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Background Osteoarthritis (OA) is a common degenerative chronic disease accounting for physical pain, tissue stiffness and mobility restriction. Current therapeutic approaches fail to prevent the progression of the disease considering the limited knowledge on OA pathobiology. During OA progression, the extracellular matrix (ECM) of the cartilage is aberrantly remodeled by chondrocytes. Chondrocytes, being the main cell population of the cartilage, participate in cartilage regeneration process. To this end, modern tissue engineering strategies involve the recruitment of mesenchymal stem cells (MSCs) due to their regenerative capacity as to promote chondrocyte self-regeneration. Methods and results In the present study, we evaluated the role of type II collagen, as the main matrix macromolecule in the cartilage matrix, to promote chondrogenic differentiation in two MSC in vitro culture systems. The chondrogenic differentiation of human Wharton’s jelly- and dental pulp-derived MSCs was investigated over a 24-day culture period on type II collagen coating to improve the binding affinity of MSCs. Functional assays, demonstrated that type II collagen promoted chondrogenic differentiation in both MSCs tested, which was confirmed through gene and protein analysis of major chondrogenic markers. Conclusions Our data support that type II collagen contributes as a natural bioscaffold enhancing chondrogenesis in both MSC models, thus enhancing the commitment of MSC-based therapeutic approaches in regenerative medicine to target OA and bring therapy closer to the clinical use.

Extracellular matrixes (ECMs) are intricate 3-dimensional macromolecular networks of unique architectures with regulatory roles in cell morphology and functionality. As a dynamic native biomaterial, ECM undergoes constant but tightly controlled remodeling that is crucial for the maintenance of normal cellular behavior. Under pathological conditions like cancer, ECM remodeling ceases to be subjected to control resulting in disease initiation and progression. ECM is comprised of a staggering number of molecules that interact not only with one another, but also with neighboring cells via cell surface receptors. Such interactions, too many to tally, are of paramount importance for the identification of novel disease biomarkers and more personalized therapeutic intervention. Recent advances in big data analytics have allowed the development of online databases where researchers can take advantage of a stochastic evaluation of all the possible interactions and narrow them down to only those of interest for their study, respectively. This novel approach addresses the limitations that currently exist in studies, expands our understanding on ECM interactions, and has the potential to advance the development of targeted therapies. In this article we present the current trends in ECM biology research and highlight its importance in tissue integrity, the main interaction networks, ECM-mediated cell functional properties and issues related to pharmacological targeting.

Air pollution by pathogens has posed serious concern on global health during the last decades, especially since the breakout of the last pandemic. Therefore, advanced high-efficiency techniques for air purification are highly on demand. However, in air-filtering devices, the prevention of secondary pollution that may occur on the filters remains a challenge. Toward this goal, in the present work, we demonstrate a facile and eco-friendly process for the biocidal treatment of commercial high-efficiency particulate air filters. The antibacterial filters were successfully prepared through spray coating of aqueous solutions based on biocidal water-soluble polymers, poly(sodium 4-styrene sulfonate

Exosomes are nanosized vesicles that are produced in normal and cancer cells, promoting intracellular communication. In head and neck cancer (HNC), exosomes are involved in many undesirable events of cancer development and progression, including angiogenesis, tumor microenvironment (TME) remodeling, invasion, epithelial-to-mesenchymal transition (EMT), metastasis, extracellular matrix (ECM) degradation, and drug resistance. Exosomes are involved in altering the signaling pathways in recipient cells by the cargoes they carry. Proteins, lipids, and nucleic acids such as DNA fragments and RNAs (i.e., mRNAs, miRNAs, and long non-coding RNAs) are carried in the exosomes to promote cell communication. EMT is a critical cellular process in which epithelial cells are forced to become mesenchymal cells by the actions of SNAIL/SLUG, TWIST, and ZEB family transcription factors carried in exosomes that facilitate metastasis. In this critical review, we focused on exosome biogenesis, their cargoes, and their involvement in EMT induction and metastasis during HNC. Insights into exosome isolation and characterization, as well as their key role in ECM remodeling and degradation, are also presented and critically discussed. More importantly, this article addresses the role of exosomes in HNC and drug resistance induced in drug-sensitive cancer cells. In addition, exosomes have a great potential to be used as diagnostic and therapeutic tools. A better understanding on exosome biogenesis, composition, and functions in HNC will aid in developing novel therapeutic strategies to treat HNC, overcome therapy resistance, and avoid metastasis, which is a significant cause of cancer death.

