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Extracellular Matrix in the Tumor Microenvironment

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 28765

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Special Issue Editor

Prof. Dr. Martin Götte

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Guest Editor

Department of Gynecology and Obstetrics, Münster University Hospital, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
Interests: endometriosis; gynecological oncology; microRNAs; stem cells; proteoglycans; extracellular matrix; inflammation
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Dear Colleagues,

The malignant behavior of cancer cells is determined not only by cell-autonomous factors but also by a permissive microenvironment. The extracellular matrix (ECM) plays a major role in either supporting or inhibiting tumor cell behavior. Epigenetic mechanisms and a dysregulated endocrine milieu favor altered ECM synthesis. Aberrant production and secretion of large matrix glycoproteins including collagens, fibronectin, tenascins, laminins, thrombospondin, small leucin-rich proteoglycans, and the glycosaminoglycan hyaluronan into the peritumoral ECM conveys signals to tumor cells via matrix receptors. These receptors include integrins, CD44, DDRs, and cell surface proteoglycans. These interactions promote metastatic behavior, unlimited tumor growth, and cancer stem cell function linked to therapeutic resistance and relapse. ECM composition affects matrix stiffness and rigidity, which in turn affects tumor cell motility and determines different patterns of tumor cell migration. Proteoglycans and integrins mediate matrix-dependent signaling events via growth factors and chemokines, modulating angiogenesis and immune cell function in the tumor microenvironment. Finally, ECM degradation by MMPs and heparanase affects tumor progression by removing sterical hindrances, which promotes the release of cytokines, and by generating antiangiogenic matrix fragments. The multitude of functions in the tumor microenvironment marks the ECM as a prime target for novel therapeutic approaches targeting cancer progression and relapse.

Prof. Dr. Martin Götte
Guest Editor

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Keywords

extracellular matrix
collagen
proteoglycans
heparanase
integrins
MMPs
stem cell niche
matrix stiffness
immune cells
angiogenesis

Published Papers (7 papers)

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Research

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17 pages, 8515 KiB

Open AccessArticle

Deletion of Col15a1 Modulates the Tumour Extracellular Matrix and Leads to Increased Tumour Growth in the MMTV-PyMT Mouse Mammary Carcinoma Model

by Guillermo Martínez-Nieto, Ritva Heljasvaara, Anne Heikkinen, Hanne-Kaisa Kaski, Raman Devarajan, Otto Rinne, Charlotta Henriksson, Emmi Thomson, Camilla von Hertzen, Ilkka Miinalainen, Heli Ruotsalainen, Taina Pihlajaniemi and Sanna-Maria Karppinen

Int. J. Mol. Sci. 2021, 22(18), 9978; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189978 - 15 Sep 2021

Cited by 7 | Viewed by 2682

Abstract

Basement membrane (BM) zone-associated collagen XV (ColXV) has been shown to suppress the malignancy of tumour cells, and its restin domain can inhibit angiogenesis. In human breast cancer, as well as in many other human carcinomas, ColXV is lost from the epithelial BM zone prior to tumour invasion. Here, we addressed the roles of ColXV in breast carcinogenesis using the transgenic MMTV-PyMT mouse mammary carcinoma model. We show here for the first time that the inactivation of Col15a1 in mice leads to changes in the fibrillar tumour matrix and to increased mammary tumour growth. ColXV is expressed by myoepithelial and endothelial cells in mammary tumours and is lost from the ductal BM along with the loss of the myoepithelial layer during cancer progression while persisting in blood vessels and capillaries, even in invasive tumours. However, despite the absence of anti-angiogenic restin domain, neovascularisation was reduced rather than increased in the ColXV-deficient mammary tumours compared to controls. We also show that, in robust tumour cell transplantation models or in a chemical-induced fibrosarcoma model, the inactivation of Col15a1 does not affect tumour growth or angiogenesis. In conclusion, our results support the proposed tumour suppressor function of ColXV in mammary carcinogenesis and reveal diverse roles of this collagen in different cancer types. Full article

(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment)

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24 pages, 3813 KiB

Open AccessArticle

Syndecan-1 Depletion Has a Differential Impact on Hyaluronic Acid Metabolism and Tumor Cell Behavior in Luminal and Triple-Negative Breast Cancer Cells

by Sofía Valla, Nourhan Hassan, Daiana Luján Vitale, Daniela Madanes, Fiorella Mercedes Spinelli, Felipe C. O. B. Teixeira, Burkhard Greve, Nancy Adriana Espinoza-Sánchez, Carolina Cristina, Laura Alaniz and Martin Götte

