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Matrix Glycans as Multifunctional Pathogenesis Factors and Therapeutic Targets in Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 14126

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Special Issue Editors

Prof. Dr. Ludwig Kiesel

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Guest Editor

Department of Gynecology and Obstetrics, Münster University Hospital, Albert-Schweitzer-Campus 1, 48149 Münster, Germany

Prof. Dr. Martin Götte

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Co-Guest Editor

Department of Gynecology and Obstetrics, Münster University Hospital, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
Interests: proteoglycans; glycosaminoglycans; syndecans; heparan sulfate; cancer cell biology; microRNA; cancer stem cells
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Special Issue Information

Dear Colleagues,

Cancer is a leading cause of mortality within the aging population. Therapeutic targeting is hampered by the complexity of the disease, which includes not only molecular changes within the tumor cell itself, but also within its microenvironment. Tumor angiogenesis, tumor–stroma interactions, interactions with immune cells and the extracellular matrix and cancer stem cell niches allow for malignant cell survival and promote metastasis, the leading cause for cancer-associated mortality. Proteoglycans (PGs) and glycosaminoglycans (GAGs) – structurally diverse carbohydrates of the extracellular matrix and cell surfaces – have emerged as novel biomarkers and molecular players both within tumor cells and their microenvironment, as they integrate signals from growth factors, chemokines and integrins, and cell–cell and cell–matrix adhesion. Furthermore, most constituents of the extracellular matrix are glycosylated, including large structural glycoproteins such as collagens, laminins, and tenascins, with important implications for molecular interactions and functions. Matrix glycoproteins are further modulated by degradative and editing enzymes such as heparanases and HSulfs. Importantly, their expression is dysregulated in numerous tumor entities, and modulates all molecular steps towards cancer metastasis. Pharmacological interference with their function thus emerges as an attractive multitargeted antitumoral approach that simultaneously acts at multiple levels of disease progression.

This Special Issue of Cancers, therefore, encompasses new research articles and timely reviews on all aspects of the role of matrix glycans in human cancer.

Prof. Dr. Ludwig Kiesel
Prof. Dr. Martin Götte
Guest Editors

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Keywords

Proteoglycans
glycosaminoglycans
heparanase
glycosylation
glycosyltransferase
cancer, cancer therapy
biomarker
tumor microenvironment
extracellular matrix

Published Papers (6 papers)

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Research

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19 pages, 11788 KiB

Open AccessArticle

SPOCK1 Overexpression Suggests Poor Prognosis of Ovarian Cancer

by Lóránd Váncza, Anna Horváth, Lee Seungyeon, András Rókusz, Katalin Dezső, Andrea Reszegi, Gábor Petővári, Martin Götte, Ilona Kovalszky and Kornélia Baghy

Cancers 2023, 15(7), 2037; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15072037 - 29 Mar 2023

Cited by 2 | Viewed by 1641

Abstract

Purpose: Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) has been found in a variety of malignant tumors and is associated with a poor prognosis. We aimed to explore the role of SPOCK1 in ovarian cancer. Methods: Ovarian cancer cell lines SKOV3 and SW626 were transfected with SPOCK1 overexpressing or empty vector using electroporation. Cells were studied by immunostaining and an automated Western blotting system. BrdU uptake and wound healing assays assessed cell proliferation and migration. SPOCK1 expression in human ovarian cancer tissues and in blood samples were studied by immunostaining and ELISA. Survival of patients with tumors exhibiting low and high SPOCK1 expression was analyzed using online tools. Results: Both transfected cell lines synthesized different SPOCK1 variants; SKOV3 cells also secreted the proteoglycan. SPOCK1 overexpression stimulated DNA synthesis and cell migration involving p21^CIP1. Ovarian cancer patients had increased SPOCK1 serum levels compared to healthy controls. Tumor cells of tissues also displayed abundant SPOCK1. Moreover, SPOCK1 levels were higher in untreated ovarian cancer serum and tissue samples and lower in recipients of chemotherapy. According to in silico analyses, high SPOCK1 expression was correlated with shorter survival. Conclusion: Our findings suggest SPOCK1 may be a viable anti-tumor therapeutic target and could be used for monitoring ovarian cancer. Full article

