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The Role of Extracellular Matrix in Cancer Development and Progression

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (30 July 2021) | Viewed by 38805

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Special Issue Editors

Prof. George Tzanakakis

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Guest Editor

Laboratories of Anatomy and Histology-Embryology, School of Medicine, The University of Crete, Heraklion, Greece
Interests: matrix pathobiology; tumor biology; signal transduction; disease markers; molecular targets; proteoglycans; glycosaminoglycans; matrix cell surface receptors; tumorigenesis; inflammation; cytotoxicity

Dr. Dragana Nikitovic

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Guest Editor

Laboratory of Histology-Embryology, School of Medicine, The University of Crete, 71003 Heraklion, Greece
Interests: matrix pathobiology; cancer; inflammation; oxidative stress; cytotoxicity; matrix pathobiology
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The consecutive steps of tumor growth, local invasion, intravasation, extravasation, and invasion of anatomically distant sites, as well as immunosuppression, are obligatorily perpetrated through specific interactions of the tumor cells with their microenvironment. During cancer progression, significant changes can be observed in the properties of extracellular matrices (ECMs) components, which deregulate the behavior of stromal cells, promote tumor-associated angiogenesis and inflammation, and lead to the generation of a tumorigenic microenvironment. Thus, mediators that originate from the ECM have a vital effect on all cellular functions implicated in cancer development and progression. ECM components, including fibrillar proteins, proteoglycans, and glycosaminoglycans, modulate the bioavailability of active mediators, control the stiffness of the stroma immediately correlated to cancer cell invasion, and regulate the metastatic processes and angiogenesis. Various ECM-derived components also have the ability to modulate the immune response and affect the response to therapy and thus need to be taken into account when designing efficient anticancer therapy. Indeed, the ECM effectors regulate processes correlated to chemoresistance, including autophagy and apoptosis.

This Special Issue of Biomolecules entitled “Role of Extracellular Matrix in Development and Cancer Progression” focuses on recent findings in the structural and functional characterization of ECM components and how they relate to the processes involved in the pathogenesis of cancer, and response to therapy. Focusing on the crosstalk between the ECM and cellular processes has helped to identify novel disease markers and therapeutic targets. We invite researchers to submit reviews or regular research articles focusing on this vital crosstalk.

Professor George Tzanakakis
Professor Dragana Nikitovic
Guest Editors

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Keywords

extracellular matrix
tumor microenvironment
cancer
proteoglycans
glycosaminoglycans
fibrillar proteins
chemoresistance
autophagy
cancer cell functions
cancer immunobiology
cancer therapy targets
hyaluronan in cancer
epithelial to mesenchymal transition
metastatic cascade and ECM effectors
ECM-driven angiogenesis
matrix metalloproteinases
matrikines as tumor effectors

Published Papers (10 papers)

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Editorial

Jump to: Research, Review

3 pages, 169 KiB

Open AccessEditorial

Preface of the Special Issue on the Role of Extracellular Matrix in Development and Cancer Progression

by George Tzanakakis and Dragana Nikitovic

Biomolecules 2022, 12(3), 362; https://doi.org/10.3390/biom12030362 - 25 Feb 2022

Cited by 3 | Viewed by 1132

Abstract

The consecutive steps of tumor growth, local invasion, intravasation, extravasation, invasion of anatomically distant sites, and immunosuppression are obligatorily perpetrated through specific interactions of the tumor cells with their microenvironment [...] Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Cancer Development and Progression)

Research

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14 pages, 2575 KiB

Open AccessFeature PaperArticle

Sulfated Hyaluronan Modulates the Functional Properties and Matrix Effectors Expression of Breast Cancer Cells with Different Estrogen Receptor Status

by Christos Koutsakis, Anastasia-Gerasimoula Tavianatou, Dimitris Kokoretsis, Georgios Baroutas and Nikos K. Karamanos

Biomolecules 2021, 11(12), 1916; https://doi.org/10.3390/biom11121916 - 20 Dec 2021

