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Extracellular Matrix Proteins in Cancer
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Extracellular Matrix Proteins in Cancer

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

Deadline for manuscript submissions: closed (31 July 2025) | Viewed by 20473

Special Issue Editors

Dr. Dragana Nikitovic

E-Mail Website
Guest Editor
Laboratory of Histology-Embryology, School of Medicine, The University of Crete, 71003 Heraklion, Greece
Interests: matrix pathobiology; cancer; inflammation; oxidative stress; cytotoxicity
Special Issues, Collections and Topics in MDPI journals
Dr. Aikaterini Berdiaki

E-Mail Website
Guest Editor
Laboratory of Histology-Embryology, Medical School, University of Crete, 71003 Heraklion, Greece
Interests: histology; cytology; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The transformed extracellular matrix (ECM) constitutes the non-cellular component of a cancerous microenvironment, and its interactions with cellular components (tumor cells, normal tissue cells, blood vessels, stromal cells and cells of the immune system) modulate cell function and morphology, signaling transductions and subsequently tumor development. Protein ECM components include proteoglycans (extracellular, pericellular/basement membrane and cell surface PGs), fibrous proteins (collagens, elastin) and glycoproteins (laminin, fibronectin). ECM remodeling and changes in composition influence cell proliferation, motility, adhesion and invasion.

This Special Issue focuses on describing and updating the role of ECM proteins in different cancer-type microenvironments as well as defining ECM-associated molecular and structural mechanisms in tumor development.

Original research articles and review articles related to the topic are invited for this Special Issue.

We look forward to receiving your contributions.

Dr. Dragana Nikitovic
Dr. Aikaterini Berdiaki
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • extracellular matrix
  • cancer
  • tumor microenvironment
  • ECM proteins
  • proteoglycans
  • glycoproteins
  • collagens
  • fibrous proteins
  • molecular mechanisms

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Published Papers (8 papers)

