36 results on '"Theocharis AD"'
Search Results
2. The Expression of Serglycin Is Required for Active Transforming Growth Factor β Receptor I Tumorigenic Signaling in Glioblastoma Cells and Paracrine Activation of Stromal Fibroblasts via CXCR-2.
- Author
-
Manou D, Golfinopoulou MA, Alharbi SND, Alghamdi HA, Alzahrani FM, and Theocharis AD
- Subjects
- Humans, Cell Line, Tumor, Cell Proliferation genetics, Paracrine Communication, Receptor, Transforming Growth Factor-beta Type I metabolism, Receptor, Transforming Growth Factor-beta Type I genetics, Brain Neoplasms metabolism, Brain Neoplasms pathology, Brain Neoplasms genetics, Gene Expression Regulation, Neoplastic, Stromal Cells metabolism, Stromal Cells pathology, Carcinogenesis genetics, Carcinogenesis metabolism, Carcinogenesis pathology, Glioblastoma metabolism, Glioblastoma pathology, Glioblastoma genetics, Receptors, Interleukin-8B metabolism, Receptors, Interleukin-8B genetics, Signal Transduction, Proteoglycans metabolism, Proteoglycans genetics, Fibroblasts metabolism, Fibroblasts pathology, Vesicular Transport Proteins metabolism, Vesicular Transport Proteins genetics
- Abstract
Serglycin (SRGN) is a pro-tumorigenic proteoglycan expressed and secreted by various aggressive tumors including glioblastoma (GBM). In our study, we investigated the interplay and biological outcomes of SRGN with TGFβRI, CXCR-2 and inflammatory mediators in GBM cells and fibroblasts. SRGN overexpression is associated with poor survival in GBM patients. High SRGN levels also exhibit a positive correlation with increased levels of various inflammatory mediators including members of TGFβ signaling pathway, cytokines and receptors including CXCR-2 and proteolytic enzymes in GBM patients. SRGN-suppressed GBM cells show decreased expressions of TGFβRI associated with lower responsiveness to the manipulation of TGFβ/TGFβRI pathway and the regulation of pro-tumorigenic properties. Active TGFβRI signaling in control GBM cells promotes their proliferation, invasion, proteolytic and inflammatory potential. Fibroblasts cultured with culture media derived by control SRGN-expressing GBM cells exhibit increased proliferation, migration and overexpression of cytokines and proteolytic enzymes including CXCL-1, IL-8, IL-6, IL-1β, CCL-20, CCL-2, and MMP-9. Culture media derived by SRGN-suppressed GBM cells fail to induce the above properties to fibroblasts. Importantly, the activation of fibroblasts by GBM cells not only relies on the expression of SRGN in GBM cells but also on active CXCR-2 signaling both in GBM cells and fibroblasts.
- Published
- 2024
- Full Text
- View/download PDF
3. Resistance to hormone therapy in breast cancer cells promotes autophagy and EGFR signaling pathway.
- Author
-
Siatis KE, Giannopoulou E, Manou D, Sarantis P, Karamouzis MV, Raftopoulou S, Fasseas K, Alzahrani FM, Kalofonos HP, and Theocharis AD
- Subjects
- Humans, Female, Fulvestrant pharmacology, Phosphatidylinositol 3-Kinases metabolism, Cell Line, Tumor, Signal Transduction, Tamoxifen pharmacology, Tamoxifen therapeutic use, Cell Proliferation, MCF-7 Cells, Autophagy, Drug Resistance, Neoplasm, ErbB Receptors metabolism, Breast Neoplasms drug therapy, Breast Neoplasms metabolism
- Abstract
Breast cancer is the leading cause of cancer deaths for women worldwide. Endocrine therapies represent the cornerstone for hormone-dependent breast cancer treatment. However, in many cases, endocrine resistance is induced with poor prognosis for patients. In the current study, we have developed MCF-7 cell lines resistant to fulvestrant (MCF-7Fulv) and tamoxifen (MCF-7Tam) aiming at investigating mechanisms underlying resistance. Both resistant cell lines exerted lower proliferation capacity in two-dimensional (2-D) cultures but retain estrogen receptor α (ERα) expression and proliferate independent of the presence of estrogens. The established cell lines tend to be more aggressive exhibiting advanced capacity to form colonies, increased expression of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and heterodimerization of ERBB family receptors and activation of EGFR downstream pathways like MEK/ERK1/2 and PI3K/AKT. Tyrosine kinase inhibitors tested against resistant MCF-7Fulv and MCF-7Tam cells showed moderate efficacy to inhibit cell proliferation, except for lapatinib, which concomitantly inhibits both EGFR and HER2 receptors and strongly reduced cell proliferation. Furthermore, increased autophagy was observed in resistant MCF-7Fulv and MCF-7Tam cells as shown by the presence of autophagosomes and increased Beclin-1 levels. The increased autophagy in resistant cells is not associated with increased apoptosis, suggesting a cytoprotective role for autophagy that may favor cells' survival and aggressiveness. Thus, by exploiting those underlying mechanisms, new targets could be established to overcome endocrine resistance. NEW & NOTEWORTHY The development of resistance to hormone therapy caused by both fulvestrant and tamoxifen promotes autophagy with concomitant apoptosis evasion, rendering cells capable of surviving and growing. The fact that resistance also triggers ERBB family signaling pathways, which are poorly inhibited by tyrosine kinase inhibitors might attribute to cells' aggressiveness. It is obvious that the development of endocrine therapy resistance involves a complex interplay between deregulated ERBB signaling and autophagy that may be considered in clinical practice.
- Published
- 2023
- Full Text
- View/download PDF
4. Proteoglycans Determine the Dynamic Landscape of EMT and Cancer Cell Stemness.
- Author
-
Karagiorgou Z, Fountas PN, Manou D, Knutsen E, and Theocharis AD
- Abstract
Proteoglycans (PGs) are pivotal components of extracellular matrices, involved in a variety of processes such as migration, invasion, morphogenesis, differentiation, drug resistance, and epithelial-to-mesenchymal transition (EMT). Cellular plasticity is a crucial intermediate phenotypic state acquired by cancer cells, which can modulate EMT and the generation of cancer stem cells (CSCs). PGs affect cell plasticity, stemness, and EMT, altering the cellular shape and functions. PGs control these functions, either by direct activation of signaling cascades, acting as co-receptors, or through regulation of the availability of biological compounds such as growth factors and cytokines. Differential expression of microRNAs is also associated with the expression of PGs and their interplay is implicated in the fine tuning of cancer cell phenotype and potential. This review summarizes the involvement of PGs in the regulation of EMT and stemness of cancer cells and highlights the molecular mechanisms.
- Published
- 2022
- Full Text
- View/download PDF
5. Synthesis and Antiproliferative Activity of Novel Dehydroabietic Acid-Chalcone Hybrids.
- Author
-
Grigoropoulou S, Manou D, Antoniou AI, Tsirogianni A, Siciliano C, Theocharis AD, and Athanassopoulos CM
- Subjects
- Abietanes, Cell Line, Tumor, Cell Proliferation, Drug Screening Assays, Antitumor, Estrogens pharmacology, Female, Fluorouracil pharmacology, Humans, Molecular Structure, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Chalcone pharmacology, Chalcones pharmacology
- Abstract
Dehydroabietic Acid (DHA, 1 ) derivatives are known for their antiproliferative properties, among others. In the context of this work, DHA was initially modified to two key intermediates bearing a C18 methyl ester, a phenol moiety at C12, and an acetyl or formyl group at C13 position. These derivatives allowed us to synthesize a series of DHA-chalcone hybrids, suitable for structure-activity relationship studies (SARS), following their condensation with a variety of aryl-aldehydes and methyl ketones. The antiproliferative evaluation of the synthesized DHA-chalcone hybrids against three breast cancer cell lines (the estrogen-dependent MCF-7 and the estrogen-independent MDA-MB-231 and Hs578T) showed that eight derivatives ( 33, 35, 37, 38, 39, 41, 43, 44 ) exhibit low micromolar activity levels (IC
50 2.21-11.5 μΜ/MCF-7). For instance, some of them showed better activity compared to the commercial anticancer drug 5-FU against MCF-7 cells ( 33, 41, 43, 44 ) and against MDA-MB231 ( 33 and 41 ). Hybrid 38 is a promising lead compound for the treatment of MCF-7 breast cancer, exhibiting comparable activity to 5-FU and being 12.9 times less toxic (SI = 22.7). Thus, our findings suggest that DHA-chalcone hybrids are drug candidates worth pursuing for further development in the search for novel breast cancer therapies.- Published
- 2022
- Full Text
- View/download PDF
6. Serglycin Is Involved in TGF-β Induced Epithelial-Mesenchymal Transition and Is Highly Expressed by Immune Cells in Breast Cancer Tissue.