(This article belongs to the Special Issue Matrix Glycans as Multifunctional Pathogenesis Factors and Therapeutic Targets in Cancer)

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17 pages, 4093 KiB

Open AccessArticle

Glycosaminoglycan Analysis of FFPE Tissues from Prostate Cancer and Benign Prostate Hyperplasia Patients Reveals Altered Regulatory Functions and Independent Markers for Survival

by Gábor Tóth, Simon Sugár, Domonkos Pál, Kata Dorina Fügedi, László Drahos, Gitta Schlosser, Csilla Oláh, Henning Reis, Ilona Kovalszky, Tibor Szarvas and Lilla Turiák

Cancers 2022, 14(19), 4867; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194867 - 05 Oct 2022

Cited by 1 | Viewed by 1681

Abstract

Prostate cancer is one of the most frequent cancer types among men. Several biomarkers and risk assessment methods are already available; however, enhancing their selectivity and sensitivity is still necessary. For improving therapeutic decisions, both basic and clinical research studies are still ongoing for a better understanding of the underlying molecular mechanisms. The enzymatic digests of heparan sulfate (HS) and chondroitin sulfate (CS) chains were investigated in tissue samples taken from patients with prostate cancer (PCa) and benign prostate hyperplasia (BPH) with the HPLC–MS methodology. None of the HS species analyzed showed correlating alterations with currently used markers such as clinical stage, Gleason score, or prostate-specific antigen (PSA) level. The total quantity and sulfation motifs of CS were both significantly different among BPH and different risk groups of PCa. Furthermore, the cancer-specific survival of patients can be predicted based on the levels of non-sulfated and doubly sulfated CS disaccharides as well as the total HS content and the doubly and triply sulfated HS disaccharide ratios. These disaccharide ratios proved to be independent markers from clinical parameters. Further investigations of glycosaminoglycan motifs were proposed for the validation of the results on independent patient cohorts as well. Full article

(This article belongs to the Special Issue Matrix Glycans as Multifunctional Pathogenesis Factors and Therapeutic Targets in Cancer)

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13 pages, 3562 KiB

Open AccessEditor’s ChoiceArticle

The Matrisome Is Associated with Metabolic Reprograming in Stem-like Phenotypes of Gastric Cancer

by Ji-Yong Sung and Jae-Ho Cheong

Cancers 2022, 14(6), 1438; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061438 - 10 Mar 2022

Cited by 8 | Viewed by 2555

Abstract

The extracellular matrix (ECM) is an important regulator of all cellular functions, and the matrisome represents a major component of the tumor microenvironment. The matrisome is an essential component comprising genes encoding ECM glycoproteins, collagens, and proteoglycans; however, its role in cancer progression and the development of stem-like molecular subtypes in gastric cancer is unknown. We analyzed gastric cancer data from five molecular subtypes (n = 497) and found that metabolic reprograming differs based on the state of the matrisome. Approximately 95% of stem-like cancer type samples of gastric cancer were in the high-matrisome category, and energy metabolism was considerably increased in the high-matrisome group. Particularly, high glycosaminoglycan biosynthesis-chondroitin sulfate metabolic reprograming was associated with an unfavorable prognosis. Glycosaminoglycan biosynthesis-chondroitin sulfate metabolic reprograming may occur according to the matrisome status and contribute to the development of stem-like phenotypes. Our analysis suggests the possibility of precision medicine for anticancer therapies. Full article

(This article belongs to the Special Issue Matrix Glycans as Multifunctional Pathogenesis Factors and Therapeutic Targets in Cancer)

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Review

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24 pages, 2453 KiB

Open AccessReview

Revisiting the Syndecans: Master Signaling Regulators with Prognostic and Targetable Therapeutic Values in Breast Carcinoma

by Juliana Maria Motta, Hebatallah Hassan and Sherif Abdelaziz Ibrahim

Cancers 2023, 15(6), 1794; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15061794 - 16 Mar 2023