Breast cancer constitutes a heterogeneous disease. The expression profiles of estrogen receptors (ERs), as well as the expression patterns of extracellular matrix (ECM) macromolecules, determine its development and progression. Hyaluronan (HA) is an ECM molecule that regulates breast cancer cells' properties in a molecular size-dependent way. Previous studies have shown that 200-kDa HA fragments modulate the functional properties, morphology, and expression of several matrix mediators of the highly metastatic ERα−/ERβ+ MDA-MB-231 cells. In order to evaluate the effects of HA fragments (

Proteoglycans consist one of the major extracellular matrix class of biomolecules that demonstrate nodal roles in cancer progression. Modern diagnostic and therapeutic approaches include proteoglycan detection and pharmacological targeting in various cancer types. Proteoglycans orchestrate critical signaling pathways for cancer development and progression through dynamic interactions with matrix components. It is well established that the epigenetic signatures of cancer cells play critical role in guiding their functional properties and metastatic potential. Secreted microRNAs (miRNAs) reside in a complex network with matrix proteoglycans, thus affecting cell-cell and cell-matrix communication. This mini-review aims to highlight current knowledge on the cell-surface proteoglycan-mediated signaling cascades that regulate miRNA biogenesis in cancer. Moreover, the miRNA-mediated proteoglycan regulation during cancer progression and mechanistic aspects on the way that proteoglycans affect miRNA expression are presented. Recent advances on the role of cell surface proteoglycans in exosome biogenesis and miRNA packaging and expression are also discussed.

In this special interview series, we profile members of The FEBS Journal editorial board to highlight their research focus, perspectives on the journal and future directions in their field. Nikos Karamanos is Professor of Biochemistry in the Department of Chemistry, University of Patras in Greece. He joined the editorial board of The FEBS Journal in 2020, having previously served on the advisory board for several years.

Expression of miRNAs is critical for the regulation of several cell functions including proliferation, migration, differentiation, and survival, as well as extracellular matrix (ECM) remodeling. The dynamic interplay between miRNAs, ECM macromolecules, and the tumor microenvironment plays critical roles in many aspects of human diseases such as metabolic disorders and cancers. Circulating and secreted miRNAs, via membrane vesicles, affect cell-cell communication and cellular metabolic pathways, underscoring their significance in tumor progression. The primary goal of this article is to highlight the importance of epigenetic regulatory factors, focusing on miRNA-mediated ECM reorganization and their functional relationships, and how matrix-mediated miRNAs affect tumor progression.

Extracellular matrix (ECM) is a dynamic 3-dimensional network of macromolecules that provides structural support for the cells and tissues. Accumulated knowledge clearly demonstrated over the last decade that ECM plays key regulatory roles since it orchestrates cell signaling, functions, properties and morphology. Extracellularly secreted as well as cell-bound factors are among the major members of the ECM family. Proteins/glycoproteins, such as collagens, elastin, laminins and tenascins, proteoglycans and glycosaminoglycans, hyaluronan, and their cell receptors such as CD44 and integrins, responsible for cell adhesion, comprise a well-organized functional network with significant roles in health and disease. On the other hand, enzymes such as matrix metalloproteinases and specific glycosidases including heparanase and hyaluronidases contribute to matrix remodeling and affect human health. Several cell processes and functions, among them cell proliferation and survival, migration, differentiation, autophagy, angiogenesis, and immunity regulation are affected by certain matrix components. Structural alterations have been also well associated with disease progression. This guide on the composition and functions of the ECM gives a broad overview of the matrisome, the major ECM macromolecules, and their interaction networks within the ECM and with the cell surface, summarizes their main structural features and their roles in tissue organization and cell functions, and emphasizes the importance of specific ECM constituents in disease development and progression as well as the advances in molecular targeting of ECM to design new therapeutic strategies.

Tumor extracellular matrix (ECM) operates in a coordinated mode with cancer and stroma cells to evoke the multistep process of metastatic potential. The remodeled tumor-associated matrix provides a point for direct or complementary therapeutic targeting. Here, we cover and critically address the importance of ECM networks and their macromolecules in cancer. We focus on the roles of key structural and functional ECM components, and their degradation enzymes and extracellular vesicles, aiming at improving our understanding of the mechanisms contributing to tumor initiation, growth, and dissemination, and discuss potential new approaches for ECM-based therapeutic targeting and diagnosis.