- Author
-
Tellez-Gabriel M, Tekpli X, Reine TM, Hegge B, Nielsen SR, Chen M, Moi L, Normann LS, Busund LR, Calin GA, Mælandsmo GM, Perander M, Theocharis AD, Kolset SO, and Knutsen E
- Abstract
Serglycin is a proteoglycan highly expressed by immune cells, in which its functions are linked to storage, secretion, transport, and protection of chemokines, proteases, histamine, growth factors, and other bioactive molecules. In recent years, it has been demonstrated that serglycin is also expressed by several other cell types, such as endothelial cells, muscle cells, and multiple types of cancer cells. Here, we show that serglycin expression is upregulated in transforming growth factor beta (TGF-β) induced epithelial-mesenchymal transition (EMT). Functional studies provide evidence that serglycin plays an important role in the regulation of the transition between the epithelial and mesenchymal phenotypes, and it is a significant EMT marker gene. We further find that serglycin is more expressed by breast cancer cell lines with a mesenchymal phenotype as well as the basal-like subtype of breast cancers. By examining immune staining and single cell sequencing data of breast cancer tissue, we show that serglycin is highly expressed by infiltrating immune cells in breast tumor tissue., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with the author ADT., (Copyright © 2022 Tellez-Gabriel, Tekpli, Reine, Hegge, Nielsen, Chen, Moi, Normann, Busund, Calin, Mælandsmo, Perander, Theocharis, Kolset and Knutsen.)
- Published
- 2022
- Full Text
- View/download PDF
7. A guide to the composition and functions of the extracellular matrix.
- Author
-
Karamanos NK, Theocharis AD, Piperigkou Z, Manou D, Passi A, Skandalis SS, Vynios DH, Orian-Rousseau V, Ricard-Blum S, Schmelzer CEH, Duca L, Durbeej M, Afratis NA, Troeberg L, Franchi M, Masola V, and Onisto M
- Subjects
- Animals, Extracellular Matrix chemistry, Humans, Extracellular Matrix metabolism
- Abstract
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., (© 2021 Federation of European Biochemical Societies.)
- Published
- 2021
- Full Text
- View/download PDF
8. Complexity of matrix phenotypes.
- Author
-
Iozzo RV, Theocharis AD, Neill T, and Karamanos NK
- Abstract
The extracellular matrix is engaged in an ever-evolving and elegant ballet of dynamic reciprocity that directly and bi-directionally regulates cell behavior. Homeostatic and pathophysiological changes in cell-matrix signaling cascades manifest as complex matrix phenotypes. Indeed, the extracellular matrix can be implicated in virtually every known human disease, thus, making it the most critical and dynamic "organ" in the human body. The overall goal of this Special Issue is to provide an accurate and inclusive functional definition that addresses the inherent complexity of matrix phenotypes. This goal is summarily achieved via a corpus of expertly written articles, reviews and original research, focused at answering this question empirically and fundamentally via state-of-the-art methods and research strategies., Competing Interests: The authors declare no conflicts of interest., (© 2020 The Author(s).)
- Published
- 2020
- Full Text
- View/download PDF
9. Serglycin activates pro-tumorigenic signaling and controls glioblastoma cell stemness, differentiation and invasive potential.
- Author
-
Manou D, Bouris P, Kletsas D, Götte M, Greve B, Moustakas A, Karamanos NK, and Theocharis AD
- Abstract
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-18
shSRGN ) 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., Competing Interests: The authors declare that no conflict of interest exists., (© 2020 The Authors.)- Published
- 2020
- Full Text
- View/download PDF
10. The extracellular matrix as a multitasking player in disease.
- Author
-
Theocharis AD, Manou D, and Karamanos NK
- Subjects
- Animals, Carcinogenesis genetics, Extracellular Matrix chemistry, Extracellular Matrix pathology, Extracellular Matrix Proteins genetics, Fibrosis genetics, Fibrosis metabolism, Humans, Osteoarthritis genetics, Carcinogenesis metabolism, Extracellular Matrix metabolism, Extracellular Matrix Proteins metabolism, Osteoarthritis metabolism
- Abstract
Extracellular matrices (ECMs) are highly specialized and dynamic three-dimensional (3D) scaffolds into which cells reside in tissues. ECM is composed of a variety of fibrillar components, such as collagens, fibronectin, and elastin, and non-fibrillar molecules as proteoglycans, hyaluronan, and glycoproteins including matricellular proteins. These macromolecular components are interconnected forming complex networks that actively communicate with cells through binding to cell surface receptors and/or matrix effectors. ECMs exert diverse roles, either providing tissues with structural integrity and mechanical properties essential for tissue functions or regulating cell phenotype and functions to maintain tissue homeostasis. ECM molecular composition and structure vary among tissues, and is markedly modified during normal tissue repair as well as during the progression of various diseases. Actually, abnormal ECM remodeling occurring in pathologic circumstances drives disease progression by regulating cell-matrix interactions. The importance of matrix molecules to normal tissue functions is also highlighted by mutations in matrix genes that give rise to genetic disorders with diverse clinical phenotypes. In this review, we present critical and emerging issues related to matrix assembly in tissues and the multitasking roles for ECM in diseases such as osteoarthritis, fibrosis, cancer, and genetic diseases. The mechanisms underlying the various matrix-based diseases are also discussed. Research focused on the highly dynamic 3D ECM networks will help to discover matrix-related causative abnormalities of diseases as well as novel diagnostic tools and therapeutic targets., (© 2019 Federation of European Biochemical Societies.)
- Published
- 2019
- Full Text
- View/download PDF
11. IGF-IR cooperates with ERα to inhibit breast cancer cell aggressiveness by regulating the expression and localisation of ECM molecules.
- Author
-
Afratis NA, Bouris P, Skandalis SS, Multhaupt HA, Couchman JR, Theocharis AD, and Karamanos NK
- Subjects
- Cell Proliferation, Extracellular Matrix metabolism, Humans, MCF-7 Cells, Signal Transduction, Breast Neoplasms pathology, Cell Movement, Estrogen Receptor alpha metabolism, Receptor, IGF Type 1 metabolism
- Abstract
IGF-IR is highly associated with the behaviour of breast cancer cells. In ERα-positive breast cancer, IGF-IR is present at high levels. In clinical practice, prolonged treatment with anti-estrogen agents results in resistance to the therapy with activation of alternative signaling pathways. Receptor Tyrosine Kinases, and especially IGF-IR, have crucial roles in these processes. Here, we report a nodal role of IGF-IR in the regulation of ERα-positive breast cancer cell aggressiveness and the regulation of expression levels of several extracellular matrix molecules. In particular, activation of IGF-IR, but not EGFR, in MCF-7 breast cancer cells results in the reduction of specific matrix metalloproteinases and their inhibitors. In contrast, IGF-IR inhibition leads to the depletion by endocytosis of syndecan-4. Global important changes in cell adhesion receptors, which include integrins and syndecan-4 triggered by IGF-IR inhibition, regulate adhesion and invasion. Cell function assays that were performed in MCF-7 cells as well as their ERα-suppressed counterparts indicate that ER status is a major determinant of IGF-IR regulatory role on cell adhesion and invasion. The strong inhibitory role of IGF-IR on breast cancer cells aggressiveness for which E2-ERα signaling pathway seems to be essential, highlights IGF-IR as a major molecular target for novel therapeutic strategies.
