Impact of Extracellular Matrix on Cellular Behavior: A Source of Molecular Targets in Disease

Fibrosis is a debilitating condition that can lead to impairment of the affected organ’s function. Excessive deposition of extracellular matrix (ECM) molecules is characteristic of most fibrotic tissues. Fibroblasts activated by cytokines or growth factors differentiate into myofibroblasts that drive fibrosis by depositing ECM molecules, such as collagen, fibronectin, and connective tissue growth factor. Transforming growth factor- 𝛽 (TGF- 𝛽 ) is one of the major profibrotic cytokines which promotes fibrosis by signaling abnormal ECM regulation. Hyaluronan (HA) is a major ECM glycosaminoglycan that is regulated by TGF- 𝛽 and whose role in fibrosis is emerging. Aside from its role as a hydrating, space filling polymer, HA regulates different cellular functions and is known to have a role in wound healing and inflammation. Importantly, HA deposition is increased in multiple fibrotic diseases. In this review we highlight studies that link HA to fibrosis and discuss what is known about the role of HA, its receptors, and its anabolic and catabolic enzymes in different fibrotic diseases. In the present pilot study, we examined the presence of serglycin in lung, breast, prostate, and colon cancer and evaluated its expression in cell lines and tissues. We found that serglycin was expressed and constitutively secreted in culture medium in high levels in more aggressive cancer cells. It is worth noticing that aggressive cancer cells that harbor KRAS or EGFR mutations secreted serglycin constitutively in elevated levels. Furthermore, we detected the transcription of an alternative splice variant of serglycin lacking exon 2 in specific cell lines. In a limited number of tissue samples analyzed, serglycin was detected in normal epithelium but was also expressed in higher levels in advanced grade tumors as shown by immunohistochemistry. Serglycin staining was diffuse, granular, and mainly cytoplasmic. In some cancer cells serglycin also exhibited membrane and/or nuclear immunolocalization. Interestingly, the stromal cells of the reactive tumor stroma were positive for serglycin, suggesting an enhanced biosynthesis for this proteoglycan in activated tumor microenvironment. Our study investigated for first time the distribution of serglycin in normal epithelial and cancerous lesions in most common cancer types. The elevated levels of serglycin in aggressive cancer and stromal cells may suggest a key role for serglycin in disease progression. Intervertebral disc (IVD) degeneration is strongly associated with low back pain, a major cause of disability worldwide. An in-depth understanding of IVD cell physiology is required for the design of novel regenerative therapies. Accordingly, aim of this work was the study of IVD cell responses to mitogenic growth factors in a three-dimensional (3D) organotypic milieu, comprising characteristic molecules of IVD’s extracellular matrix. In particular, annulus fibrosus (AF) cells were cultured inside collagen type-I gels, while nucleus pulposus (NP) cells in chondroitin sulfate A (CSA) supplemented collagen gels, and the effects of Platelet-Derived Growth Factor (PDGF), basic Fibroblast Growth Factor (bFGF), and Insulin-Like Growth Factor-I (IGF-I) were assessed. All three growth factors stimulated DNA synthesis in both AF and NP 3D cell cultures, with potencies similar to those observed previously in monolayers. CSA supplementation inhibited basal DNA synthesis rates, without affecting the response to growth factors. ERK and Akt were found to be phosphorylated following growth factor stimulation. Blockade of these two signaling pathways using pharmacologic inhibitors significantly, though not completely, inhibited growth factor-induced DNA synthesis. The proposed culture systems may prove useful for further in vitro studies aiming at future interventions for IVD regeneration. Glycosaminoglycans, including chondroitin, dermatan, and heparan sulfate, have various roles in a wide range of biological events such as cell signaling, cell proliferation, tissue morphogenesis, and interactions with various growth factors. Their polysaccharides covalently attach to the serine residues on specific core proteins through the common linker region tetrasaccharide, -xylose-galactose-galactose-glucuronic acid, which is produced through the stepwise addition of respective monosaccharides by four distinctglycosyltransferases.Mutationsinthehumangenesencodingtheglycosyltransferasesresponsibleforthebiosynthesisofthelinkerregiontetrasaccharidecauseanumberofgeneticdisorders,calledglycosaminoglycanlinkeropathies,includingDesbuquoisdysplasiatype2,spondyloepimetaphysealdysplasia,Ehlers-Danlossyndrome,andLarsensyndrome.Thisreviewfocusedonrecentstudiesongeneticdiseasescausedbydefectsinthebiosynthesisofthecommonlinkerregiontetrasaccharide. Most of the cytotoxic chemotherapeutic agents have poor aqueous solubility. These molecules are associated with poor physicochemical and biopharmaceutical properties, which makes the formulation difficult. An important approach in this regard is the use of combination of cyclodextrin and nanotechnology in delivery system. This paper provides an overview of limitations associated with anticancer drugs, their complexation with cyclodextrins, loading/encapsulating the complexed drugs into carriers, and various approaches used for the delivery. The present review article aims to assess the utility of cyclodextrin-based carriers like liposomes, niosomes, nanoparticles, micelles, millirods, and siRNA for delivery of antineoplastic agents. These systems based on cyclodextrin complexation and nanotechnology will camouflage the undesirable properties of drug and lead to synergistic or additive effect. Cyclodextrin-based nanotechnology seems to provide better therapeutic effect and sustain long life of healthy and recovered cells. Still, considerable study on delivery system and administration routes of cyclodextrin-based carriers is necessary with respect to their pharmacokinetics and toxicology to substantiate their safety and efficiency. In future, it would be possible to resolve the conventional and current issues associated with the development and commercialization of antineoplastic agents. The metastatic disease is one of the main consequences of tumor progression, being responsible for most cancer-related deaths worldwide. This review intends to present and discuss data on the relationship between integrins and heparan sulfate proteoglycans in health and cancer progression. Integrins are a family of cell surface transmembrane receptors, responsible for cell-matrix and cell-cell adhesion. Integrins’ main functions include cell adhesion, migration, and survival. Heparan sulfate proteoglycans (HSPGs) are cell surface molecules that play important roles as cell receptors, cofactors, and overall direct or indirect contributors to cell organization. Both molecules can act in conjunction to modulate cell behavior and affect malignancy. In this review, we will discuss the different contexts in which various integrins, such as 𝛼 5, 𝛼 V, 𝛽 1, and 𝛽 3, interact with HSPGs species, such as syndecans and perlecans, affecting tissue homeostasis.