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Research

Jump to: Review

22 pages, 3810 KB  
Article
Spheroid-Based 3D Models to Decode Cell Function and Matrix Effectors in Breast Cancer
by Sylvia Mangani, Christos Koutsakis, Nikolaos E. Koletsis, Zoi Piperigkou, Marco Franchi, Martin Götte and Nikos K. Karamanos
Cancers 2025, 17(21), 3512; https://doi.org/10.3390/cancers17213512 - 31 Oct 2025
Viewed by 1156
Abstract
Background/Objectives: Conventional two-dimensional (2D) cell cultures offer valuable insights into cancer cell biology; however, they lack in replicating the complex interactions present in solid tumors. Therefore, research has shifted towards the development of three-dimensional (3D) cell models that recapitulate the dynamic cell–cell [...] Read more.
Background/Objectives: Conventional two-dimensional (2D) cell cultures offer valuable insights into cancer cell biology; however, they lack in replicating the complex interactions present in solid tumors. Therefore, research has shifted towards the development of three-dimensional (3D) cell models that recapitulate the dynamic cell–cell and cell–matrix interactions within the complex tumor microenvironment (TME), better resembling tumor growth and initial stages of dissemination. Extracellular matrix, a key component within the TME, regulates cell morphology and signaling, influencing key functional properties. Breast cancer remains the most frequently diagnosed cancer type in women and a leading cause of cancer-related mortality. Methods: The aim of the present study was the development of breast cancer cell-derived spheroids, utilizing two breast cancer cell lines with differential estrogen receptor (ER) expression profile, and their characterization in terms of morphology, functional properties, and expression of epithelial-to-mesenchymal transition (EMT) markers and matrix signatures implicated in breast cancer progression. To this end, the ERα-positive MCF-7, and ERβ-positive MDA-MB-231 breast cancer cell lines were utilized. Results: Our findings revealed notable phenotypic transitions between 2D and 3D cultures, which were further supported by differential EMT markers expression. Moreover, spheroids exhibited distinct expression profiles of key receptors [ERs, epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor (IGF1R)] and matrix molecules (syndecans, and matrix metalloproteinases), accompanied by altered functional cell properties. Bioinformatic tools further emphasized the interplay between the studied matrix regulators and their prognostic relevance in breast cancer. Conclusions: Overall, this study introduces a simple yet informative 3D breast cancer model that captures key TME features to better predict cell behavior in vitro. Full article
(This article belongs to the Special Issue Extracellular Matrix Proteins in Cancer)
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19 pages, 1781 KB  
Article
Physiopathological Features in a Three-Dimensional In Vitro Model of Hepatocellular Carcinoma: Hypoxia-Driven Oxidative Stress and ECM Remodeling
by Maria Giovanna Rizzo, Enza Fazio, Claudia De Pasquale, Emanuele Luigi Sciuto, Giorgia Cannatà, Cristiana Roberta Multisanti, Federica Impellitteri, Federica Gilda D’Agostino, Salvatore Pietro Paolo Guglielmino, Caterina Faggio and Sabrina Conoci
Cancers 2025, 17(18), 3082; https://doi.org/10.3390/cancers17183082 - 21 Sep 2025
Viewed by 1068
Abstract
Background: Hypoxia is a hallmark of solid tumors, including hepatocellular carcinoma (HCC), where it drives oxidative stress and extracellular matrix (ECM) remodeling, promoting tumor invasion and metastasis. Investigating these mechanisms in patients remains challenging due to the complexity of the tumor microenvironment. [...] Read more.
