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Purpose of review The extracellular matrix (ECM) is critical for all aspects of vascular pathobiology. In vascular disease the balance of its structural components is shifted. In atherosclerotic plaques there is in fact a dynamic battle between stabilizing and proinflammatory responses. This review explores the most recent strides that have been made to detail the active role of the ECM - and its main binding partners - in driving atherosclerotic plaque development and destabilization. Recent findings Proteoglycans-glycosaminoglycans (GAGs) synthesis and remodelling, as well as elastin synthesis, cross-linking, degradation and its elastokines potentially affect disease progression, providing multiple steps for potential therapeutic intervention and diagnostic targeted imaging. Of note, GAGs biosynthetic enzymes modulate the phenotype of vascular resident and infiltrating cells. In addition, while plaque collagen structure exerts very palpable effects on its immediate surroundings, a new role for collagen is also emerging on a more systemic level as a biomarker for cardiovascular disease as well as a target for selective drug-delivery. Summary The importance of studying the ECM in atherosclerosis is more and more acknowledged and various systems are being developed to visualize, target and mimic it.

Cancer stem cell populations are important for the initiation, progression and metastasis of tumors. The mechanisms governing cancer stem cell control are only partially understood, but activation of the Notch3 pathway plays a crucial role in the maintenance of breast cancer stem cells. Expression of Cartilage Oligomeric Matrix Protein (COMP) in breast cancer cells is correlated with poor survival and higher recurrence rates in patients. In this study, we provide in vivo and in vitro evidence that COMP expression increases the proportion of cancer stem cells in breast cancer. Thus, MDA-MB-231 and BT-20 cells expressing COMP formed larger tumorspheres in vivo and in vitro and displayed higher ALDH-activity than cells lacking COMP. Additionally, BT-20 COMP-expressing cells displayed higher expression of CD133 compared with the control cells. Furthermore, among the different Notch receptors, Notch3 is specifically activated in COMP-expressing cells. Mechanistically, activation of Notch3 is mediated by secreted, polymeric COMP, which interacts with both Notch3 and its ligand Jagged1, bridging the receptor and ligand together, enhancing Notch3-specific signaling. COMP-dependent Notch3 activation also leads to cross-talk with β-Catenin and AKT pathways. Using the model of MMTV-PyMT mouse breast tumorigenesis, we observed a decrease in the size of tumors and the amount of cancer stem cells as well as reduced Notch3 activation, in COMP knockout mice in comparison to wild type mice. In conclusion, we reveal a novel molecular mechanism whereby COMP regulates the cancer stem cell population through increasing the interaction between Notch3 and Jagged1, leading to increased activation of Notch3 signaling.

Schizophrenia risk is associated with increased gene copy number and brain expression of complement component 4 (C4). Because the complement system facilitates synaptic pruning, the C4 association has renewed interest in a hypothesis that excessive pruning contributes to schizophrenia pathogenesis. However, little is known about complement regulation in neural tissues or whether such regulation could be relevant to psychiatric illness. Intriguingly, common variation within CSMD1, which encodes a putative complement inhibitor, has consistently associated with schizophrenia at genome-wide significance. We found that Csmd1 is predominantly expressed in the brain by neurons, and is enriched at synapses; that human stem cell-derived neurons lacking CSMD1 are more vulnerable to complement deposition; and that mice lacking Csmd1 have increased brain complement activity, fewer synapses, aberrant complement-dependent development of a neural circuit, and synaptic elements that are preferentially engulfed by cultured microglia. These data suggest that CSMD1 opposes the complement cascade in neural tissues.Graphic Abstract.Our findings support a model in which CSMD1 opposes actions of the complement cascade in neural tissues (top left). We investigated two models in which Csmd1 was genetically ablated: human cortical neurons derived from embryonic stem cells, and a back-crossed C57bl6-Tac mouse line (top right). Csmd1 is normally expressed by neurons and present at synapses where it can protect them from complement (bottom left); in the absence of Csmd1 (bottom right), we find more deposition of complement (on cultured human cortical neurons and in the mouse visual system), reduced numbers of synapses (in the mouse visual system), and synaptic fractions that are more readily engulfed by microglia (ex vivo). Created with BioRender.com.

Extracellular matrix (ECM) is a non-cellular three-dimensional macromolecular network composed of collagens, proteoglycans/glycosaminoglycans, elastin, fibronectin, laminins, and several other glycoproteins. Matrix components bind each other as well as cell adhesion receptors forming a complex network into which cells reside in all tissues and organs. Cell surface receptors transduce signals into cells from ECM, which regulate diverse cellular functions, such as survival, growth, migration, and differentiation, and are vital for maintaining normal homeostasis. ECM is a highly dynamic structural network that continuously undergoes remodeling mediated by several matrix-degrading enzymes during normal and pathological conditions. Deregulation of ECM composition and structure is associated with the development and progression of several pathologic conditions. This article emphasizes in the complex ECM structure as to provide a better understanding of its dynamic structural and functional multipotency. Where relevant, the implication of the various families of ECM macromolecules in health and disease is also presented.

