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PubMed2002

The cerebromicrovasculature: a key player in the pathogenesis of Alzheimer's disease.

Neuronal cell death is the primary underlying pathogenic lesion in Alzheimer's disease (AD). Despite intense research efforts, the mechanisms that contribute to neuronal cell death have not been clarified. In this debate we address the question, Is AD a vascular or metabolic disorder? Here we defend the hypothesis that the cerebromicrovasculature is a key player in the pathogenesis of AD. Evidence is presented that vascular amyloid beta (Abeta) is more closely associated with tau pathology than the distribution of diffuse or neuritic plaque Abeta. Furthermore, brain endothelial cells are identified as important regulators of the neuronal microenvironment, including Abeta levels. Finally, evidence is presented that brain endothelial cells undergo cellular and biochemical changes in AD and that the release of neurotoxic factors from these dysfunctional cells contributes to the neuronal cell loss characteristic of AD.

Aged↗

PubMedDate not supplied

Cellular and molecular biology of human melanoma.

Melanoma develops from a series of architectural and phenotypically distinct stages and becomes progressively aggressive culminating in metastasis. Over the years, considerable progress has been made in understanding the biological, pathological and immunological aspects of human melanoma progression. Epidemiological and experimental studies have suggested that intense exposures during early childhood to UV radiation may lead to melanoma in adults, but molecular and genetic studies have revealed few autosomal abnormalities, infrequent mutational spectra and very little epistatic and epigenetic mechanisms. At the cellular level it has become clear that deregulated homeostatic control in the skin microenvironment occurs through alterations in the expression of specific proteins. These include growth factors and their receptors, adhesion molecules and their ligands, proteases and their substrates, and transcription factors and their target genes. Like in most other human tumors, there are alterations in the regulatory networks involving signal transduction in human melanoma. Appropriate models mimicking the human disease have been developed. However, these have not yet led to major advances in delineating the precise molecular determinants responsible for melanoma progression. Results from recent studies have put more impetus on identification of new molecules that promise to become better therapeutic targets. This review focuses on the most recent progress in understanding the molecular determinants of tumor progression with a particular emphasis on melanoma as a biological responder to altered homeostasis.

Cadherins↗

PubMed1992

c-kit receptor and ligand expression in postnatal development of the mouse cerebellum suggests a function for c-kit in inhibitory interneurons.

The c-kit receptor and its cognate ligand, KL, are encoded at the white spotting locus (W) and the steel locus (Sl) of the mouse, respectively. Sl and W mutations affect the same cellular targets in melanogenesis, gametogenesis and hematopoiesis during embryonic development and in adult life. c-kit is expressed in cellular targets of W and Sl mutations, whereas KL is expressed in the microenvironment of these targets. c-kit and KL, however, are also expressed in tissues and cell types that are not targets of W and Sl mutations, including the brain. The cerebellum contains a small number of neural cell types whose developmental origins, pathways of migration, and synaptic contacts are known. We have investigated the patterns of expression of the c-kit and KL RNA and protein products in postnatal cerebellar development of the mouse. In the adult cerebellum, c-kit RNA and protein expression was evident in basket, stellate, and Golgi neurons. Most strikingly, the c-kit protein is expressed in the basket cell axons that form "basket" and "pinceau" structures entwining the Purkinje cell soma and the initial segment of the Purkinje cell axon. KL RNA expression was found in Purkinje cells, and the KL protein was detected in Purkinje cell bodies and dendrites. Soluble KL protein was also present in c-kit-expressing basket, stellate, and Golgi cells, presumably as a result of internalization of ligand-receptor complexes. During postnatal development, c-kit and KL RNA and protein expression in Golgi and Purkinje neurons, respectively, was evident by day 0 and persisted subsequently. c-kit expression in basket and stellate cells was detected from their time of birth, starting at day 4. These results suggest a role for the c-kit receptor system in postnatal development of the cerebellum.

Aging↗

PubMed1988

Neuron-glia interrelations.