- Published
- 2017
- Full Text
- View/download PDF
12. Syndecans - key regulators of cell signaling and biological functions.
- Author
-
Afratis NA, Nikitovic D, Multhaupt HA, Theocharis AD, Couchman JR, and Karamanos NK
- Subjects
- Actin Cytoskeleton chemistry, Actin Cytoskeleton metabolism, Animals, Calcium metabolism, Cell Adhesion, Cell Movement, Extracellular Matrix chemistry, Extracellular Matrix metabolism, Extracellular Matrix Proteins genetics, Gene Expression Regulation, Homeostasis, Humans, Integrins genetics, Neoplasms genetics, Neoplasms pathology, Protein Domains, Protein Kinases genetics, Receptors, Growth Factor genetics, Syndecans genetics, Extracellular Matrix Proteins metabolism, Integrins metabolism, Neoplasms metabolism, Protein Kinases metabolism, Receptors, Growth Factor metabolism, Signal Transduction, Syndecans metabolism
- Abstract
Syndecans are a small family of four transmembrane proteoglycans in mammals. They have similar structural organization, consisting of an N-terminal ectodomain, single transmembrane domain and C-terminal cytoplasmic domain. Over the years, the association between syndecans and the actin cytoskeleton has been established, which has consequences for the regulation of cell adhesion and migration. Specifically, ecto- and cytoplasmic domains are responsible for the interaction with extracellular matrix molecules and intracellular kinases, respectively. These interactions indicate syndecans as key molecules during cancer initiation and progression. Particularly syndecans interact with other cell surface receptors, such as growth factor receptors and integrins, which lead to activation of downstream signaling pathways, which are critical for the cellular behavior. Moreover, this review describes the key role of syndecans in intracellular calcium regulation and homeostasis. The syndecan-mediated regulation of calcium metabolism is highly correlated with cells' adhesion phenotype through the actin cytoskeleton and formation of junctions, with implications during differentiation and disease progression., (© 2016 Federation of European Biochemical Societies.)
- Published
- 2017
- Full Text
- View/download PDF
13. Epidermal growth factor receptor status and Notch inhibition in non-small cell lung cancer cells.
- Author
-
Giannopoulou E, Nikolakopoulos A, Kotsirilou D, Lampropoulou A, Raftopoulou S, Papadimitriou E, Theocharis AD, Makatsoris T, Fasseas K, and Kalofonos HP
- Subjects
- Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, ErbB Receptors genetics, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Receptors, Notch genetics, Signal Transduction, Tumor Suppressor Proteins genetics, Carcinoma, Non-Small-Cell Lung metabolism, ErbB Receptors metabolism, Lung Neoplasms metabolism, Mutation, Receptors, Notch metabolism, Tumor Suppressor Proteins metabolism
- Abstract
Background: Notch may behave as an oncogene or a tumor suppressor gene in lung cancer cells. Notch receptor undergoes cleavage by enzymes, including γ-secretase, generating the active Notch intracellular domain (NICD). The aim of the present study was to investigate the effect of DAPT, a γ-secretase inhibitor, in non-small cell lung cancer (NSCLC) cells, as well as the impact of epidermal growth factor (EGF) that is over-expressed by NSCLC cells, on Notch signaling. H23, A549, H661 and HCC827 human NSCLC cell lines were used, expressing various NICD and EGF receptor (EGFR) protein levels., Results: DAPT decreased the number of H661 cells in a concentration-dependent manner, while it had a small effect on H23 and A549 cells and no effect on HCC827 cells that carry mutated EGFR. Notch inhibition did not affect the stimulatory effect of EGF on cell proliferation, while EGF prevented DAPT-induced NICD decrease in H23 and H661 cells. The type of cell death induced by DAPT seems to depend on the cell type., Conclusions: Our data indicate that inhibition of Notch cleavage may not affect cell number in the presence of EGFR mutations and that EGFR may affect Notch signalling suggesting that a dual inhibition of these pathways might be promising in NSCLC.
- Published
- 2015
- Full Text
- View/download PDF
14. Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells.
- Author
-
Bouris P, Skandalis SS, Piperigkou Z, Afratis N, Karamanou K, Aletras AJ, Moustakas A, Theocharis AD, and Karamanos NK
- Subjects
- Breast Neoplasms genetics, Breast Neoplasms metabolism, Cell Movement, Cell Proliferation, Estrogen Receptor alpha metabolism, Extracellular Matrix genetics, Female, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, MCF-7 Cells, Breast Neoplasms pathology, Epithelial-Mesenchymal Transition, Estrogen Receptor alpha genetics, Extracellular Matrix metabolism
- Abstract
The 17β-estradiol (E2)/estrogen receptor alpha (ERα) signaling pathway is one of the most important pathways in hormone-dependent breast cancer. E2 plays pivotal roles in cancer cell growth, survival, and architecture as well as in gene expression regulatory mechanisms. In this study, we established stably transfected MCF-7 cells by knocking down the ERα gene (designated as MCF-7/SP10+ cells), using specific shRNA lentiviral particles, and compared them with the control cells (MCF-7/c). Interestingly, ERα silencing in MCF-7 cells strongly induced cellular phenotypic changes accompanied by significant changes in gene and protein expression of several markers typical of epithelial to mesenchymal transition (EMT). Notably, these cells exhibited enhanced cell proliferation, migration and invasion. Moreover, ERα suppression strongly affected the gene and protein expression of EGFR and HER2 receptor tyrosine kinases, and various extracellular matrix (ECM) effectors, including matrix metalloproteinases and their endogenous inhibitors (MMPs/TIMPs) and components of the plasminogen activation system. The action caused by E2 in MCF-7/c cells in the expression of HER2, MT1-MMP, MMP1, MMP9, uPA, tPA, and PAI-1 was abolished in MCF-7/SP10+ cells lacking ERα. These data suggested a regulatory role for the E2/ERα pathway in respect to the composition and activity of the extracellular proteolytic molecular network. Notably, loss of ERα promoted breast cancer cell migration and invasion by inducing changes in the expression levels of certain matrix macromolecules (especially uPA, tPA, PAI-1) through the EGFR-ERK signaling pathway. In conclusion, loss of ERα in breast cancer cells results in a potent EMT characterized by striking changes in the expression profile of specific matrix macromolecules highlighting the potential nodal role of matrix effectors in breast cancer endocrine resistance., (Copyright © 2015. Published by Elsevier B.V.)
- Published
- 2015
- Full Text
- View/download PDF
15. ADAMTS expression in colorectal cancer.
- Author
-
Filou S, Korpetinou A, Kyriakopoulou D, Bounias D, Stavropoulos M, Ravazoula P, Papachristou DJ, Theocharis AD, and Vynios DH
- Subjects
- Aged, Aged, 80 and over, Angiogenesis Inhibitors pharmacology, Angiogenesis Inhibitors therapeutic use, Cell Line, Tumor, Colorectal Neoplasms blood supply, Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology, Drug Discovery, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, ADAM Proteins genetics, ADAM Proteins metabolism, Colorectal Neoplasms genetics, Gene Expression Regulation, Neoplastic
- Abstract
ADAMTSs are a family of secreted proteinases that share the metalloproteinase domain with matrix metalloproteinases (MMPs). By acting on a large panel of extracellular substrates, they control several cell functions such as fusion, adhesion, proliferation and migration. Through their thrombospondin motifs they also possess anti-angiogenic properties. We investigated whether ADAMTSs participate in colorectal cancer progression and invasion. Their expression was investigated at both mRNA and protein levels. Using RT-PCR, the expression of ADAMTS-1, -4, -5 and ADAMTS-20 was estimated in colorectal tumors of different cancer stage and anatomic site and 3 cell lines of different aggressiveness. An overexpression of ADAMTS-4 and -5 was observed, especially in tissue samples, whereas ADAMTS-1 and -20 were found to be down-regulated. Western blot analysis further supported the RT-PCR findings, revealing in addition the degradation of ADAMTS-1 and -20 in cancer. In situ expression and localization of ADAMTS-1, -4, -5 and -20 was also investigated by immunohistochemical analysis. Our data suggest a positive correlation between ADAMTS-4 and -5 expression and cancer progression, in contrast with the anti-angiogenic members of the family, ADAMTS-1 and -20, which were found to be down-regulated. Our findings support the notion that overexpression of ADAMTS-4 and ADAMTS-5 in colorectal cancer might be a possible invasive mechanism of cancer cells in order to degrade proteoglycans of ECM.