The complement system resembles a double-edged sword since its activation can either benefit or harm the host. Thus, regulation of this system is of utmost importance and performed by several circulating and membrane-bound complement inhibitors. The pool of well-established regulators has recently been enriched with proteins that either share structural homology to known complement inhibitors such as Sushi domain-containing (SUSD) protein family and Human CUB and Sushi multiple domains (CSMD) families or extracellular matrix (ECM) macromolecules that interact with and modulate complement activity. In this review, we summarize the current knowledge about newly discovered complement inhibitors and discuss their implications in complement regulation, as well as in processes beyond complement regulation such cancer development. Understanding the behavior of these proteins will introduce new mechanisms of complement regulation and may provide new avenues in the development of novel therapies.

The glycosaminoglycan heparin and its derivatives act strongly on blood coagulation, controlling the activity of serine protease inhibitors in plasma. Nonetheless, there is accumulating evidence highlighting different anticancer activities of these molecules in numerous types of cancer. Nano-heparins may have great biological significance since they can inhibit cell proliferation and invasion as well as inhibiting proteasome activation. Moreover, they can cause alterations in the expression of major modulators of the tumor microenvironment, regulating cancer cell behavior. In the present study, we evaluated the effects of two nano-heparin formulations: one isolated from porcine intestine and the other from the sea squirt Styela plicata, on a breast cancer cell model. We determined whether these nano-heparins are able to affect cell proliferation, apoptosis and invasion, as well as proteasome activity and the expression of extracellular matrix molecules. Specifically, we observed that nano-Styela compared to nano-Mammalian analogue has higher inhibitory role on cell proliferation, invasion and proteasome activity. Moreover, nano-Styela regulates cell apoptosis, expression of inflammatory molecules, such as IL-6 and IL-8 and reduces the expression levels of extracellular matrix macromolecules, such as the proteolytic enzymes MT1-MMP, uPA and the cell surface proteoglycans syndecan-1 and -2, but not on syndecan-4. The observations reported in the present article indicate that nano-heparins and especially ascidian heparin are effective agents for heparin-induced effects in critical cancer cell functions, providing an important possibility in pharmacological targeting.

Human CUB and Sushi multiple domains 1 (CSMD1) is a membrane-bound complement inhibitor suggested to act as a putative tumor suppressor gene, since allelic loss of this region encompassing 8p23 including CSMD1 characterizes various malignancies. Here, we assessed the role of CSMD1 as a tumor suppressor gene in the development of breast cancer in vitro and in vivo. We found that human breast tumor tissues expressed CSMD1 at lower levels compared to that in normal mammary tissues. The decreased expression of CSMD1 was linked to a shorter overall survival of breast cancer patients. We also revealed that expression of CSMD1 in human breast cancer cells BT-20 and MDA-MB-231 significantly inhibited their malignant phenotypes, including migration, adhesion and invasion. Conversely, stable silencing of CSMD1 expression in T47D cells enhanced cancer cell migratory, adherent and clonogenic abilities. Moreover, expression of CSMD1 in the highly invasive MDA-MB-231 cells diminished their signaling potential as well as their stem cell-like properties as assessed by measurement of aldehyde dehydrogenase activity. In a xenograft model, expression of CSMD1 blocked the ability of cancer cells to metastasize to secondary sites in vivo, likely via inhibiting local invasion but not the extravasation into distant tissues. Taken together, these findings demonstrate the role of CSMD1 as a tumor suppressor gene in breast cancer.

Nanotechnology is an evolving scientific field that has allowed the manufacturing of materials with novel physicochemical and biological properties, offering a wide spectrum of potential applications. Properties of nanoparticles that contribute to their usefulness include their markedly increased surface area in relation to mass, surface reactivity and insolubility, ability to agglomerate or change size in different media and enhanced endurance over conventional-scale substance. Here, we review nanoparticle classification and their emerging applications in several fields; from active food packaging to drug delivery and cancer research. Nanotechnology has exciting therapeutic applications, including novel drug delivery for the treatment of cancer. Additionally, we discuss that exposure to nanostructures incorporated to polymer composites, may result in potential human health risks. Therefore, the knowledge of processes, including absorption, distribution, metabolism and excretion, as well as careful toxicological assessment is critical in order to determine the effects of nanomaterials in humans and other biological systems. Expanding the knowledge of nanoparticle toxicity will facilitate designing of safer nanocomposites and their application in a beneficial manner. (C) 2016 Elsevier Ltd. All rights reserved.

Two new diastereomeric lignan amides (4 and 5) serving as dimeric caffeic acid-l-DOPA hybrids were synthesized. The synthesis involved the FeCl3-mediated phenol oxidative coupling of methyl caffeate to afford trans-diester 1a as a mixture of enantiomers, protection of the catechol units, regioselective saponification, coupling with a suitably protected l-DOPA derivative, separation of the two diastereomers thus obtained by flash column chromatography and finally global chemoselective deprotection of the catechol units. The effect of hybrids 4 and 5 and related compounds on the proliferation of two breast cancer cell lines with different metastatic potential and estrogen receptor status (MDA-MB-231 and MCF-7) and of one epithelial lung cancer cell line, namely A-549, was evaluated for concentrations ranging from 1 to 256μM and periods of treatment of 24, 48 and 72h. Both hybrids showed interesting and almost equipotent antiproliferative activities (IC50 64-70μM) for the MDA-MB-231 cell line after 24-48h of treatment, but they were more selective and much more potent (IC50 4-16μM) for the MCF-7 cells after 48h of treatment. The highest activity for both hybrids and both breast cancer lines was observed after 72h of treatment (IC50 1-2μM), probably as the result of slow hydrolysis of their methyl ester functions.