[Show abstract][Hide abstract] ABSTRACT: Astrocytes, members of the glial family, interact through the exchange of soluble factors
or by directly contacting neurons and other brain cells, such as microglia and endothelial
cells. Astrocytic projections interact with vessels and act as additional elements of the
Blood Brain Barrier (BBB). By mechanisms not fully understood, astrocytes can undergo
oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB
to ensure survival and continuous growth. A glioma can develop into a very aggressive
tumor, the glioblastoma (GBM), characterized by a highly heterogeneous cell population
(including tumor stem cells), extensive proliferation and migration. Nevertheless, gliomas
can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB
is crucial. Glioma cells migrate to different regions of the brain guided by the extension of
blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can
lead to tumor-derived seizures, which represent a challenge to patients and clinicians,
since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast
growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass
resulting in peritumoral edema. Although hormonal therapy is currently used to control
the edema, it is not always efficient. In this review we comment the points cited above,
considering the importance of the BBB and the concerns that arise when this barrier is
[Show abstract][Hide abstract] ABSTRACT: Among the cells that constitute the central nervous system (CNS), astrocytes are the most abundant cells in the brain. They originate from the neural tube, differently from other glial cells of the astrocyte-like, enteric glia, which originate from the neural crest. Cerebral astrocytes interact with other brain cells such as neurons, mediated by cellular contact involving extracellular matrix (ECM) elements and the integrin of astrocytes. Interactions can also occur through exchange of soluble molecules, cytokines, and growth factors, delivered by astrocytes and the interacting cells. Of the growth factors secreted by astrocytes, members of the transforming growth factor (TGF) beta family, especially TGF-β1, are highly important. TGF-β1 acts in brain development, in adult brain homeostasis, and also in orchestrating the brain’s response to injury and/or aging. These cell–cell interactions depend on the cellular membrane plasticity expressed by biophysical forces of interaction. In parallel to the properties of normal astrocytes, a growing astrocytoma develops new malignant behavior and interactions with parenchyma that differ from those of normal astrocytes. In this chapter, we analyze important points that characterize tumor progression and discuss new therapeutic approaches to treat these tumors.
Glioma Cell Biology, Edited by Sedo, Aleksi, Mentlein, Rolf, 10/2014: chapter Glioblastomas and the Special Role of Adhesion Molecules in Their Invasion: pages 293-315; Springer., ISBN: 9783709114308
[Show abstract][Hide abstract] ABSTRACT: Coagulation proteins play a critical role in numerous aspects of tumor biology. Cancer cells express tissue factor (TF), the protein that initiates blood clotting, which frequently correlates with processes related to cell aggressiveness, including primary tumor growth, invasion, and metastasis. It has been demonstrated that TF gets incorporated into tumor-derived microvesicles (MVs), a process that has been correlated with cancer-associated thrombosis. Here, we describe the exchange of TF-bearing MVs between breast cancer cell lines with different aggressiveness potential. The highly invasive and metastatic MDA-MB-231 cells displayed higher surface levels of functional TF compared with the less aggressive MCF-7 cells. MVs derived from MDA-MB-231 cells were enriched in TF and accelerated plasma coagulation, but MCF-7 cell-derived MVs expressed very low levels of TF. Incubating MCF-7 cells with MDA-MB-231 MVs significantly increased the TF activity. This phenomenon was not observed upon pretreatment of MVs with anti-TF or annexin-V, which blocks phosphatidylserine sites on the surface of MVs. Our data indicated that TF-bearing MVs can be transferred between different populations of cancer cells and may therefore contribute to the propagation of a TF-related aggressive phenotype among heterogeneous subsets of cells in a tumor.
Thrombosis Research 08/2013; 132(4)(4). DOI:10.1016/j.thromres.2013.07.026 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The co-chaperone stress-inducible protein 1 (STI1) is released by astrocytes, and has important neurotrophic properties upon binding to prion protein (PrP(C)). However, STI1 lacks a signal peptide and pharmacological approaches pointed that it does not follow a classical secretion mechanism. Ultracentrifugation, size exclusion chromatography, electron microscopy, vesicle labeling, and particle tracking analysis were used to identify three major types of extracellular vesicles (EVs) released from astrocytes with sizes ranging from 20-50, 100-200, and 300-400 nm. These EVs carry STI1 and present many exosomal markers, even though only a subpopulation had the typical exosomal morphology. The only protein, from those evaluated here, present exclusively in vesicles that have exosomal morphology was PrP(C). STI1 partially co-localized with Rab5 and Rab7 in endosomal compartments, and a dominant-negative for vacuolar protein sorting 4A (VPS4A), required for formation of multivesicular bodies (MVBs), impaired EV and STI1 release. Flow cytometry and PK digestion demonstrated that STI1 localized to the outer leaflet of EVs, and its association with EVs greatly increased STI1 activity upon PrP(C)-dependent neuronal signaling. These results indicate that astrocytes secrete a diverse population of EVs derived from MVBs that contain STI1 and suggest that the interaction between EVs and neuronal surface components enhances STI1-PrP(C) signaling.
