EGFR-dependent mechanisms in glioblastoma: towards a better therapeutic strategy

Glioblastoma is a particularly resilient cancer, and while therapies may be able to reach the brain by crossing the blood–brain barrier, they then have to deal with a highly invasive tumor that is very resistant to DNA damage. It seems clear that in order to kill aggressive glioma cells more efficiently and with fewer side effects on normal tissue, there must be a shift from classical cytotoxic chemotherapy to more targeted therapies. Since the epidermal growth factor receptor (EGFR) is altered in almost 50 % of glioblastomas, it currently represents one of the most promising therapeutic targets. In fact, it has been associated with several distinct steps in tumorigenesis, from tumor initiation to tumor growth and survival, and also with the regulation of cell migration and angiogenesis. However, inhibitors of the EGFR kinase have produced poor results with this type of cancer in clinical trials, with no clear explanation for the tumor resistance observed. Here we will review what we know about the expression and function of EGFR in cancer and in particular in gliomas. We will also evaluate which are the possible molecular and cellular escape mechanisms. As a result, we hope that this review will help improve the design of future EGFR-targeted therapies for glioblastomas.     

Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm

The parathyroid hormone (PTH) receptor type 1 (PTHR), a G protein-coupled receptor (GPCR), transmits signals to two hormone systems—PTH, endocrine and homeostatic, and PTH-related peptide (PTHrP), paracrine—to regulate different biological processes. PTHR responds to these hormonal stimuli by activating heterotrimeric G proteins, such as G_S that stimulates cAMP production. It was thought that the PTHR, as for all other GPCRs, is only active and signals through G proteins on the cell membrane, and internalizes into a cell to be desensitized and eventually degraded or recycled. Recent studies with cultured cell and animal models reveal a new pathway that involves sustained cAMP signaling from intracellular domains. Not only do these studies challenge the paradigm that cAMP production triggered by activated GPCRs originates exclusively at the cell membrane but they also advance a comprehensive model to account for the functional differences between PTH and PTHrP acting through the same receptor.     

Genetic visualization of notch signaling in mammalian neurogenesis

Notch signaling plays crucial roles in fate determination and the differentiation of neural stem cells in embryonic and adult brains. It is now clear that the notch pathway is under more complex and dynamic regulation than previously thought. To understand the functional details of notch signaling more precisely, it is important to reveal when, where, and how notch signaling is dynamically communicated between cells, for which the visualization of notch signaling is essential. In this review, we introduce recent technical advances in the visualization of notch signaling during neural development and in the adult brain, and we discuss the physiological significance of dynamic regulation of notch signaling.     

Molecular mechanisms of phagocytic uptake in mammalian cells

Phagocytosis is a highly conserved, complex process that has evolved to counter the constant threat posed by pathogens, effete cells and debris. Classically defined as a mechanism for internalising and destroying particles greater than 0.5 mum in size, it is a receptor-mediated, actin-driven process. The best-studied phagocytic receptors are the opsono-receptors, FcgammaR and CR3. Phagocytic uptake involves actin dynamics including polymerisation, bundling, contraction, severing and depolymerisation of actin filaments. Recent evidence points to the importance of membrane remodelling during phagocytosis, both in terms of changes in lipid composition and delivery of new membrane to the sites of particle binding. Here we review the molecular mechanisms of phagocytic uptake and some of the strategies developed by microbial pathogens to manipulate this process.     

Control of sperm motility and fertility: Diverse factors and common mechanisms

Spermatozoa generated in the testis are immature and incompetent for fertilization. During their journey toward the egg, the sperm acquire fertility and achieving fertilization. These sperm modifications to ensure fertilization are induced by many female or male extra-sperm factors: for example, sperm motility-activating factors from the egg jelly, sperm attractants from the eggs, and decapacitation factors from the seminal plasma. The factors controlling sperm fertility are myriad and species specific; they may be peptides, sugar chains, or small organic compounds. Nevertheless, the fundamental mechanisms underlying fertilization must be common among all animals; increase in [Ca²⁺]_i triggers all the steps in the process of fertilization, and cAMP plays important roles in many steps. Elucidating the dynamic functional and morphological changes in sperm cells is important for understanding the regulation of fertilization. Here, we introduce the diversity and generality of the control of sperm fertility. Received 28 April 2008; received after revision 13 June 2008; accepted 17 June 2008     

Sulfatase activities towards the regulation of cell metabolism and signaling in mammals

In higher vertebrates, sulfatases belong to a conserved family of enzymes that are involved in the regulation of cell metabolism and in developmental cell signaling. They cleave the sulfate from sulfate esters contained in hormones, proteins, and complex macromolecules. A highly conserved cysteine in their active site is post-translationally converted into formylglycine by the formylglycine-generating enzyme encoded by SUMF1 (sulfatase modifying factor 1). This post-translational modification activates all sulfatases. Sulfatases are extensively glycosylated proteins and some of them follow trafficking pathways through cells, being secreted and taken up by distant cells. Many proteoglycans, glycoproteins, and glycolipids contain sulfated carbohydrates, which are sulfatase substrates. Indeed, sulfatases operate as decoding factors for a large amount of biological information contained in the structures of the sulfated sugar chains that are covalently linked to proteins and lipids. Modifications to these sulfate groups have pivotal roles in modulating specific signaling pathways and cell metabolism in mammals.     