Considerable progress in our understanding of neuron and glial cell interrelationships has emerged during the last decade from in vitro and in vivo studies. Neural culture systems have provided powerful tools to delineate cellular and molecular events. Moreover, the advances in development of immunocytochemical and biochemical specific cell markers has made possible the characterization of complex cell behaviors. Glial cells actively participate in several aspects of neuronal growth and differentiation both by providing cell-cell contact interactions and by secreting neuronal growth-promoting factors. In turn, neurons influence the cellular behavior of both astrocytes and oligodendrocytes, primarily by secreting substances into the microenvironment. Such substances as neurohormones and neurotransmitters have been shown to affect several glial functions including electrophysiological responses, energy metabolism, and ionic homeostasis. In several instances these effects appear to be mediated through receptors on glial cells. Astrocytes actively participate in the regulation of the ionic environment. They take up and release several neurotransmitter substances and can modulate the concentration of a neurotransmitter substance at the synaptic cleft and thus monitor neuronal activity. The evidence of neuron-astroglia synaptic contacts supports the view that such contacts are present during early neuroembryogenesis and thus may provide contact signals for neuronal growth. The process of myelination in the CNS appears to be regulated by both neuronal signals to the oligodendrocyte and also intrinsic programming in the oligodendrocytes to produce myelin components. The prevailing view that astrocytes impede regeneration appears to be shifting towards a more favorable notion of the role of these cells in promoting this process. Of interest is the concept that there is a critical period in the ability of astrocytes either to enhance regeneration or to form a gliotic scar and impede this process. The role of glial cells in the aging process of the neuron is only beginning to be appreciated. If glial cells are actively involved in the regulation of the microenvironment, then it follows that any changes in the behavior of glial cells with aging will ultimately affect neuronal function. It is abundantly clear from in vitro studies that glial cells are pluripotential cells with several functional capabilities. Their responsiveness to an environment in which neurons are maturing as compared to an environment where neurons are injured or aging clearly portrays the multifunctional role of the astrocyte.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2007

Role of autophagy in cancer: management of metabolic stress.

Human breast, ovarian, and prostate tumors display allelic loss of the essential autophagy gene beclin1 with high frequency, and an increase in the incidence of tumor formation is observed in beclin1(+/-) mutant mice. These findings suggest a role for beclin1 and autophagy in tumor suppression; however, the mechanism by which this occurs has been unclear. Autophagy is a bulk degradation process whereby organelles and cytoplasm are engulfed and targeted to lysosomes for proteolysis,(1,2) There is evidence that autophagy sustains cell survival during nutrient deprivation through catabolism, but also that autophagy is a means of achieving cell death when executed to completion. If or how either of these diametrically opposing functions proposed for autophagy may be related to tumor suppression is unknown. We found that metabolic stress is a potent trigger of apoptotic cell death, defects in which enable long-term survival that is dependent on autophagy both in vitro and in tumors in vivo.(3) These findings raise the conundrum whereby inactivation of a survival pathway (autophagy) promotes tumorigenesis. Interestingly, when cells with defects in apoptosis are denied autophagy, this creates the inability to tolerate metabolic stress, reduces cellular fitness, and activates a necrotic pathway to cell death. This necrosis in tumors is associated with inflammation and enhancement of tumor growth, due to the survival of a small population of surviving, but injured, cells in a microenvironment that favors oncogenesis. Thus, by sustaining metabolism through autophagy during periods of metabolic stress, cells can limit energy depletion, cellular damage, and cell death by necrosis, which may explain how autophagy can prevent cancer, and how loss of a survival function can be tumorigenic.

Animals↗

PubMed1999

The tumor microenvironment as a determinant of drug response and resistance.