Background: Hypoxia is a hallmark of solid tumors, including hepatocellular carcinoma (HCC), where it drives oxidative stress and extracellular matrix (ECM) remodeling, promoting tumor invasion and metastasis. Investigating these mechanisms in patients remains challenging due to the complexity of the tumor microenvironment. Methods: We developed a scaffold-free three-dimensional (3D) spheroid model of HCC using human hepatocellular carcinoma HepG2 cells (ATCC HB-8065). To characterize hypoxia-driven processes, a multiparametric approach combining MTT assays for metabolic activity, confocal microscopy for viability and ECM organization, flow cytometry for apoptosis and ROS detection, qRT-PCR for gene expression, and FTIR spectroscopy for biochemical profiling were performed. Results: The 3D model exhibited progressive ROS accumulation, stabilization of HIF-1α, and metabolic reprogramming toward aerobic glycolysis. In parallel, ECM remodeling was evident, with increased expression of SPARC and FN1 and collagen fiber alignment, reflecting an invasive tumor phenotype. Conclusions: This scaffold-free 3D HCC model recapitulates key physiopathological features of tumor progression, providing a robust and physiologically relevant platform to investigate the hypoxia–ROS–ECM relationship and to support preclinical evaluation of targeted therapeutic strategies. Full article
(This article belongs to the Special Issue Extracellular Matrix Proteins in Cancer)
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18 pages, 17950 KB  
Article
From Structure to Function: The Impact of EGFR and IGF-IR in 3D Breast Cancer Spheroids
by Chrisavgi Gourdoupi, Spyros Kremmydas, Sylvia Mangani, Paraskevi Ioannou, Nikolaos A. Afratis, Zoi Piperigkou and Nikos K. Karamanos
Cancers 2025, 17(16), 2606; https://doi.org/10.3390/cancers17162606 - 8 Aug 2025
Cited by 2 | Viewed by 2032
Abstract
Background: Breast cancer, one of the most researched cancers in oncology, remains the primary cause of cancer-related mortality in women. Its biological complexity, which includes phenotypic, genetic, and microenvironmental aspects, makes modeling and treatment quite difficult. The need for more physiologically realistic [...] Read more.
Background: Breast cancer, one of the most researched cancers in oncology, remains the primary cause of cancer-related mortality in women. Its biological complexity, which includes phenotypic, genetic, and microenvironmental aspects, makes modeling and treatment quite difficult. The need for more physiologically realistic models is highlighted by the comparison of two-dimensional (2D) cell cultures with 3D breast-cancer-derived spheroids, which discloses how important pathways such as epidermal growth factor receptor (EGFR) and insulin-like growth factor I receptor (IGF-IR) influence cell behavior and extracellular matrix (ECM) macromolecular expression. Methods: The purpose of this study was to utilize novel 3D cell platforms to assess the effect of inhibiting the EGFR and IGF-IR pathways, alone or in combination, on the functional properties and the expression levels of certain matrix metalloproteinases (MMPs) which are implicated in breast cancer progression (i.e., triple-negative and luminal A breast cancer subtypes) and related with the EGFR and IGF-ΙR molecular network, as also demonstrated through STRING analysis. Results: Our results demonstrated potential crosstalk between EGFR and IGF-IR signaling, which influences cell proliferation and spheroid growth, dissemination, and migration. Significant phenotypic changes proposed between 2D and 3D cell cultures, and alterations in the expression of MMPs, were also recorded. Conclusions: Both breast cancer cell lines retained acknowledged characteristics across the tested models while also exhibiting new, condition-dependent properties. Overall, our findings enhance our understanding on the interplay between the EGFR and IGF-IR pathways and underscore the value of 3D models in revealing key biological processes underlying distinct breast cancer phenotypes. Full article
(This article belongs to the Special Issue Extracellular Matrix Proteins in Cancer)
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28 pages, 15072 KB  
Article
Unravelling Paclitaxel Resistance in Gastric Cancer: The Role of Small Extracellular Vesicles in Epithelial Mesenchymal Transition and Extracellular Matrix Remodelling
by Giorgia Panzetta, Annalisa Schirizzi, Francesco Balestra, Maria De Luca, Nicoletta Depalo, Federica Rizzi, Angela Dalia Ricci, Giampiero De Leonardis, Claudio Lotesoriere, Gianluigi Giannelli, Rosalba D’Alessandro and Maria Principia Scavo
Cancers 2025, 17(8), 1360; https://doi.org/10.3390/cancers17081360 - 18 Apr 2025
Viewed by 1300
Abstract
Background: Gastric cancer (GC) is a highly aggressive disease often complicated by resistance to chemotherapy agents like paclitaxel (PTX), which targets microtubules to induce apoptosis. Resistance arises through complex molecular mechanisms, including the overexpression of pro-angiogenic factors (VEGFA, ANG-2), activation of survival pathways [...] Read more.