The response of Ca-mediated action potentials and contractile activity in mammalian ventricular myocardium towards alkalosis

Summary Alkalosis (pH 7.8) produced by reduction of CO₂ concentration augmented both upstroke velocity of Ca action potentials and isometric contractile force of mammalian heart muscle. If the increase of pH to 7.8 was achieved by a raise of HCO₃ concentration (with simultaneous reduction of CO₂ concentration), the positive inotropic response was not accompanied by an augmented Ca current. Obviously, the well-known positive inotropic effect of alkalosis does not only depend upon the enhancement of transmembrane Ca influx during excitation, but can be mediated alone by affecting intracellular Ca movements as well.     

Dictyostelium mobile elements: strategies to amplify in a compact genome

Dictyostelium discoideum is a eukaryotic microorganism that is attractive for the study of fundamental biological phenomena such as cell-cell communication, formation of multicellularity, cell differentiation and morphogenesis. Large-scale sequencing of the D. discoideum genome has provided new insights into evolutionary strategies evolved by transposable elements (TEs) to settle in compact microbial genomes and to maintain active populations over evolutionary time. The high gene density (about 1 gene/2.6 kb) of the D. discoideum genome leaves limited space for selfish molecular invaders to move and amplify without causing deleterious mutations that eradicate their host. Targeting of transfer RNA (tRNA) gene loci appears to be a generally successful strategy for TEs residing in compact genomes to insert away from coding regions. In D. discoideum, tRNA gene-targeted retrotransposition has evolved independently at least three times by both non-long termina l repeat (LTR) retrotransposons and retrovirus-like LTR retrotransposons. Unlike the nonspecifically inserting D. discoideum TEs, which have a strong tendency to insert into preexisting TE copies and form large and complex clusters near the ends of chromosomes, the tRNA gene-targeted retrotransposons have managed to occupy 75% of the tRNA gene loci spread on chromosome 2 and represent 80% of the TEs recognized on the assembled central 6.5-Mb part of chromosome 2. In this review we update the available information about D. discoideum TEs which emerges both from previous work and current large-scale genome sequencing, with special emphasis on the fact that tRNA genes are principal determinants of retrotransposon insertions into the D. discoideum genome. Received 10 May 2002; received after revision 10 June 2002; accepted 12 June 2002 RID="*" ID="*"Corresponding author.     

The response of Ca-mediated action potentials and contractile activity in mammalian ventricular myocardium towards alkalosis.

Alkalosis (pH 7.8) produced by reduction of CO2 concentration augmented both upstroke velocity of Ca action potentials and isometric contractile force of mammalian heart muscle. If the increase of pH to 7.8 was achieved by a raise of HCO3 concentration (with simultaneous reduction of CO2 concentration), the positive inotropic response was not accompanied by an augmented Ca current. Obviously, the well-known positive inotropic effect of alkalosis does not only depend upon the enhancement of transmembrane Ca influx during excitation, but can be mediated alone by affecting intracellular Ca movements as well.     

Kinetics of chemo-attraction of polymorphonuclear leukocytes towards N-formyl peptide studied with a novel polycarbonate (Nucleopore) membrane in the Boyden chamber

The motile responses of human polymorphonuclear leukocytes (PMN) to N-formyl-methionyl-leucyl-phenylalanine (FMLP) in the Boyden chamber using a new sparse-pore polycarbonate membrane (pores 3 micron in diameter and occupying 0.1% of surface area) were compared with those demonstrated by using a standard polycarbonate (Nuclepore) filtration membrane (pores 3 micron in diameter and occupying 5% of surface area). Motility of PMN in gradients of FMLP using the new membrane was not influenced by chemokinetic effects of the factor, and the 'background' migration of the cells was minimal. However, motility of PMN in gradients of FMLP using the standard membrane was found to be influenced by chemokinetic effects of the chemotactic factor, and the 'background' or 'control' migration (in the absence of chemotactic factor) of the cells was substantial. Greater directional migration of PMN according to steepness of the gradient of chemotactic factor was demonstrated with the use of the new membrane. The new membrane may be of considerable value in the further study of the chemotactic responses of PMN.     

