Formation and role of exosomes in cancer

Exosomes offer new insight into cancer biology with both diagnostic and therapeutic implications. Because of their cell-to-cell communication, exosomes influence tumor progression, metastasis, and therapeutic efficacy. They can be isolated from blood and other bodily fluids to reveal disease processes occurring within the body, including cancerous growth. In addition to being a reservoir of cancer biomarkers, they can be re-engineered to reinstate tumor immunity. Tumor exosomes interact with various cells of the microenvironment to confer tumor-advantageous changes that are responsible for stromal activation, induction of the angiogenic switch, increased vascular permeability, and immune escape. Exosomes also contribute to metastasis by aiding in the epithelial-to-mesenchymal transition and formation of the pre-metastatic niche. Furthermore, exosomes protect tumor cells from the cytotoxic effects of chemotherapy drugs and transfer chemoresistance properties to nearby cells. Thus, exosomes are essential to many lethal elements of cancer and it is important to understand their biogenesis and role in cancer.     

Pleiotropic effects of sonic hedgehog on muscle satellite cells

Muscle satellite cells are believed to form a stable, self-renewing pool of stem cells in adult muscle where they function in tissue growth and repair. A regulatory disruption of growth and differentiation of these cells is assumed to result in tumor formation. Here we provide for the first time evidence that sonic hedgehog (Shh) regulates the cell fate of adult muscle satellite cells in mammals. Shh promotes cell division of satellite cells (and of the related model C2C12 cells) and prevents their differentiation into multinucleated myotubes. In addition, Shh inhibits caspase-3 activation and apoptosis induced by serum deprivation. These effects of Shh are reversed by simultaneous administration of cyclopamine, a specific inhibitor of the Shh pathway. Taken together, Shh acts as a proliferation and survival factor of satellite cells in the adult muscle. Our results support the hypothesis of the rhabdomyosarcoma origin from satellite cells and suggest a role for Shh in this process.Received 23 February 2005; received after revision 2 May 2005; accepted 9 June 2005     

Multiple roles of class I HDACs in proliferation, differentiation, and development

Class I Histone deacetylases (HDACs) play a central role in controlling cell cycle regulation, cell differentiation, and tissue development. These enzymes exert their function by deacetylating histones and a growing number of non-histone proteins, thereby regulating gene expression and several other cellular processes. Class I HDACs comprise four members: HDAC1, 2, 3, and 8. Deletion and/or overexpression of these enzymes in mammalian systems has provided important insights about their functions and mechanisms of action which are reviewed here. In particular, unique as well as redundant functions have been identified in several paradigms. Studies with small molecule inhibitors of HDACs have demonstrated the medical relevance of these enzymes and their potential as therapeutic targets in cancer and other pathological conditions. Going forward, better understanding the specific role of individual HDACs in normal physiology as well as in pathological settings will be crucial to exploit this protein family as a useful therapeutic target in a range of diseases. Further dissection of the pathways they impinge on and of their targets, in chromatin or otherwise, will form important avenues of research for the future.     

Portfolio managers' and novices' forecasts of risk and return: are there predictable forecast errors?

This study aims to investigate the individual behaviour that underlies the overreaction hypothesis by conducting a controlled experiment. Two areas that were not captured by previous research on the validity of the overreaction hypothesis are investigated. First, actual portfolio managers are employed as forecasters. Second a real‐world assessment task is given in the form of predicting the prices of stocks traded on the exchange on a real time basis. The purpose is to explore return expectations and risk perceptions of portfolio managers as well as financially unsophisticated investors by using point and interval forecasts provided for different forecast horizons in bull and bear markets. Contributions stem from three sources. (1) The use of financially sophisticated subjects for the first time in an experimental framework testing the overreaction hypothesis makes possible to control for the effect of expertise. (2) The use of different forecast horizons controls for the effect of forecast period. (3) The use of real‐time forecasts of specific stocks traded at the stock exchange, for the first time in an experimental framework testing the overreaction hypothesis enables to control for ecological validity. Discussions will be given as to the portfolio managers' versus naive investors' interpolating asset prices from past trends and hedging behaviour, due to their caution in projections of ranges for future prices. Copyright © 2002 John Wiley & Sons, Ltd.     