Background: Gastric cancer (GC) is a highly aggressive disease often complicated by resistance to chemotherapy agents like paclitaxel (PTX), which targets microtubules to induce apoptosis. Resistance arises through complex molecular mechanisms, including the overexpression of pro-angiogenic factors (VEGFA, ANG-2), activation of survival pathways (PDGFRβ, PPARγ), and epithelial-mesenchymal transition (EMT) driven by proteins such as VIM, E-CAD, N-CAD, and FLOT-1. The extracellular matrix (ECM), regulated by COL1A1 and influenced by PPARγ, acts as a physical barrier to drug penetration. Small extracellular vesicles (sEVs) have emerged as critical mediators of intercellular communication and may influence these resistance pathways. Methods: This study investigated the role of sEVs isolated from metastatic GC patients treated with Ramucirumab and PTX. Patients were stratified by progression-free survival (PFS) into rapidly progressing (RP) and controlled disease (CD) groups. sEVs from these patients were applied to HCEC-1CT and HEPA-RG cell lines. Cell viability assays, gene and protein expression analyses, and bioinformatic studies were conducted to assess the impact of sEVs on resistance-related markers. Results: Results showed that sEVs from CD patients reduced the expression of markers associated with drug resistance, while sEVs from RP patients increased these markers, promoting angiogenesis, EMT, and ECM remodeling. These changes correlated with enhanced cell survival and resistance phenotypes. Bioinformatic analyses confirmed that sEVs modulate inflammation, ECM dynamics, and EMT pathways. Conclusions: In conclusion, sEVs from metastatic GC patients significantly influence chemoresistance and tumor progression. Targeting sEV-mediated signaling may offer novel therapeutic strategies to overcome resistance and improve treatment outcomes in gastric cancer. Full article
(This article belongs to the Special Issue Extracellular Matrix Proteins in Cancer)
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18 pages, 2615 KB  
Article
The Vimentin-Targeting Drug ALD-R491 Partially Reverts the Epithelial-to-Mesenchymal Transition and Vimentin Interactome of Lung Cancer Cells
by Marieke Rosier, Anja Krstulović, Hyejeong Rosemary Kim, Nihardeep Kaur, Erhumuoghene Mary Enakireru, Deebie Symmes, Katalin Dobra, Ruihuan Chen, Caroline A. Evans and Annica K. B. Gad
Cancers 2025, 17(1), 81; https://doi.org/10.3390/cancers17010081 - 30 Dec 2024
Cited by 2 | Viewed by 2523
Abstract
Background: The epithelial-to-mesenchymal transition (EMT) is a common feature in early cancer invasion. Increased vimentin is a canonical marker of the EMT; however, the role of vimentin in EMT remains unknown. Methods: To clarify this, we induced EMT in lung cancer cells with [...] Read more.
Background: The epithelial-to-mesenchymal transition (EMT) is a common feature in early cancer invasion. Increased vimentin is a canonical marker of the EMT; however, the role of vimentin in EMT remains unknown. Methods: To clarify this, we induced EMT in lung cancer cells with TGF-β1, followed by treatment with the vimentin-targeting drug ALD-R491, live-cell imaging, and quantitative proteomics. Results: We identified 838 proteins in the intermediate filament fraction of cells. TGF-β1 treatment increased the proportion of vimentin in this fraction and the levels of 24 proteins. Variants of fibronectin showed the most pronounced increase (137-fold), followed by regulators of the cytoskeleton, cell motility, and division, such as the mRNA-splicing protein SON. TGF-β1 increased cell spreading and cell migration speed, and changed a positive correlation between cell migration speed and persistence to negative. ALD-R491 reversed these mesenchymal phenotypes to epithelial and the binding of RNA-binding proteins, including SON. Conclusions: These findings present many new interactors of intermediate filaments, describe how EMT and vimentin filament dynamics influence the intermediate filament interactome, and present ALD-R491 as a possible EMT-inhibitor. The observations support the hypothesis that the dynamic turnover of vimentin filaments and their interacting proteins govern mesenchymal cell migration, EMT, cell invasion, and cancer metastasis. Full article
(This article belongs to the Special Issue Extracellular Matrix Proteins in Cancer)
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Review