Kinetics of chemo-attraction of polymorphonuclear leukocytes towards N-formyl peptide studied with a novel polycarbonate (Nuclepore) membrane in the Boyden chamber

Summary The motile responses of human polymorphonuclear leukocytes (PMN) to N-formyl-methionyl-leucyl-phenylalanine (FMLP) in the Boyden chamber using a new sparse-pore polycarbonate membrane (pores 3 m in diameter and occupying 0.1% of surface area) were compared with those demonstrated by using a standard polycarbonate (Nuclepore) filtration membrane (pores 3 m in diameter and occupying 5% of surface area). Motility of PMN in gradients of FMLP using the new membrane was not influenced by chemokinetic effects of the factor, and the background migration of the cells was minimal. However, motility of PMN in gradients of FMLP using the standard membrane was found to be influenced by chemokinetic effects of the chemotactic factor, and the background or control migration (in the absence of chemotactic factor) of the cells was substantial. Greater directional migration of PMN according to steepness of the gradient of chemotactic factor was demonstrated with the use of the new membrane. The new membrane may be of considerable value in the further study of the chemotactic responses of PMN.     

Exchange of genetic material: a new paradigm in bone cell communications

An emerging concept in intercellular communication in mammals is that communication can be mediated by exchange of genetic material, mainly in the form of RNAs. In this review, we discuss recent studies that describe the trafficking of genetic material with a focus on bone cell communication. Three major carriers are discussed: gap junctions, protein-binding complexes, and genetic material exchange mediated by extracellular vesicles. While protein-level exchange has been well documented, no review has summarized the novel paradigm of cell-to-cell communication by genetic information exchange in bone tissues or its biological relevance in terms of bone homeostasis and bone-related diseases. The purpose of this review is to promote further understanding of this novel discovery regarding bone cell communication and provide references for further investigations.     

Cytokinesis in development and disease: variations on a common theme

Cytokinesis is a crucial step in cell proliferation, and remarkably, it is also an important mechanism for developmental regulation in the generation of diverse cell types in eukaryotic organisms. Successful cytokinesis relies on the assembly and activation of an actomyosin-based contractile ring and membrane deposition/fusion in a spatially and temporally precise manner. As such, the molecular pathways governing cytokinesis are highly complex, involving a large number of components forming intricate interactive networks. The complexity of this system, however, may have also provided a rich platform for evolutionary ‘tinkering’ to achieve specific morphogenetic and developmental outcomes. Furthermore, failed or altered cytokinesis appears to contribute to the development of cancer in unexpected ways. Received 25 June 2007; received after revision 20 July 2007; accepted 16 August 2007     

Regular oscillations in suspensions of a putatively chaotic mutant of Dictyostelium discoideum

We have tested the light-scattering properties of suspensions of the Dictyostelium discoideum mutant HH201 derived from the mutant Fr17. Previous studies indicated that HH201 and Fr17 possess highly irregular rhythmic properties which might represent aperiodic oscillations, i.e. chaos. We report that the former mutant can display regular oscillatory behavior. Possible explanations for this result are discussed, including that of a transition from chaotic to periodic behavior resulting from some parameter change or from strong intercellular coupling in cell suspensions.     

Incredulity towards Lyotard: a critique of a postmodernist account of science and knowledge

Philosophers of science have paid little attention, positive or negative, to Lyotard’s book The postmodern condition, even though it has been popular in other fields. We set out some of the reasons for this neglect. Lyotard thought that sciences could be justified by non-scientific narratives (a position he later abandoned). We show why this is unacceptable, and why many of Lyotard’s characterisations of science are either implausible or are narrowly positivist. One of Lyotard’s themes is that the nature of knowledge has changed and thereby so has society itself. However much of what Lyotard says muddles epistemological matters about the definition of ‘knowledge’ with sociological claims about how information circulates in modern society. We distinguish two kinds of legitimation of science: epistemic and socio-political. In proclaiming ‘incredulity towards metanarratives’ Lyotard has nothing to say about how epistemic and methodological principles are to be justified (legitimated). He also gives a bad argument as to why there can be no epistemic legitimation, which is based on an act/content confusion, and a confusion between making an agreement and the content of what is agreed to. As for socio-political legitimation, Lyotard’s discussion remains at the abstract level of science as a whole rather than at the level of the particular applications of sciences. Moreover his positive points can be accepted without taking on board any of his postmodernist account of science. Finally we argue that Lyotard’s account of paralogy, which is meant to provide a ‘postmodern’ style of justification, is a failure.