- Published
- 2015
- Full Text
- View/download PDF
16. Increased Expression of Serglycin in Specific Carcinomas and Aggressive Cancer Cell Lines.
- Author
-
Korpetinou A, Papachristou DJ, Lampropoulou A, Bouris P, Labropoulou VT, Noulas A, Karamanos NK, and Theocharis AD
- Subjects
- Alternative Splicing genetics, Breast metabolism, Breast pathology, Caco-2 Cells, Carcinoma pathology, Colon metabolism, Colon pathology, Female, Humans, Lung metabolism, Lung pathology, MCF-7 Cells, Male, Prostate metabolism, Prostate pathology, Proteoglycans genetics, Tissue Array Analysis, Vesicular Transport Proteins genetics, Carcinoma genetics, Proteoglycans biosynthesis, Tumor Microenvironment genetics, Vesicular Transport Proteins biosynthesis
- Abstract
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.
- Published
- 2015
- Full Text
- View/download PDF
17. Cell-matrix interactions: focus on proteoglycan-proteinase interplay and pharmacological targeting in cancer.
- Author
-
Theocharis AD, Gialeli C, Bouris P, Giannopoulou E, Skandalis SS, Aletras AJ, Iozzo RV, and Karamanos NK
- Subjects
- ADAM Proteins antagonists & inhibitors, Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Glycosaminoglycans metabolism, Humans, Matrix Metalloproteinase Inhibitors pharmacology, Matrix Metalloproteinase Inhibitors therapeutic use, Molecular Targeted Therapy, Neoplasms drug therapy, ADAM Proteins metabolism, Cathepsins metabolism, Matrix Metalloproteinases metabolism, Neoplasms pathology, Proteoglycans metabolism
- Abstract
Proteoglycans are major constituents of extracellular matrices, as well as cell surfaces and basement membranes. They play key roles in supporting the dynamic extracellular matrix by generating complex structural networks with other macromolecules and by regulating cellular phenotypes and signaling. It is becoming evident, however, that proteolytic enzymes are required partners for matrix remodeling and for modulating cell signaling via matrix constituents. Proteinases contribute to all stages of diseases, particularly cancer development and progression, and contextually participate in either the removal of damaged products or in the processing of matrix molecules and signaling receptors. The dynamic interplay between proteoglycans and proteolytic enzymes is a crucial biological step that contributes to the pathophysiology of cancer and inflammation. Moreover, proteoglycans are implicated in the expression and secretion of proteolytic enzymes and often modulate their activities. In this review, we describe the emerging biological roles of proteoglycans and proteinases, with a special emphasis on their complex interplay. We critically evaluate this important proteoglycan-proteinase interactome and discuss future challenges with respect to targeting this axis in the treatment of cancer., (© 2014 FEBS.)
- Published
- 2014
- Full Text
- View/download PDF
18. Syndecans as modulators and potential pharmacological targets in cancer progression.
- Author
-
Barbouri D, Afratis N, Gialeli C, Vynios DH, Theocharis AD, and Karamanos NK
- Abstract
Extracellular matrix (ECM) components form a dynamic network of key importance for cell function and properties. Key macromolecules in this interplay are syndecans (SDCs), a family of transmembrane heparan sulfate proteoglycans (HSPGs). Specifically, heparan sulfate (HS) chains with their different sulfation pattern have the ability to interact with growth factors and their receptors in tumor microenvironment, promoting the activation of different signaling cascades that regulate tumor cell behavior. The affinity of HS chains with ligands is altered during malignant conditions because of the modification of chain sequence/sulfation pattern. Furthermore, matrix degradation enzymes derived from the tumor itself or the tumor microenvironment, like heparanase and matrix metalloproteinases, ADAM as well as ADAMTS are involved in the cleavage of SDCs ectodomain at the HS and protein core level, respectively. Such released soluble SDCs "shed SDCs" in the ECM interact in an autocrine or paracrine manner with the tumor or/and stromal cells. Shed SDCs, upon binding to several matrix effectors, such as growth factors, chemokines, and cytokines, have the ability to act as competitive inhibitors for membrane proteoglycans, and modulate the inflammatory microenvironment of cancer cells. It is notable that SDCs and their soluble counterparts may affect either the behavior of cancer cells and/or their microenvironment during cancer progression. The importance of these molecules has been highlighted since HSPGs have been proposed as prognostic markers of solid tumors and hematopoietic malignancies. Going a step further down the line, the multi-actions of SDCs in many levels make them appealing as potential pharmacological targets, either by targeting directly the tumor or indirectly the adjacent stroma.
- Published
- 2014
- Full Text
- View/download PDF
19. Serglycin: at the crossroad of inflammation and malignancy.
- Author
-
Korpetinou A, Skandalis SS, Labropoulou VT, Smirlaki G, Noulas A, Karamanos NK, and Theocharis AD
- Abstract
Serglycin has been initially characterized as an intracellular proteoglycan expressed by hematopoietic cells. All inflammatory cells highly synthesize serglycin and store it in granules, where it interacts with numerous inflammatory mediators, such as proteases, chemokines, cytokines, and growth factors. Serglycin is implicated in their storage into the granules and their protection since they are secreted as complexes and delivered to their targets after secretion. During the last decade, numerous studies have demonstrated that serglycin is also synthesized by various non-hematopoietic cell types. It has been shown that serglycin is highly expressed by tumor cells and promotes their aggressive phenotype and confers resistance against drugs and complement system attack. Apart from its direct beneficial role to tumor cells, serglycin may promote the inflammatory process in the tumor cell microenvironment thus enhancing tumor development. In the present review, we discuss the role of serglycin in inflammation and tumor progression.
- Published
- 2014
- Full Text
- View/download PDF
20. Serglycin is implicated in the promotion of aggressive phenotype of breast cancer cells.
- Author
-
Korpetinou A, Skandalis SS, Moustakas A, Happonen KE, Tveit H, Prydz K, Labropoulou VT, Giannopoulou E, Kalofonos HP, Blom AM, Karamanos NK, and Theocharis AD
- Subjects
- Cell Line, Tumor, Cell Movement genetics, Cell Movement physiology, Cell Proliferation, Female, Humans, MCF-7 Cells, Mannose-Binding Lectin metabolism, Protein Binding, Breast Neoplasms metabolism, Proteoglycans metabolism, Vesicular Transport Proteins metabolism
- Abstract
Serglycin is a proteoglycan expressed by some malignant cells. It promotes metastasis and protects some tumor cells from complement system attack. In the present study, we show for the first time the in situ expression of serglycin by breast cancer cells by immunohistochemistry in patients' material. Moreover, we demonstrate high expression and constitutive secretion of serglycin in the aggressive MDA-MB-231 breast cancer cell line. Serglycin exhibited a strong cytoplasmic staining in these cells, observable at the cell periphery in a thread of filaments near the cell membrane, but also in filopodia-like structures. Serglycin was purified from conditioned medium of MDA-MB-231 cells, and represented the major proteoglycan secreted by these cells, having a molecular size of ~ 250 kDa and carrying chondroitin sulfate side chains, mainly composed of 4-sulfated (~ 87%), 6-sulfated (~ 10%) and non-sulfated (~ 3%) disaccharides. Purified serglycin inhibited early steps of both the classical and the lectin pathways of complement by binding to C1q and mannose-binding lectin. Stable expression of serglycin in less aggressive MCF-7 breast cancer cells induced their proliferation, anchorage-independent growth, migration and invasion. Interestingly, over-expression of serglycin lacking the glycosaminoglycan attachment sites failed to promote these cellular functions, suggesting that glycanation of serglycin is a pre-requisite for its oncogenic properties. Our findings suggest that serglycin promotes a more aggressive cancer cell phenotype and may protect breast cancer cells from complement attack supporting their survival and expansion.