Exosomes are a subtype of extracellular vesicles (EVs) composed of a lipid bilayer, which carry various cargoes such as nucleic acids, proteins, and bioactive lipids. Cancer cells release exosomes to promote cell communication and interaction with the extracellular matrix (ECM). ECM regulates the secretion and uptake of exosomes. Moreover, the cargo of exosomes can control ECM remodeling, thus affecting cancer progression. Aside from the rearrangement of ECM, exosomal cargo also modulates different signaling pathways that maintain homeostasis and play a major role in tumor growth and immune evasion in the tumor microenvironment (TME). Exosomes are now widely recognized as circulating biomarkers for diagnosis and prognosis. Their role in cancer initiation, progression, and chemoresistance is becoming increasingly clear from preclinical and clinical investigations, thereby gaining interest for their potential use as cancer diagnostics tools, but also for the development of future innovative cancer therapeutics. In this mini review we outline and discuss the correlation between exosomes, TME and cancer progression, while focusing on the potential role of exosomes as diagnostic and prognostic biomarkers, as well as therapeutic vehicles for drug delivery.

Hyaluronan (HA) is a linear nonsulfated glycosaminoglycan of the extracellular matrix that plays a pivotal role in a variety of biological processes. High-molecular weight HA exhibits different biological properties than oligomers and low-molecular weight HA. Depending on their molecular size, HA fragments can influence cellular behavior in a different mode of action. This phenomenon is attributed to the different manner of interaction with the HA receptors, especially CD44 and RHAMM. Both receptors can trigger signaling cascades that regulate cell functional properties, such as proliferation migration, angiogenesis, and wound healing. HA fragments are able to enhance or attenuate the HA receptor-mediated signaling pathways, as they compete with the endogenous HA for binding to the receptors. The modulation of these pathways could be crucial for the development of pathological conditions, such as inflammation and cancer. The primary goal of this review is to critically present the importance of HA molecular size on cellular signaling, functional cell properties, and morphology in normal and pathological conditions, including inflammation and cancer. A deeper understanding of these mechanisms could contribute to the development of novel therapeutic strategies.

Extracellular matrix is a highly dynamic macromolecular network. Proteoglycans are major components of extracellular matrix playing key roles in its structural organization and cell signaling contributing to the control of numerous normal and pathological processes. As multifunctional molecules, proteoglycans participate in various cell functions during morphogenesis, wound healing, inflammation and tumorigenesis. Their interactions with matrix effectors, cell surface receptors and enzymes enable them with unique properties. In malignancy, extensive remodeling of tumor stroma is associated with marked alterations in proteoglycans' expression and structural variability. Proteoglycans exert diverse functions in tumor stroma in a cell-specific and context-specific manner and they mainly contribute to the formation of a permissive provisional matrix for tumor growth affecting tissue organization, cell-cell and cell-matrix interactions and tumor cell signaling. Proteoglycans also modulate cancer cell phenotype and properties, the development of drug resistance and tumor stroma angiogenesis. This review summarizes the proteoglycans remodeling and their novel biological roles in malignancies with particular emphasis to the underlying molecular mechanisms.

The overall structure and architecture of the extracellular matrix undergo dramatic alterations in composition, form, and functionality over time. The stochasticity begins during development, essential for maintaining organismal homeostasis and is heavily implicated in many pathobiological states including fibrosis and cancer. Modeling and remodeling of the matrix is driven by the local cellular milieu and secreted and cell-associated components in a framework of dynamic reciprocity. This collection of expertly-written reviews aims to relay state-of-the-art information concerning the mechanisms of matrix modeling and remodeling in physiological development and disease.

Obesity is a remarkably important factor for breast carcinogenesis and aggressiveness. The implication of increased BMI in triple negative breast cancer (TNBC) development is also well established. A malignancy-promoting role of the adipose tissue has been supposed, where the adipocytes that constitute the majority of stromal cells release pro-inflammatory cytokines and growth factors. Alterations in adipokines and their receptors play significant roles in breast cancer initiation, progression, metastasis, and drug response. Classic adipokines, such as leptin, adiponectin, and resistin, have been extensively studied in breast cancer and connected with breast cancer risk and progression. Notably, new molecules are constantly being discovered and the list is continuously growing. Additionally, substantial progress has been made concerning their differential expression in association with clinical and pathological parameters of tumors and the prognostic and predictive value of their dysregulation in breast cancer carcinogenesis. However, evidence regarding the mechanisms by which adipose tissue is involved in the development of TNBC is lacking. In the present article we comment on current data on the suggested involvement of these mediators in breast cancer development and progression, with particular emphasis on TNBC, to draw attention to the design of novel targeted therapies and biomarkers.