Fibrocytes: a unique cell population implicated in wound healing

Following tissue damage, host wound healing ensues. This process requires an elaborate interplay between numerous cell types which orchestrate a series of regulated and overlapping events. These events include the initiation of an antigen-specific host immune response, blood vessel formation, as well as the production of critical extracellular matrix molecules, cytokines and growth factors which mediate tissue repair and wound closure. Connective tissue fibroblasts are considered essential for successful wound healing; however, their origin remains a mystery. A unique cell population, known as fibrocytes, has been identified and characterized. One of the unique features of these blood-borne cells is their ability to home to sites of tissue damage. This article reviews the identification and characterization of fibrocytes, summarizes the potential role of fibrocytes in the numerous steps of the wound-healing process and highlights the potential role of fibrocytes in fibrotic disease pathogenesis.Received 25 November 2002; received after revision 31 December 2002; accepted 16 January 2003     

Current knowledge on exosome biogenesis and release

Exosomes are nanosized membrane vesicles released by fusion of an organelle of the endocytic pathway, the multivesicular body, with the plasma membrane. This process was discovered more than 30 years ago, and during these years, exosomes have gone from being considered as cellular waste disposal to mediate a novel mechanism of cell-to-cell communication. The exponential interest in exosomes experienced during recent years is due to their important roles in health and disease and to their potential clinical application in therapy and diagnosis. However, important aspects of the biology of exosomes remain unknown. To explore the use of exosomes in the clinic, it is essential that the basic molecular mechanisms behind the transport and function of these vesicles are better understood. We have here summarized what is presently known about how exosomes are formed and released by cells. Moreover, other cellular processes related to exosome biogenesis and release, such as autophagy and lysosomal exocytosis are presented. Finally, methodological aspects related to exosome release studies are discussed.     

Edward Williams Morley and the Atomic Weight of Oxygen: the Death of Prout's Hypothesis Revisited

Prout's hypothesis was influential in—if not necessary for—the establishment of the atomic weight of oxygen, a figure conclusively demonstrated in 1895. Ironically, the successful determination of oxygen's weight also led to a final refutation of the hypothesis (at least the hypothesis in the classical sense). But more than this, the end of Prout's hypothesis via the determination of oxygen's atomic weight was due to three fundamental changes that characterized the way chemistry was practised and communicated in the late nineteenth century. First, encyclopaedia‐like presentations of past atomic‐weight investigations became the focus in numerous and influential studies. Second, there was a dramatic change in the way professional publications presented investigations and experiments, characterized by experimental detail and apparatus design at the expense of theoretical discussion. Finally, the production of hydrogen became the focus of research, as it was one of the principal components of any investigation into atomic weights. Here I present Prout's hypothesis in its historical context by focusing on these three developments and their influence on the research of Edward Williams Morley. While doing so I also illustrate the way marginalized scientists were able to take advantage of their otherwise dubious position and participate in an active and important role in atomic‐weight investigations.     

Amyloid precursor protein products concentrate in a subset of exosomes specifically endocytosed by neurons

Amyloid beta peptide (Aβ), the main component of senile plaques of Alzheimer’s disease brains, is produced by sequential cleavage of amyloid precursor protein (APP) and of its C-terminal fragments (CTFs). An unanswered question is how amyloidogenic peptides spread throughout the brain during the course of the disease. Here, we show that small lipid vesicles called exosomes, secreted in the extracellular milieu by cortical neurons, carry endogenous APP and are strikingly enriched in CTF-α and the newly characterized CTF-η. Exosomes from N2a cells expressing human APP with the autosomal dominant Swedish mutation contain Aβ peptides as well as CTF-α and CTF-η, while those from cells expressing the non-mutated form of APP only contain CTF-α and CTF-η. APP and CTFs are sorted into a subset of exosomes which lack the tetraspanin CD63 and specifically bind to dendrites of neurons, unlike exosomes carrying CD63 which bind to both neurons and glial cells. Thus, neuroblastoma cells secrete distinct populations of exosomes carrying different cargoes and targeting specific cell types. APP-carrying exosomes can be endocytosed by receiving cells, allowing the processing of APP acquired by exosomes to give rise to the APP intracellular domain (AICD). Thus, our results show for the first time that neuronal exosomes may indeed act as vehicles for the intercellular transport of APP and its catabolites.     

Perlecan: how does one molecule do so many things?

Perlecan is a large multi-domain extracellular matrix proteoglycan that plays a crucial role in tissue development and organogenesis. In vertebrates, perlecan functions in a diverse range of developmental and biological processes, from the establishment of cartilage to the regulation of wound healing. How can a single molecule modulate such a wide variety of processes? We suggest that perlecan employs the same basic mechanism, based on interactions with growth factors, morphogens and matrix proteins, to regulate each of these processes and that the local extracellular environment determines the function of perlecan and consequently its downstream effects on the structure and function of the organ. We discuss this hypothesis in relation to its role in three major vertebrate developmental processes: angiogenesis, chondrogenesis and endochondral ossification.     