Cellular and Molecular Life Sciences CMLS 03/2013; 70(17). DOI:10.1007/s00018-013-1328-y · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exosomes are membrane vesicles that are released by cells upon fusion of multivesicular bodies with the plasma membrane. Their
molecular composition reflects their origin in endosomes as intraluminal vesicles. In addition to a common set of membrane
and cytosolic molecules, exosomes harbor unique subsets of proteins linked to cell type–associated functions. Exosome secretion
participates in the eradication of obsolete proteins but several findings, essentially in the immune system, indicate that
exosomes constitute a potential mode of intercellular communication. Release of exosomes by tumor cells and their implication
in the propagation of unconventional pathogens such as prions suggests their participation in pathological situations. These
findings open up new therapeutic and diagnostic strategies.
Journal of Biochemistry 08/2006; 140(1):13-21. DOI:10.1093/jb/mvj128 · 2.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prion diseases are neurodegenerative disorders associated in most cases with the accumulation in the central nervous system of PrPSc (conformationally altered isoform of cellular prion protein (PrPC); Sc for scrapie), a partially protease-resistant isoform of the PrPC. PrPSc is thought to be the causative agent of transmissible spongiform encephalopathies. The mechanisms involved in the intercellular transfer of PrPSc are still enigmatic. Recently, small cellular vesicles of endosomal origin called exosomes have been proposed to contribute to the spread of prions in cell culture models. Retroviruses such as murine leukemia virus (MuLV) or human immunodeficiency virus type 1 (HIV-1) have been shown to assemble and bud into detergent-resistant microdomains and into intracellular compartments such as late endosomes/multivesicular bodies. Here we report that moloney murine leukemia virus (MoMuLV) infection strongly enhances the release of scrapie infectivity in the supernatant of coinfected cells. Under these conditions, we found that PrPC, PrPSc and scrapie infectivity are recruited by both MuLV virions and exosomes. We propose that retroviruses can be important cofactors involved in the spread of the pathological prion agent.
The EMBO Journal 07/2006; 25(12):2674-85. DOI:10.1038/sj.emboj.7601162 · 10.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exosomes are membrane vesicles that are released by cells upon fusion of multivesicular bodies with the plasma membrane. Their molecular composition reflects their origin in endosomes as intraluminal vesicles. In addition to a common set of membrane and cytosolic molecules, exosomes harbor unique subsets of proteins linked to cell type– associated functions. Exosome secretion participates in the eradication of obsolete pro-teins but several findings, essentially in the immune system, indicate that exosomes constitute a potential mode of intercellular communication. Release of exosomes by tumor cells and their implication in the propagation of unconventional pathogens such as prions suggests their participation in pathological situations. These findings open up new therapeutic and diagnostic strategies. Multivesicular bodies (MVBs), and their intraluminal vesi-cles (ILVs), are involved in the sequestration of proteins destined for degradation in lysosomes (1). An alternative fate of MVBs is their exocytic fusion with the plasma mem-brane leading to the release of the 50–90 nm ILVs into the extracellular milieu (Fig. 1). The secreted ILVs are then called exosomes (reviewed in Refs. 2 and 3). After their initial description as vesicles of endosomal origin secreted by reticulocytes during differentiation (4), vesicles with the hallmarks of exosomes appeared to be released by other cells. Exosomes are present in the culture superna-tant of several cell types of hematopoietic origin [B cells (5), dendritic cells (6), mast cells (7), T cells (8) and platelets (9)] and of non hematopoietic origin [intestinal epithelial cells (10), tumor cells (11), Schwann cells (12) and neuronal cells (13)]. In addition there is increasing evidence for the presence of exosomes in physiological fluids such as plasma (14), malignant and pleural effusions (15, 16) and urine (17). As a consequence of proteins and lipids sorting at the limiting membrane of endosomes during the formation of the ILVs in MVBs, exosomes harbour a specific set of molecules. The sorting process and the generation of ILVs require the recognition of cargo proteins by a series of multiprotein complexes that form the ESCRT machinery [for review (18)] (Fig. 2). There is increasing evidence, how-ever, that cargo sorting and MVB generation is not solely dependent on ESCRT components. The mechanisms lead-ing to the fusion of MVBs with the plasma membrane and the consequent release of exosomes are unknown,
Journal of Biochemistry 01/2006; 140:13-21. · 2.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exosomes are membrane vesicles released into the extracellular environment upon exocytic fusion of multivesicular endosomes with the cell surface. Exosome secretion can be used by cells to eject molecules targeted to intraluminal vesicles of multivesicular bodies, but particular cell types may exploit exosomes as intercellular communication devices for transfer of proteins and lipids among cells. The glycosylphosphatyidylinositol-linked prion protein (PrP) in both its normal (PrPc) and scrappie (PrPsc) conformation is associated with exosomes. Targeting of exosomes containing the normal cellular PrP could confer susceptibility of cells that do not express PrP to prion multiplication. Furthermore, exosomes bearing proteinase-K resistant PrPsc are infectious, suggesting a model in which exosomes secreted by infected cells could serve as vehicles for propagation of prions. Thus, cells may exploit the nature of endosome-derived exosomes to communicate with each other in normal and pathological situations, providing for a novel route of cell-to-cell communication and therefore of pathogen transmission. These findings open the possibility that methods to interfere with trafficking of such unconventional pathogens could be envisioned from insights on the mechanisms involved in exosome formation, secretion and targeting.