Classically, studies of drug resistance in cancer have focused on the molecular biology of single cancer cells. These types of studies have provided important information regarding certain drug resistance mechanisms, including mechanisms that reduce intracellular drug accumulation, alter or repair drug-induced damage, and reduce drug-induced apoptosis. While these cellular mechanisms undoubtedly contribute to the overall phenomenon of drug resistance, it is now evident that the tumor cell microenvironment also influences how a tumor cell behaves and responds to cytotoxic drugs or radiation. Two different forms of tumor cell-environmental interaction may explain how some tumor cells survive initial drug exposure and eventually express classical mechanisms of drug resistance. The first form involves soluble mediators, such as interleukins, that are secreted by non-tumor, stromal cells. Interleukin-6 (IL-6) is a classical example of how a soluble mediator secreted by the tumor microenvironment is capable of enhancing tumor cell survival and perhaps blocking apoptosis. The second form of tumor cell-environment interaction requires direct cell contact and has been given the term cell-adhesion-mediated drug resistance (CAM-DR). In this case, binding extracellular matrix ligands in the tumor microenvironment may activate cell adhesion molecules, such as the integrins, and these interactions result in the activation of signal transduction pathways that block drug-induced apoptosis. Interrupting the tumor cell-environment interactions or the associated signal transduction pathways may represent a new approach for the treatment of cancer. Copyright 1999 Harcourt Publishers Ltd.

Journal Article↗

PubMed2002

Polymorphonuclear neutrophil and megakaryocyte mutual involvement in myelofibrosis pathogenesis.

The study presented here, performed on the bone marrow from patients with idiopathic myelofibrosis (MF) and on a murine model of MF, demonstrates a pathological interaction between PMN leukocytes and megakaryocyte (Mk), correlated with MF development. The data obtained revealed abnormal subcellular P-selectin distribution, which appeared to correlate with excessive and pathological emperipolesis of PMN leukocytes within Mk, leading to the destruction of Mk storage organelles and leakage of alpha-granular contents into the bone marrow microenvironment. The prominent role of growth factors, PDGF and TGFbeta, stored in the Mk alpha-granular compartment in the generation of MF has been previously largely documented. Both growth factors are essential for the Mk-dependent fibroblast proliferation. The destructive mutual cellular interaction of Mk and PMN leading to the pathological release of PDGF and TGFbeta within the bone marrow microenvironment may participate, through fibroblast activation, to the generation of MF. Therefore, this study provides insight into the possible pathophysiological mechanisms for the genesis of MF.

Animals↗

PubMed2003

Microenvironmental and cellular consequences of altered blood flow in tumours.

Tumour angiogenesis is triggered by various signals characteristic of the tumour microenvironment, including low oxygen tension, low extracellular pH and low glucose concentration. Tumour microvasculature is chaotic, producing perfusion heterogeneities which can be visualized by MRI and other modalities. Inefficient perfusion in tumours produces regions of transient and chronic hypoxia. Tumour hypoxia is associated with adverse clinical outcomes and reduced patient survival. Hypoxia may be a factor in activation of extracellular matrix-degrading proteases, and some studies have correlated primary tumour hypoxia with likelihood of tumour cell dissemination. Exposure to hypoxia either induces or selects for cells that are hyperglycolytic, and this in turn produces local acidosis which is also a common feature of solid tumours. Increased glucose uptake in hyperglycolyzing tumour cells is the basis of lesion-visualization in positron emission tomography using 18F-fluorodeoxyglucose. Tumour acidity can reduce the effectiveness of weak-base drugs, but can be exploited to increase the anti-tumour activity of weak-acid chemotherapeutics. Evidence linking tumour acidity with increased activity of several extracellular matrix-degrading enzyme systems is examined. High levels of lactate, another end-product of glycolysis, in primary lesions have been correlated with increased likelihood of metastasis. In the numerous studies correlating hypoxia, acidity and lactate with metastasis, the direction of the causality has not been adequately established. We hypothesize that adoption of a hyperglycolytic phenotype is a necessary feature of carcinogenesis itself, and confers a survival and proliferative advantage to tumour cells over surrounding normal cells. Empirical evidence supporting this "acid-mediated tumour invasion" model is discussed.

Cell Hypoxia↗

PubMed2002

The cellular and molecular basis of hyperthermia.