Mesodermal fate decisions of a stem cell: the Wnt switch

Stem cells are a powerful resource for cell-based transplantation therapies in osteodegenerative disorders, but before some kinds of stem cells can be applied clinically, several aspects of their expansion and differentiation need to be better controlled. Wnt molecules and members of the Wnt signaling cascade have been ascribed a role in both these processes in vitro as well as normal development in vivo. However some results are controversial. In this review we will present the hypothesis that both canonical and non-canonical signaling are involved in mesenchymal cell fate regulation, such as adipogenesis, chondrogenesis and osteogenesis, and that in vitro it is a timely switch between the two that specifies the identity of the differentiating cell. We will specifically focus on the in vitro differentiation of adipocytes, chondrocytes and osteoblasts contrasting embryonic and mesenchymal stem cells as well as the role of Wnts in mesenchymal fate specification during embryogenesis.     

Adipocyte extracellular matrix composition, dynamics and role in obesity

The central role of the adipose tissue in lipid metabolism places specific demands on the cell structure of adipocytes. The protein composition and dynamics of the extracellular matrix (ECM) is of crucial importance for the functioning of those cells. Adipogenesis is a bi-phasic process in which the ECM develops from a fibrillar to a laminar structure as cells move from the commitment phase to the growth phase characterized by storage of vast amounts of triglycerides. Mature adipocytes appear to spend a lot of energy on the maintenance of the ECM. ECM remodeling is mediated by a balanced complement of constructive and destructive enzymes together with their enhancers and inhibitors. ECM remodeling is an energy costing process regulated by insulin, by the energy metabolism, and by mechanical forces. In the obese, overgrowth of adipocytes may lead to instability of the ECM, possibly mediated by hypoxia.     

The therapeutic potential of GPR43: a novel role in modulating metabolic health

GPR43 is a receptor for short-chain fatty acids. Preliminary data suggest a putative role for GPR43 in regulating systemic health via processes including inflammation, carcinogenesis, gastrointestinal function, and adipogenesis. GPR43 is involved in secretion of gastrointestinal peptides, which regulate appetite and gastrointestinal motility. This suggests GPR43 may have a role in weight control. Moreover, GPR43 regulates plasma lipid profile and inflammatory processes, which further indicates that GPR43 could have the ability to modulate the etiology and pathogenesis of metabolic diseases such as obesity, type 2 diabetes mellitus, and cardiovascular disease. This review summarizes the current evidence regarding the ability of GPR43 to mediate both systemic and tissue specific functions and how GPR43 may be modulated in the treatment of metabolic disease.     

Epigenetic regulation of skin: focus on the Polycomb complex

Chromatin regulators have recently emerged as key players in the control of tissue development and tumorigenesis. One specific chromatin regulator, the Polycomb complex, has been shown to regulate the identity of embryonic stem cells, but its role in controlling fates of multipotent progenitors in developing tissues is still largely unknown. Recent findings have revealed that this complex plays a critical role in control of skin stem cell renewal and differentiation. Moreover, the expression of Polycomb complex components is often aberrant in skin diseases, including skin cancers. This review will detail recent findings on Polycomb control of skin and highlight critical unknown questions.     

Revisiting the metabolic syndrome: the emerging role of aquaglyceroporins

The metabolic syndrome (MetS) includes a group of medical conditions such as insulin resistance (IR), dyslipidemia and hypertension, all associated with an increased risk for cardiovascular disease. Increased visceral and ectopic fat deposition are also key features in the development of IR and MetS, with pathophysiological sequels on adipose tissue, liver and muscle. The recent recognition of aquaporins (AQPs) involvement in adipose tissue homeostasis has opened new perspectives for research in this field. The members of the aquaglyceroporin subfamily are specific glycerol channels implicated in energy metabolism by facilitating glycerol outflow from adipose tissue and its systemic distribution and uptake by liver and muscle, unveiling these membrane channels as key players in lipid balance and energy homeostasis. Being involved in a variety of pathophysiological mechanisms including IR and obesity, AQPs are considered promising drug targets that may prompt novel therapeutic approaches for metabolic disorders such as MetS. This review addresses the interplay between adipose tissue, liver and muscle, which is the basis of the metabolic syndrome, and highlights the involvement of aquaglyceroporins in obesity and related pathologies and how their regulation in different organs contributes to the features of the metabolic syndrome.     

