses of gene trees from mitochondrial DNA and Y-chromosome sequences. In this review, we discuss the different genetic and statistical methods that are available for studying human population history, and identify the most plausible models of human evolution that can accommodate the contrasting patterns observed at different loci throughout the genome.     

The bacterial species definition in the genomic era

The bacterial species definition, despite its eminent practical significance for identification, diagnosis, quarantine and diversity surveys, remains a very difficult issue to advance. Genomics now offers novel insights into intra-species diversity and the potential for emergence of a more soundly based system. Although we share the excitement, we argue that it is premature for a universal change to the definition because current knowledge is based on too few phylogenetic groups and too few samples of natural populations. Our analysis of five important bacterial groups suggests, however, that more stringent standards for species may be justifiable when a solid understanding of gene content and ecological distinctiveness becomes available. Our analysis also reveals what is actually encompassed in a species according to the current standards, in terms of whole-genome sequence and gene-content diversity, and shows that this does not correspond to coherent clusters for the environmental Burkholderia and Shewanella genera examined. In contrast, the obligatory pathogens, which have a very restricted ecological niche, do exhibit clusters. Therefore, the idea of biologically meaningful clusters of diversity that applies to most eukaryotes may not be universally applicable in the microbial world, or if such clusters exist, they may be found at different levels of distinction.     

Understanding the tumor metabolic phenotype in the genomic era

Now, at the beginning of a new century, 80 years after Warburg's Nobel prize winning discoveries, we are beginning to make sense of the underlying causes of the well known metabolic phenotype of tumor cells. Building on decades of research to understand the interrelationships between respiration and glycolysis in cancer, the tumor metabolic phenotype can now begin to be understood in a genomic context. With the discovery of hypoxia inducible factor-1 (HIF-1), which is widely overexpressed across a broad range of cancers, modern molecular tools have allowed us to put together the pattern of events that might explain the metabolic differences between tumor and normal cells. HIF-1 controls cellular and systemic responses to oxygen availability and coordinates up-regulation of genes involved in many pathways concerned with tumour growth and metabolism including angiogenesis, glucose and energy metabolism, cellular proliferation, differentiation and viability, apoptosis, pH regulation and matrix metabolism. These findings begin to explain how glucose uptake and glycolysis could be up-regulated in cancer cells (through binding to a core DNA recognition sequence) in a co-ordinated and constitutive fashion that may also allow us to elucidate new targets for tumor therapy.     

Assessing the origin of species in the genomic era

Advances in genomics have rapidly accelerated research into the genetics of species differences, reproductive isolating barriers, and hybrid incompatibility. Recent genomic analyses in Drosophila species suggest that modified olfactory cues are involved in discrimination that is reinforced by natural selection.     

Primate molecular phylogenetics in a genomic era

A primary objective of molecular phylogenetics is to use molecular data to elucidate the evolutionary history of living organisms. Dr. Morris Goodman founded the journal Molecular Phylogenetics and Evolution as a forum where scientists could further our knowledge about the tree of life, and he recognized that the inference of species trees is a first and fundamental step to addressing many important evolutionary questions. In particular, Dr. Goodman was interested in obtaining a complete picture of the primate species tree in order to provide an evolutionary context for the study of human adaptations. A number of recent studies use multi-locus datasets to infer well-resolved and well-supported primate phylogenetic trees using consensus approaches (e.g., supermatrices). It is therefore tempting to assume that we have a complete picture of the primate tree, especially above the species level. However, recent theoretical and empirical work in the field of molecular phylogenetics demonstrates that consensus methods might provide a false sense of support at certain nodes. In this brief review we discuss the current state of primate molecular phylogenetics and highlight the importance of exploring the use of coalescent-based analyses that have the potential to better utilize information contained in multi-locus data.