Cited by 4 | Viewed by 3056

Abstract

Hyaluronan (HA) is an extracellular matrix glycosaminoglycan (GAG) that plays a pivotal role in breast cancer. While HA is the only GAG not normally substituted with sulfate groups, sulfated hyaluronan (sHA) has previously been used in studies with promising antitumor results. The aim of the present study was to evaluate the effects sHA fragments have on breast cancer cells with different estrogen receptor (ER) status. To this end, ERα-positive MCF-7, and ERβ-positive MDA-MB-231 cells were treated with non-sulfated HA or sHA fragments of 50 kDa. The functional properties of the breast cancer cells and the expression of key matrix effectors were investigated. According to the results, sHA attenuates cell proliferation, migration, and invasion, while increasing adhesion on collagen type I. Furthermore, sHA modulates the expression of epithelial-to-mesenchymal transition (EMT) markers, such as e-cadherin and snail2/slug. Additionally, sHA downregulates matrix remodeling enzymes such as the matrix metalloproteinases MT1-MMP, MMP2, and MMP9. Notably, sHA exhibits a stronger effect on the breast cancer cell properties compared to the non-sulfated counterpart, dependent also on the type of cancer cell type. Consequently, a deeper understanding of the mechanism by which sHA facilitate these processes could contribute to the development of novel therapeutic strategies. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Cancer Development and Progression)

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15 pages, 5364 KiB

Open AccessArticle

Diagnostic and Prognostic Utility of the Extracellular Vesicles Subpopulations Present in Pleural Effusion

by Joman Javadi, André Görgens, Hanna Vanky, Dhanu Gupta, Anders Hjerpe, Samir EL-Andaloussi, Daniel Hagey and Katalin Dobra

Biomolecules 2021, 11(11), 1606; https://doi.org/10.3390/biom11111606 - 29 Oct 2021

Cited by 12 | Viewed by 2226

Abstract

Extracellular vesicles (EVs), comprising exosomes, microvesicles, and apoptotic bodies, are released by all cells into the extracellular matrix and body fluids, where they play important roles in intercellular communication and matrix remodeling in various pathological conditions. Malignant pleural mesothelioma (MPM) is a primary tumor of mesothelial origin, predominantly related to asbestos exposure. The detection of MPM at an early stage and distinguishing it from benign conditions and metastatic adenocarcinomas (AD) is sometimes challenging. Pleural effusion is often the first available biological material and an ideal source for characterizing diagnostic and prognostic factors. Specific proteins have previously been identified as diagnostic markers in effusion, but it is not currently known whether these are associated with vesicles or released in soluble form. Here, we study and characterize tumor heterogeneity and extracellular vesicle diversity in pleural effusion as diagnostic or prognostic markers for MPM. We analyzed extracellular vesicles and soluble proteins from 27 pleural effusions, which were collected and processed at the department of pathology and cytology at Karolinska University Hospital, representing three different patient groups, MPM (n = 9), benign (n = 6), and AD (n = 12). The vesicles were fractionated into apoptotic bodies, microvesicles, and exosomes by differential centrifugation and characterized by nanoparticle tracking analysis and Western blotting. Multiplex bead-based flow cytometry analysis showed that exosomal markers were expressed differently on EVs present in different fractions. Further characterization of exosomes by a multiplex immunoassay (Luminex) showed that all soluble proteins studied were also present in exosomes, though the ratio of protein concentration present in supernatant versus exosomes varied. The proportion of Angiopoietin-1 present in exosomes was generally higher in benign compared to malignant samples. The corresponding ratios of Mesothelin, Galectin-1, Osteopontin, and VEGF were higher in MPM effusions compared to those in the benign group. These findings demonstrate that relevant diagnostic markers can be recovered from exosomes. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Cancer Development and Progression)

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14 pages, 3103 KiB

Open AccessArticle

AG-9, an Elastin-Derived Peptide, Increases In Vitro Oral Tongue Carcinoma Cell Invasion, through an Increase in MMP-2 Secretion and MT1-MMP Expression, in a RPSA-Dependent Manner

by Clara Bretaudeau, Stéphanie Baud, Aurélie Dupont-Deshorgue, Rémi Cousin, Bertrand Brassart and Sylvie Brassart-Pasco