Simple Summary Proteolytic enzymes, such as matrix metalloproteinases, plasminogen activators and cathepsins, as well as non-proteolytic enzymatic partners, such as heparanase and hyaluron-idases, play key roles in the propagation and metastatic potential of cancer cells. This article aims to revisit the main functions of major matrix remodeling molecules and their effects in cancer meta-static potential. Moreover, the epigenetic regulation mechanisms of these molecules are discussed, in addition to recent advances in their pharmacological targeting. Finally, novel data from ongoing clinical trials on several cancer types are also provided. Overall, this review delves into the im-portance of matrix remodeling partners in cancer metastasis and explores their targeting as a promising therapeutic option for cancer management. Abstract Tissue functionality and integrity demand continuous changes in distribution of major components in the extracellular matrices (ECMs) under normal conditions aiming tissue homeostasis. Major matrix degrading proteolytic enzymes are matrix metalloproteinases (MMPs), plasminogen activators, atypical proteases such as intracellular cathepsins and glycolytic enzymes including heparanase and hyaluronidases. Matrix proteases evoke epithelial-to-mesenchymal transition (EMT) and regulate ECM turnover under normal procedures as well as cancer cell phenotype, motility, invasion, autophagy, angiogenesis and exosome formation through vital signaling cascades. ECM remodeling is also achieved by glycolytic enzymes that are essential for cancer cell survival, proliferation and tumor progression. In this article, the types of major matrix remodeling enzymes, their effects in cancer initiation, propagation and progression as well as their pharmacological targeting and ongoing clinical trials are presented and critically discussed.

Simple Summary Current data suggest that epigenetic alterations are involved in the initiation and subclonal evolution of breast cancer. During cancer progression, the extracellular matrix undergoes significant structural alterations and the epithelial–mesenchymal transition is induced. These events among other processes are closely related with the epigenetic modifiers. Triple-negative breast cancer is an aggressive molecular subgroup characterized by genomic complexity and limited therapeutic options. Recent knowledge indicates that matrix alterations in triple-negative cancer cells are epigenetically regulated and that matrix-associated events collectively increase tumor cell survival and resistance to therapy. Thus, approaches for targeting tumor microenvironment and epigenetic pathways, alone or in combination, represent potential therapeutic strategies. The present article aims to highlight the most important epigenetic regulation of extracellular matrix alterations in triple-negative breast cancer in an effort to give perspectives for future design and implementation of diagnostic and therapeutic suggestions. Abstract Triple-negative breast cancer (TNBC) is an aggressive subgroup of breast cancer characterized by genomic complexity and therapeutic options limited to only standard chemotherapy. Although it has been suggested that stratifying TNBC patients by pathway-specific molecular alterations may predict benefit from specific therapeutic agents, application in routine clinical practice has not yet been established. There is a growing body of the literature supporting that epigenetic modifications comprised by DNA methylation, chromatin remodeling and non-coding RNAs play a fundamental role in TNBC pathogenesis. Extracellular matrix (ECM) is a highly dynamic 3D network of macromolecules with structural and cellular regulatory roles. Alterations in the expression of ECM components result in uncontrolled matrix remodeling, thus affecting its ability to regulate vital functions of cancer cells, including proliferation, migration, adhesion, invasion and epithelial-to-mesenchymal transition (EMT). Recent molecular data highlight the major role of tumor microenvironment and ECM alterations in TNBC and approaches for targeting tumor microenvironment have recently been recognized as potential therapeutic strategies. Notably, many of the ECM/EMT modifications in cancer are largely driven by epigenetic events, highlighting the pleiotropic effects of the epigenetic network in TNBC. This article presents and critically discusses the current knowledge on the epigenetic alterations correlated with TNBC pathogenesis, with emphasis on those associated with ECM/EMT modifications, their prognostic and predictive value and their use as therapeutic targets.