History of the Lenz–Ising model 1965–1971: the role of a simple model in understanding critical phenomena

This is the last in a series of three papers on the history of the Lenz–Ising model from 1920 to the early 1970s. In the first paper, I studied the invention of the model in the 1920s, while in the second paper, I documented a quite sudden change in the perception of the model in the early 1960s when it was realized that the Lenz–Ising model is actually relevant for the understanding of phase transitions. In this article, which is self-contained, I study how this realization affected attempts to understand critical phenomena, which can be understood as limiting cases of (first-order) phase transitions, in the epoch from circa 1965 to 1970, where these phenomena were recognized as a research field in its own right. I focus on two questions: What kinds of insight into critical phenomena was the employment of the Lenz–Ising model thought to give? And how could a crude model, which the Lenz–Ising model was thought to be, provide this understanding? I document that the model played several roles: At first, it played a role analogous to experimental data: hypotheses about real systems, in particular relations between critical exponents and what is now called the hypothesis of scaling, which was advanced by Benjamin Widom and others, were confronted with numerical results for the model, in particular the model’s so-called critical exponents. A positive result of a confrontation was seen as positive evidence for this hypothesis. The model was also used to gain insight into specific aspects of critical phenomena, for example that diverse physical systems exhibit similar behavior close to a critical point. Later, a more systematic program of understanding critical phenomena emerged that involved an explicit formulation of what it means to understand critical phenomena, namely, the elucidation of what features of the Hamiltonian of models lead to what kinds of behavior close to critical points. Attempts to accomplish this program culminated with the so-called hypothesis of universality, put forward independently by Robert B. Griffiths and Leo P. Kadanoff in 1970. They divided critical phenomena into classes with similar critical behavior. I also study the crucial role of the Lenz–Ising model in the development and justification of these ideas.     

Roles of innervation in developing and regenerating orofacial tissues

The head is innervated by 12 cranial nerves (I–XII) that regulate its sensory and motor functions. Cranial nerves are composed of sensory, motor, or mixed neuronal populations. Sensory neurons perceive generally somatic sensations such as pressure, pain, and temperature. These neurons are also involved in smell, vision, taste, and hearing. Motor neurons ensure the motility of all muscles and glands. Innervation plays an essential role in the development of the various orofacial structures during embryogenesis. Hypoplastic cranial nerves often lead to abnormal development of their target organs and tissues. For example, Möbius syndrome is a congenital disease characterized by defective innervation (i.e., abducens (VI) and facial (VII) nerves), deafness, tooth anomalies, and cleft palate. Hence, it is obvious that the peripheral nervous system is needed for both development and function of orofacial structures. Nerves have a limited capacity to regenerate. However, neural stem cells, which could be used as sources for neural tissue maintenance and repair, have been found in adult neuronal tissues. Similarly, various adult stem cell populations have been isolated from almost all organs of the human body. Stem cells are tightly regulated by their microenvironment, the stem cell niche. Deregulation of adult stem cell behavior results in the development of pathologies such as tumor formation or early tissue senescence. It is thus essential to understand the factors that regulate the functions and maintenance of stem cells. Yet, the potential importance of innervation in the regulation of stem cells and/or their niches in most organs and tissues is largely unexplored. This review focuses on the potential role of innervation in the development and homeostasis of orofacial structures and discusses its possible association with stem cell populations during tissue repair.     

Identification of cytotoxic cells responsible for lysis of target cells pretreated with concanavalin A in spleen populations of pregnant mice with suppressive activity]

During an alloimmunization, killer cells which lyse target cells only in the presence of a lectin are generated. That these cells, as well as suppressive cells, share immunocytological properties with specific killer cells, leads to the hypothesis that these cells may be concerned with the mechanism of immunosuppression. Two experimental results presented in this paper are consistent with this hypothesis: 1) Spleens from H-2k mice pregnant by H-2d males which bear a high suppressive activity also contain a relatively large number of killer cells having the ability to lyse Concanavalin A treated target cells and 2) supernatants of suppressive systems generated through an MLC block the cytolysis of specific target cells by the bound killer cells.     

The locus ceruleus: a possible neural focus for genetic differences in emotionality

The Maudsley Reactive and Non-Reactive strains have been developed as a model for the study of individual variations in stress-reactivity, and many differences in biobehavioral systems have been found between them. This review discusses limitations of the 'emotionality' construct in accounting for differences between the Maudsley strains and offers an alternative, theoretical approach. Amaral and Sinnamon have proposed that the locus ceruleus (LC) plays a stress-attenuating role in mediating behavioral, physiological and neuroendocrine response to prepotent, emergency-provoking stimuli and, building upon this formulation, it is proposed that the LC has been an important focus for gene action in the Maudsley model. It is suggested that the LC of the Non-Reactive strain is more strongly activated by stressful stimuli than the LC of Reactive rats, and is the basis of many of the behavioral and physiological differences between them. Behavioral and biochemical evidence consistent with this proposition is reviewed. Identification of the LC as a target for gene-action in the Maudsley model has an important advantage. It substitutes variations at a specific anatomic location in the brain for a loosely defined construct like emotionality, and the hypothesis is amenable to empirical tests by a variety of experimental approaches.