Cited by 4 | Viewed by 1947

Abstract

Syndecans (SDC1 to 4), a family of cell surface heparan sulfate proteoglycans, are frequently expressed in mammalian tissues. SDCs are aberrantly expressed either on tumor or stromal cells, influencing cancer initiation and progression through their pleiotropic role in different signaling pathways relevant to proliferation, cell-matrix adhesion, migration, invasion, metastasis, cancer stemness, and angiogenesis. In this review, we discuss the key roles of SDCs in the pathogenesis of breast cancer, the most common malignancy in females worldwide, focusing on the prognostic significance and molecular regulators of SDC expression and localization in either breast tumor tissue or its microenvironmental cells and the SDC-dependent epithelial–mesenchymal transition program. This review also highlights the molecular mechanisms underlying the roles of SDCs in regulating breast cancer cell behavior via modulation of nuclear hormone receptor signaling, microRNA expression, and exosome biogenesis and functions, as well as summarizing the potential of SDCs as promising candidate targets for therapeutic strategies against breast cancer. Full article

(This article belongs to the Special Issue Matrix Glycans as Multifunctional Pathogenesis Factors and Therapeutic Targets in Cancer)

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31 pages, 2828 KiB

Open AccessReview

The Tissue Factor Pathway in Cancer: Overview and Role of Heparan Sulfate Proteoglycans

by Nourhan Hassan, Janes Efing, Ludwig Kiesel, Gerd Bendas and Martin Götte

Cancers 2023, 15(5), 1524; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15051524 - 28 Feb 2023

Cited by 8 | Viewed by 3221

Abstract

Historically, the only focus on tissue factor (TF) in clinical pathophysiology has been on its function as the initiation of the extrinsic coagulation cascade. This obsolete vessel-wall TF dogma is now being challenged by the findings that TF circulates throughout the body as a soluble form, a cell-associated protein, and a binding microparticle. Furthermore, it has been observed that TF is expressed by various cell types, including T-lymphocytes and platelets, and that certain pathological situations, such as chronic and acute inflammatory states, and cancer, may increase its expression and activity. Transmembrane G protein-coupled protease-activated receptors can be proteolytically cleaved by the TF:FVIIa complex that develops when TF binds to Factor VII (PARs). The TF:FVIIa complex can activate integrins, receptor tyrosine kinases (RTKs), and PARs in addition to PARs. Cancer cells use these signaling pathways to promote cell division, angiogenesis, metastasis, and the maintenance of cancer stem-like cells. Proteoglycans play a crucial role in the biochemical and mechanical properties of the cellular extracellular matrix, where they control cellular behavior via interacting with transmembrane receptors. For TFPI.fXa complexes, heparan sulfate proteoglycans (HSPGs) may serve as the primary receptor for uptake and degradation. The regulation of TF expression, TF signaling mechanisms, their pathogenic effects, and their therapeutic targeting in cancer are all covered in detail here. Full article

(This article belongs to the Special Issue Matrix Glycans as Multifunctional Pathogenesis Factors and Therapeutic Targets in Cancer)

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13 pages, 1021 KiB

Open AccessReview

Hyaluronan in the Cancer Cells Microenvironment

by Evgenia Karousou, Arianna Parnigoni, Paola Moretto, Alberto Passi, Manuela Viola and Davide Vigetti

Cancers 2023, 15(3), 798; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15030798 - 28 Jan 2023

Cited by 5 | Viewed by 2070

Abstract

The presence of the glycosaminoglycan hyaluronan in the extracellular matrix of tissues is the result of the cooperative synthesis of several resident cells, that is, macrophages and tumor and stromal cells. Any change in hyaluronan concentration or dimension leads to a modification in stiffness and cellular response through receptors on the plasma membrane. Hyaluronan has an effect on all cancer cell behaviors, such as evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and metastasis. It is noteworthy that hyaluronan metabolism can be dramatically altered by growth factors and matrikines during inflammation, as well as by the metabolic homeostasis of cells. The regulation of HA deposition and its dimensions are pivotal for tumor progression and cancer patient prognosis. Nevertheless, because of all the factors involved, modulating hyaluronan metabolism could be tough. Several commercial drugs have already been described as potential or effective modulators; however, deeper investigations are needed to study their possible side effects. Moreover, other matrix molecules could be identified and targeted as upstream regulators of synthetic or degrading enzymes. Finally, co-cultures of cancer, fibroblasts, and immune cells could reveal potential new targets among secreted factors. Full article

(This article belongs to the Special Issue Matrix Glycans as Multifunctional Pathogenesis Factors and Therapeutic Targets in Cancer)

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