Simple Summary Hyaluronan is a main glycosaminoglycan in extracellular matrix with an important role in breast cancer progression. Alterations in its synthesis and size may affect tu-mour growth and metastasis. Communication between stromal and breast cancer cells consists of the secretion of factors that provoke a series of cell signalling that influence cell fate and tis-sue microenvironment, by favouring tumour cell survival and motility. Here, we present the c10orf118 protein expressed in high amounts by breast tumour cells as a new regulator in hya-luronan synthesis. This protein is found both in Golgi and secreted in the extracellular matrix, whereas its role is still unknown. The secreted c10orf118 is found to induce hyaluronan synthase 2 in normal fibroblasts. Importantly, high expression of c10orf118 is positively correlated to pa-tient’s survival and to a low metastasis. Abstract Interaction between cancer cells and their microenvironment is central in defining the fate of cancer development. Tumour cells secrete signals (cytokines, chemokines, growth factors) that modify the surrounding area, while the niche supplies structures and activities necessary for tumour maintenance and growth. Hyaluronan (HA) is a glycosaminoglycan that constitute cancer cell niche and is known to influence tumour functions such as proliferation, migration and neoangiogenesis. The knowledge of the factors regulating HA synthesis and size is crucial in understanding the mechanisms sustaining tumour development. Here we show that a yet uncharacterized protein secreted by breast tumour cell lines, named c10orf118 (accession number NM_018017 in NCBI/BLAST, and Q7z3E2 according to the Uniprot identifier), with a predicted length of 898 amino acids, can induce the secretion of HA by stromal fibroblasts through the up-regulation of the hyaluronan synthase 2 gene (HAS2). Intracellularly, this protein is localized in the Golgi apparatus with a possible role in vesicle maturation and transport. The expression of c10orf118 was verified in breast cancer patient specimens and was found to be associated with the presence of estrogen receptor that characterizes a good patient survival. We suggest c10orf118 as a new player that influences the HA amount in breast cancer microenvironment and is associated with low aggressiveness of cancer.

Triple-negative breast cancer (TNBC) is defined by aggressive behavior, limited response to chemotherapy and lower overall survival rates. The increased metastatic potential of TNBC is a combined result of extensive extracellular matrix (ECM) remodeling that leads to cytoskeleton rearrangement and activation of epithelial-to-mesenchymal transition (EMT). The overexpression of epidermal growth factor receptor (EGFR) in TNBC tumors has been linked to induced expression of EMT-related molecules. EMT activation has often been associated with increased metastasis and stemness. Recently, we described the crucial role of EGFR/estrogen receptor beta (ERβ) interplay in the regulation of invasion and cell-matrix interactions. In this study, we report on the EGFR-ERβ functional relationship in connection to the aggressiveness and cancer stem cell (CSC)-like characteristics of TNBC cells. ERβ-suppressed and MDA-MB-231 cells were subjected to downstream EGFR inhibition and/or estradiol stimulation to assess alterations in functional parameters as well as in morphological characteristics, studied by scanning electron, atomic force, and immunofluorescence microscopies. Moreover, the expression and localization of key EMT and CSC-related markers were also evaluated by real-time qPCR, immunofluorescence microscopy, and flow cytometry. EGFR inhibition resulted in an overall suppression of aggressive functional characteristics, which occurred in an ERβ-mediated manner. These changes could be attributed to a reduction, at the molecular level, of EMT and stemness-linked markers, most notably reduced expression of Notch signaling constituents and the cell surface proteoglycan, syndecan-1. Collectively, our study highlights the importance of EGFR signaling as a key effector of aggressiveness, EMT, and stemness in an ERβ-dependent way in TNBC.

Βradykinin stimulation of B2 receptor is known to activate the oncogenic ERK pathway and overexpression of bradykinin receptors B1 and B2 has been reported to occur in glioma, colorectal and cervical cancers. B1R and B2R antagonists have been shown to reverse tumor proliferation and invasion. Paradoxically, B1R and B2R agonism has also been reported to elicit antiproliferative benefits. In order to complement the data accumulated to date with the natural substrate bradykinin and peptidic B2R antagonists, we decided to examine for the first time the response elicited by B2R stimulation in breast cancer lines with a non-peptidic small molecule B2R agonist. We synthesized and assessed the highly selective and potent B2R partial agonist FR-190997 in MCF-7 and MDA-MBA-231 breast cancer lines and found it possessed significant antiproliferative activity (IC50 2.14 and 0.08 μΜ, respectively). The modular nature of FR-190997 allowed us to conduct a focused SAR study and discover compound 10 which exhibits subnanomolar antiproliferative activity (IC 50 0.06 nΜ) in the TNBC MDA-MBA-231 cell line. This performance surpasses, in most cases by several orders of magnitude, those of established anticancer agents and FDA-approved breast cancer drugs. In line with the established literature we suggest that this remarkable activity precipitates from a dual mode of action involving agonist-induced receptor internalization/degradation combined with sequestration of functional intracellular B2 receptors and inhibition of the associated endosomal signaling. The latter mode may be realized by appropriate ligands regardless of B2R agonist/antagonist designation which only relates to membrane residing GCPRs. Under this prism the controversy over the antiproliferative effects of B2 agonists and antagonists is potentially neutralized.