In the last few decades, outstanding strides have been made on understanding the impact of extracellular matrices (ECMs) on cellular behavior in health and disease. It is now clear that ECMs are not inactive space-filling materials but, in contrast, apart from their structural roles they interact with cells and generate signals to control a multitude of vital cellular functions. Currently, there are strong indications that ECMs could potentially play a groundbreaking role in drug discovery since they comprise an invaluable source of multiple molecular targets. The established key roles of specific ECM effectors, such as proteoglycans, hyaluronan (HA), biosynthetic enzymes, cytokines, and growth factors, in the development and progression of several diseases suggest that ECMs hold a great potential in driving the design and development of novel disease targeting tools.
The focus of this special issue is to highlight the role and impact of specific ECM effectors on cellular behavior as well as their potential targeting that could advance the treatment of various diseases, such as skeletal and skin disorders, fibrosis, and cancer. It consists of two original research papers and four review articles covering a broad range of topics.
S. Albeiroti et al. in their paper entitled "Hyaluronan's Role in Fibrosis: A Pathogenic Factor or a Passive Player?" point out critical parameters that link HA to fibrosis and discuss the role of HA as well as its cellular receptors and HA anabolic/catabolic enzymes in different fibrotic diseases. The presented data suggest that HA and its regulatory pathways potentially represent novel targets for antifibrotic therapies.
A. Korpetinou et al. in their paper entitled "Increased Expression of Serglycin in Specific Carcinomas and Aggressive Cancer Cell Lines" evaluate the expression of the proteoglycan serglycin in several cancer cell lines and tissues and find that serglycin is expressed at high levels in more aggressive cancers. This experimental study suggests that the overexpression of serglycin by cancer and stromal cells may augment the expression of inflammatory mediators and proteases affecting the behavior of both stromal and cancer cells and providing a novel molecular target in aggressive cancers.
M. A. Soares et al. in their article entitled "Heparan Sulfate Proteoglycans May Promote or Inhibit Cancer Progression by Interacting with Integrins and Affecting Cell Migration" discuss the role of the interplay between integrins and heparan sulfate proteoglycans (such as syndecans and basement membrane proteoglycans) in health and cancer progression. This review highlights the need of further analysis and deeper understanding of the functions of integrin-heparan sulfate proteoglycans interactions in cancers in order to develop novel treatments based on analog molecules or prognostic factors that would be beneficial to patients.

BioMed Research International
The review by S. Mizumoto et al. entitled "Mutations in Biosynthetic Enzymes for the Protein Linker Region of Chondroitin/Dermatan/Heparan Sulfate Cause Skeletal and Skin Dysplasias" focuses on the recent advances in the study of cartilage and connective tissue disorders caused by defects in the biosynthesis of the common glycosaminoglycan-protein linker region tetrasaccharide in proteoglycans, called glycosaminoglycan linkeropathies. The authors describe the mutations of the glycosyltransferases responsible for the biosynthesis of the linker region and suggest that a deeper understanding of the molecular pathogeneses of glycosaminoglycan linkeropathies may lead to the design of new therapeutics for these diseases.
The review by B. Gidwani and A. Vyas entitled "A Comprehensive Review on Cyclodextrin-Based Carriers for Delivery of Chemotherapeutic Cytotoxic Anticancer Drugs" summarizes the advantages of the cyclodextrin-based nanotechnology for effective delivery of anticancer drugs aiming at minimizing off-target effects observed with other drug delivery systems.
H. Pratsinis and D. Kletsas in their paper entitled "Organotypic Cultures of Intervertebral Disc Cells: Responses to Growth Factors and Signaling Pathways Involved" use a 3D culture system in order to study intervertebral disc (IVD) degeneration. They investigate the response of IVD cells in 3D organotypic gels to growth factors as well as the signaling pathways involved and propose that these culture systems may be useful for the design of novel regenerative therapies of degenerated IVD.
In conclusion, several emerging issues related to the critical roles of ECMs molecules in the regulation of cell behavior are presented in this special issue. We hope that this issue will add to the rapidly expanding field of matrix pathobiology underlying specific diseases and will help in the development of matrix-based therapeutic strategies in the near future.