Biomolecules 2021, 11(1), 39; https://doi.org/10.3390/biom11010039 - 30 Dec 2020

Cited by 6 | Viewed by 2165

Abstract

Oral tongue squamous cell carcinoma is one of the most prevalent head and neck cancers. During tumor progression, elastin fragments are released in the tumor microenvironment. Among them, we previously identified a nonapeptide, AG-9, that stimulates melanoma progression in vivo in a mouse melanoma model. In the present paper, we studied AG-9 effect on tongue squamous cell carcinoma invasive properties. We demonstrated that AG-9 stimulates cell invasion in vitro in a modified Boyen chamber model. It increases MMP-2 secretion, analyzed by zymography and MT1-MMP expression, studied by Western blot. The stimulatory effect was mediated through Ribosomal Protein SA (RPSA) receptor binding as demonstrated by SiRNA experiments. The green tea-derived polyphenol, (−)-epigallocatechin-3-gallate (EGCG), was previously shown to bind RPSA. Molecular docking experiments were performed to compare the preferred areas of interaction of AG-9 and EGCG with RPSA and suggested overlapping areas. This was confirmed by competition assays. EGCG abolished AG-9-induced invasion, MMP-2 secretion, and MT1-MMP expression. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Cancer Development and Progression)

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Review

Jump to: Editorial, Research

17 pages, 1649 KiB

Open AccessReview

Hyaluronan Functions in Wound Repair That Are Captured to Fuel Breast Cancer Progression

by Cornelia Tolg, Britney Jodi-Ann Messam, James Benjamin McCarthy, Andrew Cook Nelson and Eva Ann Turley

Biomolecules 2021, 11(11), 1551; https://doi.org/10.3390/biom11111551 - 20 Oct 2021

Cited by 15 | Viewed by 3760

Abstract

Signaling from an actively remodeling extracellular matrix (ECM) has emerged as a critical factor in regulating both the repair of tissue injuries and the progression of diseases such as metastatic cancer. Hyaluronan (HA) is a major component of the ECM that normally functions in tissue injury to sequentially promote then suppress inflammation and fibrosis, a duality in which is featured, and regulated in, wound repair. These essential response-to-injury functions of HA in the microenvironment are hijacked by tumor cells for invasion and avoidance of immune detection. In this review, we first discuss the numerous size-dependent functions of HA and emphasize the multifunctional nature of two of its receptors (CD44 and RHAMM) in regulating the signaling duality of HA in excisional wound healing. This is followed by a discussion of how HA metabolism is de-regulated in malignant progression and how targeting HA might be used to better manage breast cancer progression. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Cancer Development and Progression)

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19 pages, 1102 KiB

Open AccessEditor’s ChoiceReview

Lumican in Carcinogenesis—Revisited

by Eirini-Maria Giatagana, Aikaterini Berdiaki, Aristidis Tsatsakis, George N. Tzanakakis and Dragana Nikitovic

Biomolecules 2021, 11(9), 1319; https://doi.org/10.3390/biom11091319 - 06 Sep 2021

Cited by 23 | Viewed by 4026

Abstract

Carcinogenesis is a multifactorial process with the input and interactions of environmental, genetic, and metabolic factors. During cancer development, a significant remodeling of the extracellular matrix (ECM) is evident. Proteoglycans (PGs), such as lumican, are glycosylated proteins that participate in the formation of the ECM and are established biological mediators. Notably, lumican is involved in cellular processes associated with tumorigeneses, such as EMT (epithelial-to-mesenchymal transition), cellular proliferation, migration, invasion, and adhesion. Furthermore, lumican is expressed in various cancer tissues and is reported to have a positive or negative correlation with tumor progression. This review focuses on significant advances achieved regardingthe role of lumican in the tumor biology. Here, the effects of lumican on cancer cell growth, invasion, motility, and metastasis are discussed, as well as the repercussions on autophagy and apoptosis. Finally, in light of the available data, novel roles for lumican as a cancer prognosis marker, chemoresistance regulator, and cancer therapy target are proposed. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Cancer Development and Progression)

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23 pages, 1286 KiB

Open AccessReview

Current Perspectives on the Role of Matrix Metalloproteinases in the Pathogenesis of Basal Cell Carcinoma

by Mircea Tampa, Simona Roxana Georgescu, Madalina Irina Mitran, Cristina Iulia Mitran, Clara Matei, Ana Caruntu, Cristian Scheau, Ilinca Nicolae, Andreea Matei, Constantin Caruntu, Carolina Constantin and Monica Neagu

Biomolecules 2021, 11(6), 903; https://doi.org/10.3390/biom11060903 - 17 Jun 2021