- Published
- 2013
- Full Text
- View/download PDF
21. Efficient TGFβ-induced epithelial-mesenchymal transition depends on hyaluronan synthase HAS2.
- Author
-
Porsch H, Bernert B, Mehić M, Theocharis AD, Heldin CH, and Heldin P
- Subjects
- Cell Movement drug effects, Cell Movement genetics, Epithelial Cells drug effects, Epithelial Cells metabolism, Gene Knockdown Techniques, Glucuronosyltransferase metabolism, Humans, Hyaluronan Receptors genetics, Hyaluronan Receptors metabolism, Hyaluronan Synthases, Hyaluronic Acid biosynthesis, Mammary Glands, Human metabolism, Mammary Glands, Human pathology, Protein Serine-Threonine Kinases metabolism, Receptor, Transforming Growth Factor-beta Type I, Receptors, Transforming Growth Factor beta metabolism, Signal Transduction, Smad Proteins metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Epithelial-Mesenchymal Transition drug effects, Epithelial-Mesenchymal Transition genetics, Glucuronosyltransferase genetics, Transforming Growth Factor beta pharmacology
- Abstract
Epithelial-mesenchymal transition (EMT) is a developmental program, which can be adopted by cancer cells to increase their migration and ability to form metastases. Transforming growth factor β (TGFβ) is a well-studied inducer of EMT. We demonstrate that TGFβ potently stimulates hyaluronan synthesis via upregulation of hyaluronan synthase 2 (HAS2) in NMuMG mammary epithelial cells. This stimulatory effect requires the kinase active type I TGFβ receptor and is dependent on Smad signaling and activation of the p38 mitogen-activated protein kinase. Knockdown of HAS2 inhibited the TGFβ-induced EMT by about 50%, as determined by the phase contrast microscopy and immunostaining using the EMT marker ZO-1. Furthermore, real-time PCR analysis of the EMT markers fibronectin, Snail1 and Zeb1 revealed decreased expressions upon HAS2 suppression, using specific small interfering RNA (siRNA) for HAS2. Removal of the extracellular hyaluronan by Streptomyces hyaluronidase or inhibiting the binding to its cell surface receptor CD44 by blocking antibodies, did not inhibit TGFβ-induced EMT. Interestingly, HAS2 suppression completely abolished the TGFβ-induced cell migration, whereas CD44 knockdown did not. These observations suggest that TGFβ-dependent HAS2 expression, but not extracellular hyaluronan, has an important regulatory role in TGFβ-induced EMT.
- Published
- 2013
- Full Text
- View/download PDF
22. In vitro reconstitution of complexes between pro-matrix metalloproteinase-9 and the proteoglycans serglycin and versican.
- Author
-
Malla N, Berg E, Theocharis AD, Svineng G, Uhlin-Hansen L, and Winberg JO
- Subjects
- Cell Line, Tumor, Cystine chemistry, Detergents chemistry, Enzyme Stability, Gelatin chemistry, Humans, Hydrogen-Ion Concentration, Multiprotein Complexes chemistry, Octoxynol chemistry, Protein Binding, Sodium Chloride chemistry, Sodium Dodecyl Sulfate chemistry, Tissue Inhibitor of Metalloproteinase-1 chemistry, Chondroitin Sulfates chemistry, Enzyme Precursors chemistry, Matrix Metalloproteinase 9 chemistry, Proteoglycans chemistry, Versicans chemistry, Vesicular Transport Proteins chemistry
- Abstract
Previously, we have shown that a proportion of the matrix metalloproteinase-9 (MMP-9) synthesized by the macrophage cell line THP-1 binds to a chondroitin sulfate proteoglycan (CSPG) core protein to form a reduction-sensitive heteromer. It was also shown that the hemopexin-like (PEX) domain and the fibronectin-like (FnII) module in the enzyme are involved in heteromer formation. In this paper, we show that reduction-sensitive and SDS-stable heteromers may be reconstituted in vitro by mixing proMMP-9 with either serglycin, versican or CSPGs isolated from various monocytic cell lines. In addition, a strong but SDS-soluble proMMP-9·CSPG heteromer was formed. The two macromolecules in the SDS-stable reduction-sensitive heteromers were not linked together by disulfide bonds. As for the heteromer isolated from THP-1 cells, in vitro reconstituted SDS-stable and SDS-soluble heteromers showed weaker binding to gelatin than the proMMP-9 monomer. Furthermore, gelatin inhibited in vitro reconstitution of the heteromers, showing that the FnII module is involved in the complex formation. Tissue inhibitor of metalloproteinase (TIMP)-1 was not be detected in the proMMP-9·CSPG complexes. However, the presence of TIMP-1 inhibited formation of the SDS-soluble heteromer, but not the SDS-stable reduction-sensitive heteromer. This indicates that different regions in the PEX domain are involved formation of these heteromers., (© 2013 FEBS.)
- Published
- 2013
- Full Text
- View/download PDF
23. Cell-surface serglycin promotes adhesion of myeloma cells to collagen type I and affects the expression of matrix metalloproteinases.
- Author
-
Skliris A, Labropoulou VT, Papachristou DJ, Aletras A, Karamanos NK, and Theocharis AD
- Subjects
- Antibodies metabolism, Bone Marrow enzymology, Bone Marrow metabolism, Bone Marrow pathology, Cell Adhesion, Cell Line, Tumor, Chondroitin ABC Lyase pharmacology, Culture Media metabolism, Flow Cytometry, Humans, Immunohistochemistry, Matrix Metalloproteinase 2 genetics, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 9 genetics, Matrix Metalloproteinase 9 metabolism, Multiple Myeloma enzymology, Multiple Myeloma metabolism, Multiple Myeloma pathology, Protein Binding, Protein Interaction Mapping, Proteoglycans antagonists & inhibitors, RNA, Messenger genetics, RNA, Messenger metabolism, Vesicular Transport Proteins antagonists & inhibitors, Collagen Type I metabolism, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Proteoglycans metabolism, Vesicular Transport Proteins metabolism
- Abstract
Serglycin (SG) is mainly expressed by hematopoetic cells as an intracellular proteoglycan. Multiple myeloma cells constitutively secrete SG, which is also localized on the cell surface in some cell lines. In this study, SG isolated from myeloma cells was found to interact with collagen type I (Col I), which is a major bone matrix component. Notably, myeloma cells positive for cell-surface SG (csSG) adhered significantly to Col I, compared to cells lacking csSG. Removal of csSG by treatment of the cells with chondroitinase ABC or blocking of csSG by an SG-specific polyclonal antibody significantly reduced the adhesion of myeloma cells to Col I. Significant up-regulation of expression of the matrix metalloproteinases MMP-2 and MMP-9 at both the mRNA and protein levels was observed when culturing csSG-positive myeloma cells on Col I-coated dishes or in the presence of soluble Col I. MMP-9 and MMP-2 were also expressed in increased amounts by myeloma cells in the bone marrow of patients with multiple myeloma. Our data indicate that csSG of myeloma cells affects key functional properties, such as adhesion to Col I and the expression of MMPs, and imply that csSG may serve as a potential prognostic factor and/or target for pharmacological interventions in multiple myeloma., (© 2013 The Authors Journal compilation © 2013 FEBS.)
- Published
- 2013
- Full Text
- View/download PDF
24. Evaluation of the coordinated actions of estrogen receptors with epidermal growth factor receptor and insulin-like growth factor receptor in the expression of cell surface heparan sulfate proteoglycans and cell motility in breast cancer cells.
- Author
-
Tsonis AI, Afratis N, Gialeli C, Ellina MI, Piperigkou Z, Skandalis SS, Theocharis AD, Tzanakakis GN, and Karamanos NK
- Subjects
- Breast Neoplasms metabolism, Breast Neoplasms pathology, ErbB Receptors antagonists & inhibitors, Estradiol pharmacology, Estrogen Receptor alpha genetics, Estrogen Receptor beta genetics, Estrogen Receptor beta metabolism, Female, Gene Expression Regulation, Glypicans genetics, Glypicans metabolism, Humans, Insulin-Like Growth Factor I antagonists & inhibitors, MCF-7 Cells, Quinazolines pharmacology, Receptor Cross-Talk, Signal Transduction, Syndecan-2 genetics, Syndecan-4 genetics, Syndecan-4 metabolism, Tyrphostins pharmacology, Cell Movement drug effects, ErbB Receptors metabolism, Estradiol metabolism, Estrogen Receptor alpha metabolism, Insulin-Like Growth Factor I metabolism, Syndecan-2 metabolism
- Abstract
Estradiol (E2)-estrogen receptor (ER) actions are implicated in initiation, growth and progression of hormone-dependent breast cancer. Crosstalk between ERs, epidermal growth factor receptor (EGFR) and/or insulin-like growth factor receptor (IGFR) is critical for the observed resistance to endocrine therapies. Cell surface heparan sulfate proteoglycans (HSPGs) are principal mediators of cancer cell properties and the E2-ER pathway as well as those activated by EGFR and IGFR have significant roles in regulating the expression of certain cell surface HSPGs, such as syndecan-2 (SDC-2), syndecan-4 (SDC-4) and glypican-1. In this study, we therefore evaluated the role of EGFR-IGFR signaling on the constitutive expression and E2-mediated expression of ERs and HSPGs as well as the effect of E2-ERs and IGFR/EGFR-mediated cell migration in ERα+ (MCF-7) and ERβ+ (MDA-MB-231) breast cancer cells using specific intracellular inhibitors of EGFR and IGFR. We report that the expression of ERα is mainly enhanced by IGFR, whereas ERβ expression is mainly coordinated by EGFR. Moreover, constitutive SDC-2 expression in ERα+ and ERβ+ cells is mainly mediated through the IGFR, whereas in ERα+ E2-treated cells EGFR is the active one. In contrast, SDC-4 expression is regulated by IGFR in the presence and absence of E2. E2 also seems to diminish the inhibitory effect of EGFR and IGFR inhibitors in breast cancer cell migration. These data suggest that the coordinated action of ERs with EGFR and/or IGFR is of crucial importance, providing potential targets for designing and developing novel multi-potent agents for endocrine therapies., (© 2013 The Authors Journal compilation © 2013 FEBS.)