The oncogenic role of hyaluronan in several aspects of tumor biology has been well established. Recent studies by us and others suggest that inhibition of hyaluronan synthesis could represent an emerging therapeutic approach with significant clinical relevance in controlling different breast cancer subtypes, including triple-negative breast cancer. Epidemiological and preclinical studies have revealed the therapeutic potential of aspirin (acetyl salicylate), a classical anti-inflammatory drug, in patients with cancer. However, the underlying molecular mechanisms remain unknown. The present study demonstrates that salicylate, a break down product of aspirin in vivo, alters the organization of hyaluronan matrices by affecting the expression levels of hyaluronan synthesizing (HAS1, 2, 3) and degrading (HYAL-1, -2) enzymes, and that of hyaluronan receptor CD44. In particular, salicylate was found to potently activate AMPK, a kinase known to inhibit HAS2 activity, and caused a dose-dependent decrease of cell associated (intracellular and membrane-bound) as well as secreted hyaluronan, followed by the down-regulation of HAS2 and the induction of HYAL-2 and CD44 in metastatic breast cancer cells. These salicylate-mediated effects were associated with the redistribution of CD44 and actin cytoskeleton that resulted in a less motile cell phenotype. Interestingly, salicylate inhibited metastatic breast cancer cell proliferation and growth by inducing cell growth arrest without signs of apoptosis as evidenced by the substantial decrease of cyclin D1 protein and the absence of cleaved caspase-3, respectively. Collectively, our study offers a possible direction for the development of new matrix-based targeted treatments of metastatic breast cancer subtypes via inhibition of hyaluronan, a pro-angiogenic, pro-inflammatory and tumor promoting glycosaminoglycan., Highlights • HAS2-synthesized hyaluronan promotes breast cancer cell metastatic potential. • Salicylate activates AMPK, down-regulates HAS2 and inhibits hyaluronan biosynthesis. • Salicylate alters the organization of cell-associated hyaluronan matrices. • Salicylate suppresses the metastatic potential of breast cancer cells. • We provide new mechanistic insights regarding the anticancer effects of aspirin.

Despite the functional role of serglycin as an intracellular proteoglycan, a variety of malignant cells depends on its expression and constitutive secretion to advance their aggressive behavior. Serglycin arose to be a biomarker for glioblastoma, which is the deadliest and most treatment-resistant form of brain tumor, but its role in this disease is not fully elucidated. In our study we suppressed the endogenous levels of serglycin in LN-18 glioblastoma cells to decipher its involvement in their malignant phenotype. Serglycin suppressed LN-18 (LN-18shSRGN) glioblastoma cells underwent astrocytic differentiation characterized by induced expression of GFAP, SPARCL-1 and SNAIL, with simultaneous loss of their stemness capacity. In particular, LN-18shSRGN cells presented decreased expression of glioma stem cell-related genes and ALDH1 activity, accompanied by reduced colony formation ability. Moreover, the suppression of serglycin in LN-18shSRGN cells retarded the proliferative and migratory rate, the invasive potential in vitro and the tumor burden in vivo. The lack of serglycin in LN-18shSRGN cells was followed by G2 arrest, with subsequent reduction of the expression of cell-cycle regulators. LN-18shSRGN cells also exhibited impaired expression and activity of proteolytic enzymes such as MMPs, TIMPs and uPA, both in vitro and in vivo. Moreover, suppression of serglycin in LN-18shSRGN cells eliminated the activation of pro-tumorigenic signal transduction. Of note, LN-18shSRGN cells displayed lower expression and secretion levels of IL-6, IL-8 and CXCR-2. Concomitant, serglycin suppressed LN-18shSRGN cells demonstrated repressed phosphorylation of ERK1/2, p38, SRC and STAT-3, which together with PI3K/AKT and IL-8/CXCR-2 signaling control LN-18 glioblastoma cell aggressiveness. Collectively, the absence of serglycin favors an astrocytic fate switch and a less aggressive phenotype, characterized by loss of pluripotency, block of the cell cycle, reduced ability for ECM proteolysis and pro-tumorigenic signaling attenuation., Highlights • Knockdown (KD) of serglycin results in glioblastoma cell differentiation and decreased stemness. • KD of serglycin diminishes the proteolytic and inflammatory potential of glioblastoma cells. • KD of serglycin represses the glioblastoma aggressiveness via attenuation of pro-tumorigenic signaling cascades.