In oncology, the term 'hyperthermia' refers to the treatment of malignant diseases by administering heat in various ways. Hyperthermia is usually applied as an adjunct to an already established treatment modality (especially radiotherapy and chemotherapy), where tumor temperatures in the range of 40-43 degrees C are aspired. In several clinical phase-III trials, an improvement of both local control and survival rates have been demonstrated by adding local/regional hyperthermia to radiotherapy in patients with locally advanced or recurrent superficial and pelvic tumors. In addition, interstitial hyperthermia, hyperthermic chemoperfusion, and whole-body hyperthermia (WBH) are under clinical investigation, and some positive comparative trials have already been completed. In parallel to clinical research, several aspects of heat action have been examined in numerous pre-clinical studies since the 1970s. However, an unequivocal identification of the mechanisms leading to favorable clinical results of hyperthermia have not yet been identified for various reasons. This manuscript deals with discussions concerning the direct cytotoxic effect of heat, heat-induced alterations of the tumor microenvironment, synergism of heat in conjunction with radiation and drugs, as well as, the presumed cellular effects of hyperthermia including the expression of heat-shock proteins (HSP), induction and regulation of apoptosis, signal transduction, and modulation of drug resistance by hyperthermia.

Cell Death↗

PubMed1999

Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis.

Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules and engages diverse ligands relevant to distinct pathological processes. One class of RAGE ligands includes glycoxidation products, termed advanced glycation end products, which occur in diabetes, at sites of oxidant stress in tissues, and in renal failure and amyloidoses. RAGE also functions as a signal transduction receptor for amyloid beta peptide, known to accumulate in Alzheimer disease in both affected brain parenchyma and cerebral vasculature. Interaction of RAGE with these ligands enhances receptor expression and initiates a positive feedback loop whereby receptor occupancy triggers increased RAGE expression, thereby perpetuating another wave of cellular activation. Sustained expression of RAGE by critical target cells, including endothelium, smooth muscle cells, mononuclear phagocytes, and neurons, in proximity to these ligands, sets the stage for chronic cellular activation and tissue damage. In a model of accelerated atherosclerosis associated with diabetes in genetically manipulated mice, blockade of cell surface RAGE by infusion of a soluble, truncated form of the receptor completely suppressed enhanced formation of vascular lesions. Amelioration of atherosclerosis in these diabetic/atherosclerotic animals by soluble RAGE occurred in the absence of changes in plasma lipids or glycemia, emphasizing the contribution of a lipid- and glycemia-independent mechanism(s) to atherogenesis, which we postulate to be interaction of RAGE with its ligands. Future studies using mice in which RAGE expression has been genetically manipulated and with selective low molecular weight RAGE inhibitors will be required to definitively assign a critical role for RAGE activation in diabetic vasculopathy. However, sustained receptor expression in a microenvironment with a plethora of ligand makes possible prolonged receptor stimulation, suggesting that interaction of cellular RAGE with its ligands could be a factor contributing to a range of important chronic disorders.

Animals↗

PubMed2006

Identification of cellular intermediates and molecular pathways induced by IL-21 in human B cells.

The complex process of B cell development is controlled by multiple factors from the surrounding microenvironment including cytokines. IL-21 is a recently identified type I cytokine, mainly produced by activated CD4(+) T cells. It has been shown to promote differentiation of human primary B cells into Ig-secreting plasma cells. The objective of our study was to describe cellular intermediates that exist during IL-21-induced transition from an activated B cell to an Ig-secreting cell and to identify molecular mechanisms involved in this process. Novel Epstein-Barr Virus-positive human B cell lines with phenotypes characteristic of Ag-activated IgG(+) B cell blasts were used as a model system to study IL-21 effects in vitro. We show that IL-21 increased both proliferation and survival of B cell lines during the first 3 days of in vitro culture. This process was associated with CD38(low/int)CD23(int)HLA-DR(high)CD19(high)CD20(int) cell surface phenotype. Continued culture with IL-21 resulted in accumulation of cells in G(0)/G(1) stage of the cell cycle and increased apoptosis. This coincided with differentiation into small, CD38(high)CD23(low/-)HLA-DR(int)CD19(int)CD20(low) late plasmablasts/early plasma cells that expressed lower levels of c-Myc protein, and secreted greater amounts of Ig than the control cells. Partial inhibition of IL-21-induced JAK/STAT signaling by the low-dose pharmacological agent, JAK inhibitor I, did not prevent the initial increase in proliferation. However, decrease in c-Myc protein expression and subsequent differentiation to late plasmablasts/early plasma cells were strongly inhibited. Our study is the first to show the link between IL-21-induced JAK/STAT signaling, c-Myc regulation, and differentiation of human B cells.