- Published
- 2013
- Full Text
- View/download PDF
25. Imatinib as a key inhibitor of the platelet-derived growth factor receptor mediated expression of cell surface heparan sulfate proteoglycans and functional properties of breast cancer cells.
- Author
-
Malavaki CJ, Roussidis AE, Gialeli C, Kletsas D, Tsegenidis T, Theocharis AD, Tzanakakis GN, and Karamanos NK
- Subjects
- Antineoplastic Agents pharmacology, Becaplermin, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Movement drug effects, Cell Proliferation, Cytostatic Agents pharmacology, Drug Screening Assays, Antitumor, Female, G2 Phase Cell Cycle Checkpoints, Glypicans genetics, Humans, Imatinib Mesylate, Ligands, M Phase Cell Cycle Checkpoints, MAP Kinase Signaling System, MCF-7 Cells, Neoplasm Invasiveness pathology, Neoplasm Invasiveness prevention & control, Phosphorylation, Proto-Oncogene Proteins c-sis pharmacology, Receptor, Platelet-Derived Growth Factor alpha antagonists & inhibitors, Receptor, Platelet-Derived Growth Factor beta antagonists & inhibitors, Receptor, Platelet-Derived Growth Factor beta metabolism, Signal Transduction, Syndecan-4 genetics, Transcriptome, Benzamides pharmacology, Gene Expression Regulation, Neoplastic drug effects, Glypicans metabolism, Piperazines pharmacology, Pyrimidines pharmacology, Receptor, Platelet-Derived Growth Factor alpha metabolism, Syndecan-4 metabolism
- Abstract
Cell surface heparan sulfate proteoglycans (HSPGs), syndecans and glypicans, play crucial roles in the functional properties of cancer cells, such as proliferation, adhesion, migration and invasion. Platelet-derived growth factor (PDGF)/PDGF receptor (PDGF-R) mediated signaling, on the other hand, is highly associated with cancer progression. Specifically, PDGF-Rα and PDGF-Rβ expressions documented in breast cancer tissue specimens as well as breast cancer cell lines are correlated with tumor aggressiveness and metastasis. Imatinib (Glivec(®)) is a tyrosine kinase inhibitor specific for PDGF-Rs, c-ΚΙΤ and BCR-ABL. In this study we evaluated the effects of imatinib on the properties of breast cancer cells as well as on the expression of HSPGs in the presence and absence of PDGF-BB. These studies have been conducted in a panel of three breast cancer cell lines of low and high metastatic potential. Our results indicate that imatinib exerts a significant inhibitory effect on breast cancer cell proliferation, invasion and migration as well as on the cell surface expression of HSPGs even after exposure of PDGF. These effects depend on the aggressiveness of breast cancer cells and the type of HSPG. It is suggested that imatinib may be of potential therapeutic usefulness in breast cancer regimes., (© 2013 The Authors Journal compilation © 2013 FEBS.)
- Published
- 2013
- Full Text
- View/download PDF
26. Expression of syndecan-4 and correlation with metastatic potential in testicular germ cell tumours.
- Author
-
Labropoulou VT, Skandalis SS, Ravazoula P, Perimenis P, Karamanos NK, Kalofonos HP, and Theocharis AD
- Subjects
- Adolescent, Adult, Aged, Cell Line, Tumor, Humans, Immunohistochemistry, Male, Microvessels pathology, Middle Aged, Neoplasm Metastasis, Neoplasms, Germ Cell and Embryonal blood supply, Neoplasms, Germ Cell and Embryonal pathology, Reverse Transcriptase Polymerase Chain Reaction, Staining and Labeling, Stromal Cells pathology, Testicular Neoplasms blood supply, Testicular Neoplasms pathology, Young Adult, Neoplasms, Germ Cell and Embryonal metabolism, Syndecan-4 metabolism, Testicular Neoplasms metabolism
- Abstract
Although syndecan-4 is implicated in cancer progression, there is no information for its role in testicular germ cell tumours (TGCTs). Thus, we examined the expression of syndecan-4 in patients with TGCTs and its correlation with the clinicopathological findings. Immunohistochemical staining in 71 tissue specimens and mRNA analysis revealed significant overexpression of syndecan-4 in TGCTs. In seminomas, high percentage of tumour cells exhibited membranous and/or cytoplasmic staining for syndecan-4 in all cases. Stromal staining for syndecan-4 was found in seminomas and it was associated with nodal metastasis (P = 0.04), vascular/lymphatic invasion (P = 0.01), and disease stage (P = 0.04). Reduced tumour cell associated staining for syndecan-4 was observed in nonseminomatous germ cell tumours (NSGCTs) compared to seminomas. This loss of syndecan-4 was associated with nodal metastasis (P = 0.01), vascular/lymphatic invasion (P = 0.01), and disease stage (P = 0.01). Stromal staining for syndecan-4 in NSGCTs did not correlate with any of the clinicopathological variables. The stromal expression of syndecan-4 in TGCTs was correlated with microvessel density (P = 0.03). Our results indicate that syndecan-4 is differentially expressed in seminomas and NSGCTs and might be a useful marker. Stromal staining in seminomas and reduced levels of syndecan-4 in tumour cells in NSGCTs are related to metastatic potential, whereas stromal staining in TGCTs is associated with neovascularization.
- Published
- 2013
- Full Text
- View/download PDF
27. Cellular microenvironment in human pathologies.
- Author
-
Vigetti D, Götte M, Pavão MS, and Theocharis AD
- Subjects
- Humans, Cellular Microenvironment, Extracellular Matrix pathology, Extracellular Matrix physiology
- Published
- 2013
- Full Text
- View/download PDF
28. Glycosaminoglycans: key players in cancer cell biology and treatment.
- Author
-
Afratis N, Gialeli C, Nikitovic D, Tsegenidis T, Karousou E, Theocharis AD, Pavão MS, Tzanakakis GN, and Karamanos NK
- Subjects
- Chondroitin Sulfates chemistry, Chondroitin Sulfates metabolism, Disease Progression, Humans, Hyaluronic Acid chemistry, Hyaluronic Acid metabolism, Intercellular Signaling Peptides and Proteins metabolism, Neoplasms pathology, Signal Transduction physiology, Glycosaminoglycans chemistry, Glycosaminoglycans metabolism, Neoplasms physiopathology, Neoplasms therapy
- Abstract
Glycosaminoglycans are natural heteropolysaccharides that are present in every mammalian tissue. They are composed of repeating disaccharide units that consist of either sulfated or non-sulfated monosaccharides. Their molecular size and the sulfation type vary depending on the tissue, and their state either as part of proteoglycan or as free chains. In this regard, glycosaminoglycans play important roles in physiological and pathological conditions. During recent years, cell biology studies have revealed that glycosaminoglycans are among the key macromolecules that affect cell properties and functions, acting directly on cell receptors or via interactions with growth factors. The accumulated knowledge regarding the altered structure of glycosaminoglycans in several diseases indicates their importance as biomarkers for disease diagnosis and progression, as well as pharmacological targets. This review summarizes how the fine structural characteristics of glycosaminoglycans, and enzymes involved in their biosynthesis and degradation, are involved in cell signaling, cell function and cancer progression. Prospects for glycosaminoglycan-based therapeutic targeting in cancer are also discussed., (© 2012 The Authors Journal compilation © 2012 FEBS.)