Cited by 24 | Viewed by 3649

Abstract

Basal cell carcinoma (BCC) is the most common skin malignancy, which rarely metastasizes but has a great ability to infiltrate and invade the surrounding tissues. One of the molecular players involved in the metastatic process are matrix metalloproteinases (MMPs). MMPs are enzymes that can degrade various components of the extracellular matrix. In the skin, the expression of MMPs is increased in response to various stimuli, including ultraviolet (UV) radiation, one of the main factors involved in the development of BCC. By modulating various processes that are linked to tumor growth, such as invasion and angiogenesis, MMPs have been associated with UV-related carcinogenesis. The sources of MMPs are multiple, as they can be released by both neoplastic and tumor microenvironment cells. Inhibiting the action of MMPs could be a useful therapeutic option in BCC management. In this review that reunites the latest advances in this domain, we discuss the role of MMPs in the pathogenesis and evolution of BCC, as molecules involved in tumor aggressiveness and risk of recurrence, in order to offer a fresh and updated perspective on this field. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Cancer Development and Progression)

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25 pages, 2178 KiB

Open AccessEditor’s ChoiceReview

Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

by Ramiz S. Ahmad, Timothy D. Eubank, Slawomir Lukomski and Brian A. Boone

Biomolecules 2021, 11(6), 901; https://doi.org/10.3390/biom11060901 - 17 Jun 2021

Cited by 19 | Viewed by 4462

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Cancer Development and Progression)

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16 pages, 737 KiB

Open AccessFeature PaperReview

Syndecan-4 as a Pathogenesis Factor and Therapeutic Target in Cancer

by Jessica Oyie Sousa Onyeisi, Carla Cristina Lopes and Martin Götte

Biomolecules 2021, 11(4), 503; https://doi.org/10.3390/biom11040503 - 26 Mar 2021

Cited by 22 | Viewed by 7672

Abstract

Cancer is an important cause of morbidity and mortality worldwide. Advances in research on the biology of cancer revealed alterations in several key pathways underlying tumorigenesis and provided molecular targets for developing new and improved existing therapies. Syndecan-4, a transmembrane heparan sulfate proteoglycan, is a central mediator of cell adhesion, migration and proliferation. Although several studies have demonstrated important roles of syndecan-4 in cell behavior and its interactions with growth factors, extracellular matrix (ECM) molecules and cytoskeletal signaling proteins, less is known about its role and expression in multiple cancer. The data summarized in this review demonstrate that high expression of syndecan-4 is an unfavorable biomarker for estrogen receptor-negative breast cancer, glioma, liver cancer, melanoma, osteosarcoma, papillary thyroid carcinoma and testicular, kidney and bladder cancer. In contrast, in neuroblastoma and colorectal cancer, syndecan-4 is downregulated. Interestingly, syndecan-4 expression is modulated by anticancer drugs. It is upregulated upon treatment with zoledronate and this effect reduces invasion of breast cancer cells. In our recent work, we demonstrated that the syndecan-4 level was reduced after trastuzumab treatment. Similarly, syndecan-4 levels are also reduced after panitumumab treatment. Together, the data found suggest that syndecan-4 level is crucial for understanding the changes involving in malignant transformation, and also demonstrate that syndecan-4 emerges as an important target for cancer therapy and diagnosis. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Cancer Development and Progression)

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23 pages, 3768 KiB

Open AccessReview

Syndecans and Pancreatic Ductal Adenocarcinoma

by Nausika Betriu, Juan Bertran-Mas, Anna Andreeva and Carlos E. Semino

Biomolecules 2021, 11(3), 349; https://doi.org/10.3390/biom11030349 - 25 Feb 2021

Cited by 12 | Viewed by 5106

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is a fatal disease with poor prognosis because patients rarely express symptoms in initial stages, which prevents early detection and diagnosis. Syndecans, a subfamily of proteoglycans, are involved in many physiological processes including cell proliferation, adhesion, and migration. Syndecans are physiologically found in many cell types and their interactions with other macromolecules enhance many pathways. In particular, extracellular matrix components, growth factors, and integrins collect the majority of syndecans associations acting as biochemical, physical, and mechanical transducers. Syndecans are transmembrane glycoproteins, but occasionally their extracellular domain can be released from the cell surface by the action of matrix metalloproteinases, converting them into soluble molecules that are capable of binding distant molecules such as extracellular matrix (ECM) components, growth factor receptors, and integrins from other cells. In this review, we explore the role of syndecans in tumorigenesis as well as their potential as therapeutic targets. Finally, this work reviews the contribution of syndecan-1 and syndecan-2 in PDAC progression and illustrates its potential to be targeted in future treatments for this devastating disease. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Cancer Development and Progression)

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