B-Lymphocytes↗

PubMed2006

The role of immune cells in the tumor microenvironment.

Interactions between tumor infiltrating leukocytes and tumor cells have been of great interest because of the possibility that immune cells either interfere with tumor progression or actively promote tumor growth. The tumor microenvironment is shaped by cells entering it, and their functions reflect the local conditions. Successive changes occurring at the tumor site during tumor progression resemble chronic inflammation. This chronic inflammatory reaction seems to be largely orchestrated by the tumor, and it seems to promote tumor survival. Molecular and cellular mechanisms linking the inflammatory reaction and cancer are emerging, and this review summarizes the current understanding of interactions between inflammatory and cancer cells in the tumor microenvironment.

B-Lymphocytes↗

PubMed2007

Endothelial cell- and lymphocyte-based in vitro systems for understanding KSHV biology.

Kaposi sarcoma (KS), the most common AIDS-associated malignancy, is a multifocal tumor characterized by deregulated angiogenesis, proliferation of spindle cells, and extravasation of inflammatory cells and erythrocytes. Kaposi sarcoma-associated herpesvirus (KSHV; also human herpesvirus-8) is implicated in all clinical forms of KS. Endothelial cells (EC) harbor the KSHV genome in vivo, are permissive for virus infection in vitro, and are thought to be the precursors of KS spindle cells. Spindle cells are rare in early patch-stage KS lesions but become the predominant cell type in later plaque- and nodular-stage lesions. Alterations in endothelial/spindle cell physiology that promote proliferation and survival are thus thought to be important in disease progression and may represent potential therapeutic targets. KSHV encodes genes that stimulate cellular proliferation and migration, prevent apoptosis, and counter the host immune response. The combined effect of these genes is thought to drive the proliferation and survival of infected spindle cells and influence the lesional microenvironment. Large-scale gene expression analyses have revealed that KSHV infection also induces dramatic reprogramming of the EC transcriptome. These changes in cellular gene expression likely contribute to the development of the KS lesion. In addition to KS, KSHV is also present in B cell neoplasias including primary effusion lymphoma and multicentric Castleman disease. A combination of virus and virus-induced host factors are similarly thought to contribute to establishment and progression of these malignancies. A number of lymphocyte- and EC-based systems have been developed that afford some insight into the means by which KSHV contributes to malignant transformation of host cells. Whereas KSHV is well maintained in PEL cells cultured in vitro, explanted spindle cells rapidly lose the viral episome. Thus, endothelial cell-based systems for studying KSHV gene expression and function, as well as the effect of infection on host cell physiology, have required in vitro infection of primary or life-extended EC. This chapter includes a review of these in vitro cell culture systems, acknowledging their strengths and weaknesses and putting into perspective how each has contributed to our understanding of the complex KS lesional environment. In addition, we present a model of KS lesion progression based on findings culled from these models as well as recent clinical advances in KS chemotherapy. Thus this unifying model describes our current understanding of KS pathogenesis by drawing together multiple theories of KS progression that by themselves cannot account for the complexities of tumor development.

Animals↗

PubMed1992

Cellular interactions in the germinal center: role of adhesion receptors and significance for the pathogenesis of AIDS and malignant lymphoma.

The germinal center forms a specialized microenvironment that is thought to play a key role in the induction of antibody synthesis, affinity maturation of B cells, isotype switching, and memory B-cell formation. Moreover, the germinal center may also be involved in the maintenance of T-cell memory. In this paper we focus on the role of adhesion receptors in cellular interactions in the germinal center, and discuss evidence indicating that these molecules play an important role in regulating B-cell activation and differentiation. Furthermore, we discuss two important diseases involving the germinal center, i.e., HIV infection and malignant lymphoma. In HIV infection, destruction of the FDC network may explain the selective loss of memory cells observed in otherwise asymptomatic patients and is likely to represent a major pathway leading to AIDS. In follicular lymphoma, escape from physiological apoptosis in the germinal center by overexpression of Bcl-2 appears be a major pathogenetic pathway.