- Published
- 2012
- Full Text
- View/download PDF
29. Versican but not decorin accumulation is related to malignancy in mammographically detected high density and malignant-appearing microcalcifications in non-palpable breast carcinomas.
- Author
-
Skandalis SS, Labropoulou VT, Ravazoula P, Likaki-Karatza E, Dobra K, Kalofonos HP, Karamanos NK, and Theocharis AD
- Subjects
- Adult, Aged, Biomarkers, Tumor metabolism, Breast metabolism, Breast pathology, Breast Neoplasms diagnostic imaging, Breast Neoplasms pathology, Calcinosis diagnostic imaging, Calcinosis pathology, Carcinoma in Situ diagnostic imaging, Carcinoma in Situ metabolism, Carcinoma in Situ pathology, Estrogen Receptor alpha metabolism, Female, Humans, Immunohistochemistry, Middle Aged, Palpation, Receptor, ErbB-2 metabolism, Receptors, Progesterone metabolism, Breast Neoplasms metabolism, Calcinosis metabolism, Decorin metabolism, Mammography, Versicans metabolism
- Abstract
Background: Mammographic density (MD) and malignant-appearing microcalcifications (MAMCs) represent the earliest mammographic findings of non-palpable breast carcinomas. Matrix proteoglycans versican and decorin are frequently over-expressed in various malignancies and are differently involved in the progression of cancer. In the present study, we have evaluated the expression of versican and decorin in non-palpable breast carcinomas and their association with high risk mammographic findings and tumor characteristics., Methods: Three hundred and ten patients with non-palpable suspicious breast lesions, detected during screening mammography, were studied. Histological examination was carried out and the expression of decorin, versican, estrogen receptor α (ERα), progesterone receptor (PR) and c-erbB2 (HER-2/neu) was assessed by immunohistochemistry., Results: Histological examination showed 83 out of 310 (26.8%) carcinomas of various subtypes. Immunohistochemistry was carried out in 62/83 carcinomas. Decorin was accumulated in breast tissues with MD and MAMCs independently of the presence of malignancy. In contrast, versican was significantly increased only in carcinomas with MAMCs (median ± SE: 42.0 ± 9.1) and MD (22.5 ± 10.1) as compared to normal breast tissue with MAMCs (14.0 ± 5.8), MD (11.0 ± 4.4) and normal breast tissue without mammographic findings (10.0 ± 2.0). Elevated levels of versican were correlated with higher tumor grade and invasiveness in carcinomas with MD and MAMCs, whereas increased amounts of decorin were associated with in situ carcinomas in MAMCs. Stromal deposition of both proteoglycans was related to higher expression of ERα and PR in tumor cells only in MAMCs., Conclusions: The specific accumulation of versican in breast tissue with high MD and MAMCs only in the presence of malignant transformation and its association with the aggressiveness of the tumor suggests its possible use as molecular marker in non-palpable breast carcinomas.
- Published
- 2011
- Full Text
- View/download PDF
30. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting.
- Author
-
Gialeli C, Theocharis AD, and Karamanos NK
- Subjects
- Antineoplastic Agents pharmacology, Cell Proliferation drug effects, Humans, Neoplasms physiopathology, Antineoplastic Agents therapeutic use, Drug Delivery Systems, Matrix Metalloproteinases metabolism, Neoplasms drug therapy
- Abstract
Matrix metalloproteinases (MMPs) consist of a multigene family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases implicated in pathological processes, such as carcinogenesis. In this regard, their activity plays a pivotal role in tumor growth and the multistep processes of invasion and metastasis, including proteolytic degradation of ECM, alteration of the cell-cell and cell-ECM interactions, migration and angiogenesis. The underlying premise of the current minireview is that MMPs are able to proteolytically process substrates in the extracellular milieu and, in so doing, promote tumor progression. However, certain members of the MMP family exert contradicting roles at different stages during cancer progression, depending among other factors on the tumor stage, tumor site, enzyme localization and substrate profile. MMPs are therefore amenable to therapeutic intervention by synthetic and natural inhibitors, providing perspectives for future studies. Multiple therapeutic agents, called matrix metalloproteinase inhibitors (MMPIs) have been developed to target MMPs, attempting to control their enzymatic activity. Even though clinical trials with these compounds do not show the expected results in most cases, the field of MMPIs is ongoing. This minireview critically evaluates the role of MMPs in relation to cancer progression, and highlights the challenges, as well as future prospects, for the design, development and efficacy of MMPIs., (© 2010 The Authors Journal compilation © 2010 FEBS.)
- Published
- 2011
- Full Text
- View/download PDF
31. Proteoglycans in health and disease: novel roles for proteoglycans in malignancy and their pharmacological targeting.
- Author
-
Theocharis AD, Skandalis SS, Tzanakakis GN, and Karamanos NK
- Subjects
- Aggrecans metabolism, Aggrecans therapeutic use, Agrin physiology, Biomarkers, Brevican, Cartilage pathology, Cell Division, Chondroitin Sulfate Proteoglycans metabolism, Decorin, Disease Progression, Extracellular Matrix Proteins metabolism, Glioma pathology, Glioma physiopathology, Humans, Hyaluronic Acid metabolism, Inflammation genetics, Lectins, C-Type metabolism, Neoplasms drug therapy, Neoplasms genetics, Neoplasms pathology, Neovascularization, Pathologic physiopathology, Nerve Tissue Proteins metabolism, Prognosis, Proteoglycans drug effects, Proteoglycans genetics, Proteoglycans metabolism, Proteoglycans therapeutic use, Versicans genetics, Versicans therapeutic use, Neoplasms physiopathology, Proteoglycans physiology
- Abstract
The expression of proteoglycans (PGs), essential macromolecules of the tumor microenvironment, is markedly altered during malignant transformation and tumor progression. Synthesis of stromal PGs is affected by factors secreted by cancer cells and the unique tumor-modified extracellular matrix may either facilitate or counteract the growth of solid tumors. The emerging theme is that this dual activity has intrinsic tissue specificity. Matrix-accumulated PGs, such as versican, perlecan and small leucine-rich PGs, affect cancer cell signaling, growth and survival, cell adhesion, migration and angiogenesis. Furthermore, expression of cell-surface-associated PGs, such as syndecans and glypicans, is also modulated in both tumor and stromal cells. Cell-surface-associated PGs bind various factors that are involved in cell signaling, thereby affecting cell proliferation, adhesion and motility. An important mechanism of action is offered by a proteolytic processing of cell-surface PGs known as ectodomain shedding of syndecans; this facilitates cancer and endothelial cell motility, protects matrix proteases and provides a chemotactic gradient of mitogens. However, syndecans on stromal cells may be important for stromal cell/cancer cell interplay and may promote stromal cell proliferation, migration and angiogenesis. Finally, abnormal PG expression in cancer and stromal cells may serve as a biomarker for tumor progression and patient survival. Enhanced understanding of the regulation of PG metabolism and the involvement of PGs in cancer may offer a novel approach to cancer therapy by targeting the tumor microenvironment. In this minireview, the implication of PGs in cancer development and progression, as well as their pharmacological targeting in malignancy, are presented and discussed., (© 2010 The Authors Journal compilation © 2010 FEBS.)
- Published
- 2010
- Full Text
- View/download PDF
32. Estradiol-estrogen receptor: a key interplay of the expression of syndecan-2 and metalloproteinase-9 in breast cancer cells.