Cancer cell invasion into the surrounding extracellular matrix (ECM) takes place when cell-cell junctions are disrupted upon epithelial-to-mesenchymal transition (EMT). Both cancer cell-stroma and cell-cell crosstalk are essential to support the continuous tumor invasion. Cancer cells release microvesicles and exosomes containing bioactive molecules and signal peptides, which are recruited by neighboring cells or carried to distant sites, thus supporting intercellular communication and cargo transfer. Besides this indirect communication mode, cancer cells can develop cytoplasmic intercellular protrusions or tunneling nanotubes (TNTs), which allow the direct communication and molecular exchange between connected distinct cells. Using scanning electron microscopy (SEM) we show for the first time that MDA-MB-231 (high metastatic potential) and shERβ MDA-MB-231 (low metastatic potential) breast cancer cells cultured on fibronectin and collagen type I or 17β-estradiol (E2) develop TNTs and very long flexible filopodia. Interestingly, the less aggressive shERβ MDA-MB-231 cells treated with E2 in 3D collagen matrix showed the highest development of TNTs and filopodia. TNTs were often associated to adhering exosomes and microvesicles surfing from one cell to another, but no filopodia exhibited vesicle-like cytoplasmic structures on their surface. Moreover, E2 affected the expression of matrix macromolecules and cell effectors mostly in the presence of ERβ. Our novel data highlights the significance of matrix substrates and the presence of E2 and ERβ in the formation of cellular protrusion and the production of surface structures, defining novel phenotypes that unravel nodal reports for breast cancer progression., Highlights • 3D cultures of breast cancer cells in different substrates develop long filopodia and TNTs. • Larger TNTs are composed of several TNTs grouped together in a spiral array. • TNTs are associated with adhering exosomes and microvesicles. • E2 enhances the formation of TNTs in shERβ MDA-MB-231 cells in a collagen microenvironment. • E2 affects the expression of matrix effectors in MDA-MB-231 cells but not in shERβ MDA-MB-231 cells.

Breast cancer is the most common malignancy among women worldwide. The role of epidermal growth factor receptor (EGFR) in many epithelial malignancies has been established, since it is dysregulated, overexpressed or mutated. Its overexpression has been associated with increased aggressiveness and metastatic potential in breast cancer. The well-established interplay between EGFR signaling pathway and estrogen receptors (ERs) as well as major extracellular matrix (ECM) mediators is crucial for regulating basic functional properties of breast cancer cells, including migration, proliferation, adhesion and invasion. EGFR activation leads to endocytosis of the receptor with implications in the regulation of downstream signaling effectors, the modulation of autophagy and cell survival. Therefore, EGFR is considered as a promising therapeutic target in breast cancer. Several anti-EGFR therapies (i.e. monoclonal antibodies and tyrosine kinase inhibitors) have been evaluated both in vitro and in vivo, making their way to clinical trials. However, the response rates of anti-EGFR therapies in the clinical trials is low mainly due to chemoresistance. Novel drug design, phytochemicals and microRNAs (miRNAs) are assessed as new therapeutic approaches against EGFR. The main goal of this review is to highlight the importance of targeting EGFR signaling pathway in terms of its crosstalk with ERs, the involvement of ECM effectors and epigenetics. Moreover, recent insights into the design of specialized delivery systems contributing in the development of novel diagnostic and therapeutic approaches in breast cancer are addressed.

Progressive loss of organ function in most organs is associated with fibrosis, a tissue state associated with abnormal matrix buildup. If highly progressive, the fibrotic process eventually leads to organ failure and death. Fibrosis is a basic connective tissue lesion defined by the increase in the amount of fibrillar extracellular matrix (ECM) components in a tissue or organ. In addition, intrinsic changes in important structural cells can induce the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix-producing myofibroblasts. ECM enzymes belonging to the family of matrix metalloproteinases (MMPs) and lysyl oxidases (LOXs) play a crucial role in ECM remodeling and regeneration. MMPs have a catalytic role in degradation of ECM, whereas LOX/LOXLs mediate ECM, especially collagen, cross-linking and stiffening. Importantly, enzymes from both families are elevated during the fibrotic response to tissue injury and its resolution. Yet, the apparent molecular competition or antagonistic activities of these enzyme families during the various stages of fibrosis is often overlooked. In this review, we discuss the diverse roles of MMPs and LOX/LOXL2 in chronic organ fibrosis. Finally, we review contemporary therapeutic strategies for fibrosis treatment, based on neutralization of MMP and LOX activity, as well as the development of novel drug delivery approaches.