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35 pages, 1864 KB  
Review
Uterine Stroma-Derived Tumors and the Extracellular Matrix: A Comparative Review of Benign and Malignant Pathologies
by Maria Marmara, Thomas Vrekoussis, Fanourios Makrygiannakis, Dragana Nikitovic and Aikaterini Berdiaki
Cancers 2025, 17(21), 3501; https://doi.org/10.3390/cancers17213501 - 30 Oct 2025
Viewed by 688
Abstract
Uterine stromal-derived tumors encompass a spectrum of rare neoplasms, ranging from benign endometrial stromal nodules to aggressive high-grade endometrial stromal sarcomas and undifferentiated uterine sarcomas. The classification of these tumors has advanced through molecular and immunohistochemical profiling, but the role of the extracellular [...] Read more.
Uterine stromal-derived tumors encompass a spectrum of rare neoplasms, ranging from benign endometrial stromal nodules to aggressive high-grade endometrial stromal sarcomas and undifferentiated uterine sarcomas. The classification of these tumors has advanced through molecular and immunohistochemical profiling, but the role of the extracellular matrix (ECM) in their biology is only beginning to be understood. The ECM provides both structural support and dynamic signaling cues, regulating tumor cell proliferation, invasion, angiogenesis, and immune evasion. Altered expression of collagens, proteoglycans, glycosaminoglycans, and matricellular proteins reshapes stromal architecture and contributes to disease progression. Moreover, ECM remodeling enzymes such as matrix metalloproteinases, together with cross-linking factors, create a stiff and pro-tumorigenic microenvironment that facilitates invasion and therapeutic resistance. Furthermore, these matrix alterations intersect with angiogenesis, mechanotransduction pathways, and immune modulation. Studies to date describe the role of ECM molecules in the function of the physiological uterine tissue and data for the uterine stroma-derived tumors is scarce. This review summarizes the existing knowledge in classification, prognosis and diagnosis, and summarizes the ECM-driven mechanisms in tumors described so far, aiming to identify new and prognostic biomarkers and novel therapeutic targets in uterine sarcomas. Full article
(This article belongs to the Special Issue Extracellular Matrix Proteins in Cancer)
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20 pages, 1081 KB  
Review
Implication of the Extracellular Matrix in Metastatic Tumor Cell Dormancy
by Chloe Redoute-Timonnier and Patrick Auguste
Cancers 2024, 16(23), 4076; https://doi.org/10.3390/cancers16234076 - 5 Dec 2024
Cited by 5 | Viewed by 8322
Abstract
Metastasis is the main cause of cancer-related deaths. The formation and growth of metastasis is a multistep process. Tumor cells extravasating in the secondary organ are in contact with a new microenvironment and a new extracellular matrix (ECM), called the metastatic niche. Some [...] Read more.
Metastasis is the main cause of cancer-related deaths. The formation and growth of metastasis is a multistep process. Tumor cells extravasating in the secondary organ are in contact with a new microenvironment and a new extracellular matrix (ECM), called the metastatic niche. Some components of the ECM, such as periostin, can induce tumor cell growth in macrometastasis. In contrast, other components, such as Thrombospondin 1 (TSP-1), can maintain isolated cells in a dormant state. During dormancy, intracellular signaling activation, such as p38, maintains tumor cells arrested in the cell-cycle G0 phase for years. At any moment, stress can induce ECM modifications and binding to their specific receptors (mainly integrins) and reactivate dormant tumor cell growth in macrometastasis. In this review, we describe the tumor microenvironment of the different niches implicated in tumor cell dormancy. The role of ECM components and their associated receptors and intracellular signaling in the reactivation of dormant tumor cells in macrometastasis will be emphasized. We also present the different methodologies and experimental approaches used to study tumor cell dormancy. Finally, we discuss the current and future treatment strategies to avoid late metastasis relapse in patients. Full article
(This article belongs to the Special Issue Extracellular Matrix Proteins in Cancer)
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17 pages, 1015 KB  
Review
The Role of eHsp90 in Extracellular Matrix Remodeling, Tumor Invasiveness, and Metastasis
by Pragya Singh and Daniel G. Jay
Cancers 2024, 16(22), 3873; https://doi.org/10.3390/cancers16223873 - 19 Nov 2024
Cited by 1 | Viewed by 2413
Abstract
Identifying proteins that act in tumor invasiveness and metastasis remains a critical unmet need in our search for effective cancer therapy. Hsp90, an abundant intracellular chaperone protein, plays a key role in maintaining cell homeostasis, and its elevated activity is pivotal in cancer [...] Read more.
Identifying proteins that act in tumor invasiveness and metastasis remains a critical unmet need in our search for effective cancer therapy. Hsp90, an abundant intracellular chaperone protein, plays a key role in maintaining cell homeostasis, and its elevated activity is pivotal in cancer progression. Due to the reliance of cancer cells on Hsp90’s chaperone function to sustain tumor growth and spread, Hsp90 inhibitors have been the subject of numerous clinical trials over the past two decades. However, these efforts have largely been unsuccessful, primarily due to the cellular toxicity caused by pan-Hsp90 inhibitors at doses required for anticancer efficacy. Therefore, novel approaches to target Hsp90 are necessary. An identified subpopulation of Hsp90 located outside cells (eHsp90) may offer a promising alternative as a therapeutic target against cancer. Studies including our own have shown that eHsp90 is released specifically by cancer cells, and eHsp90 has unique interactors and functions extracellularly to promote tumor invasiveness, the initial step in metastasis. Inhibition of eHsp90 has been shown to suppress metastasis in animal models, indicating its therapeutic potential, although the underlying mechanisms remain incompletely understood. Cancer cells modulate the tumor microenvironment (TME) during the invasion, especially the ECM proteins and the state of the ECM is a strong predictor of invasive and metastatic cancer. Given that most of the known eHsp90 clients are ECM proteins or are proteins involved in ECM modulation, ECM remodelling could be the key mechanism through which eHsp90 enhances invasiveness. This review will focus on ECM modulation by eHsp90 as a driver of cancer invasion and metastasis. We will also discuss the potency of inhibiting eHsp90 in inhibiting invasion and metastatic spread in preclinical models and the using circulating Hsp90 patient samples as a biomarker of cancer invasion and metastasis. Full article
(This article belongs to the Special Issue Extracellular Matrix Proteins in Cancer)
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