Acquired Immunodeficiency Syndrome↗

PubMed1996

Cellular interactions among marrow stromal and normal/neoplastic pre-B- and B-lymphoblastic cells.

The direct interaction between B-cells, both normal and neoplastic, and marrow stromal cells (MSC) or MSC-secreted extracellular matrix proteins is believed to play a decisive role in lymphopoiesis as well as in the sustained proliferation and homing of lymphoid malignancies. Although information has been accruing on possible obligatory cell-cell and cell-extracellular matrix adhesion molecules, our current state of knowledge regarding B-cell interaction with the marrow microenvironment is rather limited. We discuss in this review what is currently known regarding adhesion molecules involved in the apposition between B-cells and MSC. In addition, we describe how the cellular interactions are modulated by cytokines present in the marrow microenvironment. Further, we present possible signal transduction pathways activated by B-cell/MSC apposition and attempt to integrate in vitro data with in vivo observations. We close this review by providing implications for novel clinical and therapeutic applications based on the current knowledge of B-cell/MSC adhesion mechanisms and signaling pathways.

B-Lymphocytes↗

PubMed2025

Genome-wide CRISPR screens identify critical targets to enhance CAR-NK cell antitumor potency.

Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced metabolic fitness, increased secretion of proinflammatory cytokines, and expansion of cytotoxic NK cell subsets. Through high-content genome-wide CRISPR screening in NK cells, this study reveals critical regulators of NK cell function and provides a valuable resource for engineering next-generation NK cell therapies with improved efficacy against cancer.

Humans↗

PubMed1992

A population of early fetal thymocytes expressing Fc gamma RII/III contains precursors of T lymphocytes and natural killer cells.

We have identified a dominant fetal thymocyte population at day 14.5 of gestation in the mouse that lacks CD4 and CD8 but expresses Fc gamma RII/III several days prior to acquisition of the T cell receptor (TCR) in vivo. If maintained in a thymic microenvironment, this population of CD4-CD8-TCR-Fc gamma RII/III+ thymocytes differentiates first into CD4+CD8+TCRlowFc gamma RII/III- thymocytes and subsequently CD4+CD8-TCRhighFc gamma RII/III- and CD4-CD8+TCRhighFc gamma RII/III- mature Ti alpha-beta lineage T cells. However, if removed from the thymus, the CD4-CD8-TCR-Fc gamma RII/III+ thymocyte population selectively generates functional natural killer (NK) cells in vivo as well as in vitro. These findings show that a cellular pool of Fc gamma RII/III+ precursors gives rise to T and NK lineages in a microenvironment-dependent manner. Moreover, they suggest a hitherto unrecognized role for Fc receptors on primitive T cells.

Animals↗

PubMed2000

Different doses of agonistic ligand drive the maturation of functional CD4 and CD8 T cells from immature precursors.

MHC molecules are normally required for the development of thymocytes from the CD4(+)CD8(+) double-positive to the CD4 or CD8 single-positive stage. Here we show that mitogenic plant lectins can substitute for MHC molecules in driving the differentiation of phenotypically and functionally mature CD4 as well as CD8 T cells. Interestingly, lectin dosage determines whether CD4 or CD8 cells are generated, indicating that variation of cumulative signal strength (not necessarily signal quality) can result in an apparent switching of lineage preference. Thymocyte perception of differentiation-inducing signals is modulated by the cellular context, since stimuli that yield CD8 cells in the context of the thymic microenvironment fail to do so in suspension culture and generate CD4 progeny instead. Finally, we show that lectin-generated single-positive thymocytes retain the ability to respond to the ligands initially used to drive their differentiation. Our results call into question generalizations and predictions made from other experimental systems and reveal that thymocyte selection is considerably more flexible than had been anticipated.

Animals↗