Breast cancer accounts for almost one in four cancer diagnoses in women. Studies in breast cancer patients have identified several molecular markers, indicators of aggressiveness, which help toward more individual therapeutic approaches. In triple-negative breast cancer (TNBC), epidermal growth factor receptor (EGFR) overexpression is associated with increased metastatic potential and worst survival rates. Specifically, abnormal EGFR activation leads to altered matrix metalloproteinases&rsquo, (MMPs) expression and, hence, extracellular matrix (ECM) degradation, resulting in induced migration and invasion. The use of matrix substrates for cell culture gives the opportunity to mimic the natural growth conditions of the cells and their microenvironment, as well as cell&ndash, cell and cell&ndash, matrix interactions. The aim of this study was to evaluate the impact of EGFR inhibition, estrogen receptor beta (ER&beta, ) and different matrix substrates [type I collagen and fibronectin (FN)] on the functional properties, expression of MMPs and cell morphology of ER&beta, positive TNBC cells and shER&beta, ones. Our results highlight EGFR as a crucial regulator of the expression and activity levels of MMPs, while ER&beta, emerges as a mediator of MMP7 and MT1-MMP expression. In addition, the EGFR/ER&beta, axis impacts the adhesion and invasion potential of breast cancer cells on collagen type I. Images obtained by scanning electron microscope (SEM) from cultures on the different matrix substrates revealed novel observations regarding various structures of breast cancer cells (filopodia, extravesicles, tunneling nanotubes, etc.). Moreover, the significant contribution of EGFR and ER&beta, in the morphological characteristics of these cells is also demonstrated, hence highlighting the possibility of dual pharmacological targeting.

In this data article, the potential role of p53 tumor suppressor gene (p53) on the attachment ability of MCF-7 breast cancer cells was investigated. In our main article, “IGF-I/ EGF and E2 signaling crosstalk through IGF-IR conduit point affect breast cancer cell adhesion” (K. Voudouri, D. Nikitovic, A. Berdiaki, D. Kletsas, N.K. Karamanos, G.N. Tzanakakis, 2016) [1], we describe the key role of IGF-IR in breast cancer cell adhesion onto fibronectin (FN). p53 tumor suppressor gene is a principal regulator of cancer cell proliferation. Various data have demonstrated an association between p53 and IGF-IR actions on cell growth through its’ putative regulation of IGF-IR expression. According to our performed experiments, p53 does not modify IGF-IR expression and does not affect basal MCF-7 cells adhesion onto FN. Moreover, technical details about the performance of adhesion assay onto the FN substrate were provided.

Epidermal growth factor (EGF)/insulin like growth factor-I (IGF-I) and Estradiol (E2) can regulate biological functions of hormone-dependent tumor cells. Fibronectin (FN) is a large glycoprotein abundantly expressed in breast cancer extracellular matrices (ECMs) postulated to be a marker of aggressiveness during cancer pathogenesis. In this study we demonstrate that IGF-I/EGF as well E2 strongly increase the adhesion of the MCF-7 breast cancer cells onto FN. Moreover, IGF-IR is necessary for the IGF-I-/EGF- and E2-induced cell adhesion. Erk1/2 inhibition abolished the IGF-I-/EGF-/E2-induced MCF-7 cell adhesion, suggesting that this regulation of cell adhesion is perpetrated through Erk1/2 downstream signaling. Erk1/2 signaling was shown to modulate IGF-IR status as its' inhibition attenuates both IGF-IR expression and activation. Notably, EGF and E2 enhanced the mRNA as well as protein expression of IGF-IR in MCF-7 cells. Confocal microscopy demonstrated that treatment of MCF-7 cells with IGF-I or EGF induced actin reorganization, which was attenuated with Erk1/2 inhibition. Interestingly, IGF-I treatment induced a co-localization of IGF-IR and FAK, which was evident mostly at the cell membranes of MCF-7 cells. In summary, IGF-IR was shown to be a convergence point for the IGF-/EGF- and E2-dependent MCF-7 cell adhesion onto FN.

The extracellular matrix (ECM) is a multifunctional 3D network of interconnected macromolecules that mediate cellular responses in normal and pathological conditions, including wound healing, tissue homeostasis, skeletal and cardiovascular disease, cancer and drug resistance. The potential of targeting ECM components, such as proteoglycans and glycosaminoglycans, matrix-degrading enzymes and miRNAs will serve as a novel tool for innovative diagnostic methods and therapeutic strategies. With this Special Issue on Extracellular Matrix in Health and Disease, The FEBS Journal offers an updated overview of the functional properties and biological roles of several ECM components, highlighting the significance of ECM targeting in disease management.