- Author
-
Kousidou OCh, Berdiaki A, Kletsas D, Zafiropoulos A, Theocharis AD, Tzanakakis GN, and Karamanos NK
- Subjects
- Breast Neoplasms, Cell Line, Tumor, Estrogen Receptor alpha, Female, Humans, Syndecan-4, Estradiol pharmacology, Gene Expression Regulation, Neoplastic drug effects, Matrix Metalloproteinase 9 genetics, Receptors, Estrogen genetics, Syndecan-2 genetics, Tissue Inhibitor of Metalloproteinase-1 genetics
- Abstract
Estrogens are related with the growth and development of target tissues and play a critical role in breast cancer progression. The effects of estrogens are mediated by the estrogen receptors ERalpha and ERbeta, which are members of the nuclear steroid receptor superfamily. To date, it is not known how these hormones elicit many of their effects on extracellular matrix molecules and how these effects can be connected with ER expression. For this purpose, the effect of estradiol on ER expression as well as on proteoglycan and metalloproteinase expression was studied. The effect of E2 on extracellular matrix molecule expression has been studied using ERalpha suppression in breast cancer cells. Our studies using ERalpha-positive MCF-7 cells show that estradiol affects the expression of syndecan-2, but not of syndecan-4, through ERalpha. Furthermore, the ability of estradiol to affect MMP-9 and TIMP-1 expression is connected with ERalpha status. Together, these data demonstrate the significant role of ERalpha on mediating the effect of estradiol on extracellular matrix molecules.
- Published
- 2008
- Full Text
- View/download PDF
33. The biological role of chondroitin sulfate in cancer and chondroitin-based anticancer agents.
- Author
-
Asimakopoulou AP, Theocharis AD, Tzanakakis GN, and Karamanos NK
- Subjects
- Animals, Humans, Neoplasms metabolism, Proteoglycans metabolism, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Chondroitin chemistry, Chondroitin therapeutic use, Neoplasms drug therapy, Neoplasms pathology, Sulfates chemistry
- Abstract
Chondroitin sulfate proteoglycans (CSPGs) such as versican accumulate in tumor stroma and play a key role in tumor growth and invasion. The high expression of CSPGs in fast growing tissues and cells is correlated with chondroitin sulfate (CS) chains and the sulfation pattern. The negatively charged CS chains interact with a large number of ligands and receptors and activate signalling pathways which stimulate tumor growth. However, the role of chondroitin sulfate in cancer promotion seems to be controversial, as recent studies support the use of modified CS as a potent anticancer agent. In this review, the biological roles of CSPGs in cancer and the anticancer effects of modified CS are presented and discussed.
- Published
- 2008
34. Serglycin constitutively secreted by myeloma plasma cells is a potent inhibitor of bone mineralization in vitro.
- Author
-
Theocharis AD, Seidel C, Borset M, Dobra K, Baykov V, Labropoulou V, Kanakis I, Dalas E, Karamanos NK, Sundan A, and Hjerpe A
- Subjects
- Cell Line, Tumor, Durapatite chemistry, Durapatite metabolism, Humans, Multiple Myeloma metabolism, Protein Conformation, Proteoglycans chemistry, Vesicular Transport Proteins chemistry, Calcification, Physiologic, Multiple Myeloma pathology, Plasma Cells metabolism, Proteoglycans metabolism, Vesicular Transport Proteins metabolism
- Abstract
Although the biological significance of proteoglycans (PGs) has previously been highlighted in multiple myeloma (MM), little is known about serglycin, which is a hematopoietic cell granule PG. In this study, we describe the expression and highly constitutive secretion of serglycin in several MM cell lines. Serglycin messenger RNA was detected in six MM cell lines. PGs were purified from conditioned medium of four MM cell lines, and serglycin substituted with 4-sulfated chondroitin sulfate was identified as the predominant PG. Flow cytometry and confocal microscopy showed that serglycin was also present intracellularly and on the cell surface, and attachment to the cell surface was at least in part dependent on intact glycosaminoglycan side chains. Immunohistochemical staining of bone marrow biopsies showed the presence of serglycin both in benign and malignant plasma cells. Immunoblotting in bone marrow aspirates from a limited number of patients with newly diagnosed MM revealed highly increased levels of serglycin in 30% of the cases. Serglycin isolated from myeloma plasma cells was found to influence the bone mineralization process through inhibition of the crystal growth rate of hydroxyapatite. This rate reduction was attributed to adsorption and further blocking of the active growth sites on the crystal surface. The apparent order of the crystallization reaction was found to be n=2, suggesting a surface diffusion-controlled spiral growth mechanism. Our findings suggest that serglycin release is a constitutive process, which may be of fundamental biological importance in the study of MM.
- Published
- 2006
- Full Text
- View/download PDF
35. Expression of MMPs and TIMPs genes in human breast cancer epithelial cells depends on cell culture conditions and is associated with their invasive potential.
- Author
-
Kousidou OC, Roussidis AE, Theocharis AD, and Karamanos NK
- Subjects
- Breast Neoplasms genetics, Breast Neoplasms pathology, Humans, Isoenzymes, Mammary Glands, Human enzymology, Mammary Glands, Human physiology, Matrix Metalloproteinases genetics, Neoplasm Invasiveness, RNA, Messenger biosynthesis, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, Tissue Inhibitor of Metalloproteinases genetics, Tumor Cells, Cultured, Breast Neoplasms enzymology, Matrix Metalloproteinases biosynthesis, Tissue Inhibitor of Metalloproteinases biosynthesis
- Abstract
Growth and invasiveness of breast cancer cells in adjacent and distant sites is associated with the expression of metalloproteinases (MMPs), which are capable of degrading almost all extracellular matrix macromolecules of supporting stroma. In order to identify markers useful for monitoring breast cancer pathogenesis and metastatic potential, we examined the expression of mRNAs encoded for MMPs and their endogenous inhibitors (TIMPs) in a panel of four epithelial breast cancer cell lines of high (MDA-MB-231 and ZR-75-1) and low (MCF-7 and BT-20) metastatic potential, and their expression was compared with that of normal mammary cells (MCF-12A). Expression patterns were evaluated using cell cultures in serum-containing and serum-free media. Gene expression studies were performed following cell cultures, RNA isolation, reversed transcription and polymerase chain reaction. Both normal and breast cancer cells express MMPs and TIMPs at various levels, depending on cell type and culture conditions. Comparison of their mRNA levels from serum-containing media showed that MMP-9, MT2-MMP and TIMP-1 are highly expressed in all cancer cells as compared to normal ones, whereas MMP-1 and -7 are overexpressed only in breast cancer cells of high invasion potential. In serum-free cultures, the highly metastatic cells retain the overexpression profile for MMP-1 and -7. Furthermore, MT2-MMP and TIMP-1 were constitutively expressed and they can also be correlated with cancer cells, whereas constitutive expression of MMP-9 was similar in normal and cancer cells. The results of this study indicate that the expression of MMPs is dependent on the culture conditions, i.e. the growth factors present in serum-containing media. Furthermore, data suggest that, independently of cell culture conditions, the expression of MT2-MMP may be associated with malignant transformation of mammary cells and the overexpression of MMP-1 and -7 with the highly metastatic potential of epithelial breast cancer cells.
- Published
- 2004
36. STI571 as a potent inhibitor of growth and invasiveness of human epithelial breast cancer cells.
- Author
-
Roussidis AE, Mitropoulou TN, Theocharis AD, Kiamouris C, Papadopoulos S, Kletsas D, and Karamanos NK
- Subjects
- Adenocarcinoma pathology, Benzamides, Breast Neoplasms pathology, Cell Cycle drug effects, Cell Division drug effects, Cell Line, Tumor, Humans, Imatinib Mesylate, Neoplasm Invasiveness, Adenocarcinoma drug therapy, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Piperazines pharmacology, Pyrimidines pharmacology
- Abstract
STI571, a specific tyrosine kinase inhibitor, exhibits a substantial therapeutic activity in patients with chronic myeloid leukaemia and gastrointestinal stromal tumors. In this study we examined the activity of STI571 on the growth and invasiveness of three human epithelial breast cancer cell lines of low (MCF-7) and high (ZR-75-1 and MDA-MB-231) invasive potential. Growth of all cell lines in serum-containing medium was significantly inhibited by STI571 in a dose-dependent manner, with an average IC50 of approximately 5-6 microM. Flow cytometric analysis revealed that this effect is characterized by an accumulation of all breast cancer cell types tested in the G2/M-phase of the cell cycle with a concomitant decrease of the percentage of cells in the S-phase. Interestingly, no increase in apoptosis was observed, indicating that the effect of this kinase inhibitor is cytostatic rather than cytotoxic. In addition, STI571 exerts a significant inhibition effect on the invasion of the highly invasive breast cancer cell lines ZR-75-1 and MDA-MB-231. These results encourage further preclinical investigations on the mechanisms underlying the inhibitory effects of STI571, which may be of great value in breast cancer treatment.
- Published
- 2004
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.