Int. J. Mol. Sci. 2021, 22(11), 5874; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115874 - 30 May 2021

Cited by 10 | Viewed by 4153

Abstract

Glycosaminoglycans (GAGs) and proteoglycans (PGs) are major components of the glycocalyx. The secreted GAG and CD44 ligand hyaluronic acid (HA), and the cell surface PG syndecan-1 (Sdc-1) modulate the expression and activity of cytokines, chemokines, growth factors, and adhesion molecules, acting as critical regulators of tumor cell behavior. Here, we studied the effect of Sdc-1 siRNA depletion and HA treatment on hallmark processes of cancer in breast cancer cell lines of different levels of aggressiveness. We analyzed HA synthesis, and parameters relevant to tumor progression, including the stem cell phenotype, Wnt signaling constituents, cell cycle progression and apoptosis, and angiogenic markers in luminal MCF-7 and triple-negative MDA-MB-231 cells. Sdc-1 knockdown enhanced HAS-2 synthesis and HA binding in MCF-7, but not in MDA-MB-231 cells. Sdc-1-depleted MDA-MB-231 cells showed a reduced CD24-/CD44+ population. Furthermore, Sdc-1 depletion was associated with survival signals in both cell lines, affecting cell cycle progression and apoptosis evasion. These changes were linked to the altered expression of KLF4, MSI2, and miR-10b and differential changes in Erk, Akt, and PTEN signaling. We conclude that Sdc-1 knockdown differentially affects HA metabolism in luminal and triple-negative breast cancer model cell lines and impacts the stem phenotype, cell survival, and angiogenic factors. Full article

(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment)

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21 pages, 4583 KiB

Open AccessArticle

Insight into Cisplatin-Resistance Signaling of W1 Ovarian Cancer Cells Emerges mTOR and HSP27 as Targets for Sensitization Strategies

by Kathleen Wantoch von Rekowski, Philipp König, Svenja Henze, Martin Schlesinger, Piotr Zawierucha, Radosław Januchowski and Gerd Bendas

Int. J. Mol. Sci. 2020, 21(23), 9240; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239240 - 03 Dec 2020

Cited by 12 | Viewed by 2535

Abstract

The microenvironment possesses a strong impact on the tumor chemoresistance when cells bind to components of the extracellular matrix. Here we elucidate the signaling pathways of cisplatin resistance in W1 ovarian cancer cells binding to collagen type 1 (COL1) and signaling interference with constitutive cisplatin resistance in W1CR cells to discover the targets for sensitization. Proteome kinase arrays and Western blots were used to identify the signaling components, their impact on cisplatin resistance was evaluated by inhibitory or knockdown approaches. W1 cell binding to COL1 upregulates integrin-associated signals via FAK/PRAS40/mTOR, confirmed by β1-integrin (ITGB1) knockdown. mTOR appears as key for resistance, its blockade reversed COL1 effects on W1 cell resistance completely. W1CR cells compensate ITGB1-knockdown by upregulation of discoidin domain receptor 1 (DDR1) as alternative COL1 sensor. COL1 binding via DDR1 activates the MAPK pathway, of which JNK1/2 appears critical for COL1-mediated resistance. JNK1/2 inhibition inverts COL1 effects in W1CR cells, whereas intrinsic cisplatin resistance remained unaffected. Remarkably, knockdown of HSP27, another downstream MAPK pathway component overcomes intrinsic resistance completely sensitizing W1CR cells to the level of W1 cells for cisplatin cytotoxicity. Our data confirm the independent regulation of matrix-induced and intrinsic chemoresistance in W1 ovarian cancer cells and offer novel targets for sensitization. Full article

(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment)

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12 pages, 1713 KiB

Open AccessCommunication

Machine Learning Identifies Robust Matrisome Markers and Regulatory Mechanisms in Cancer

by Anni Kääriäinen, Vilma Pesola, Annalena Dittmann, Juho Kontio, Jarkko Koivunen, Taina Pihlajaniemi and Valerio Izzi

Int. J. Mol. Sci. 2020, 21(22), 8837; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228837 - 22 Nov 2020

Cited by 8 | Viewed by 3030

Abstract

The expression and regulation of matrisome genes—the ensemble of extracellular matrix, ECM, ECM-associated proteins and regulators as well as cytokines, chemokines and growth factors—is of paramount importance for many biological processes and signals within the tumor microenvironment. The availability of large and diverse multi-omics data enables mapping and understanding of the regulatory circuitry governing the tumor matrisome to an unprecedented level, though such a volume of information requires robust approaches to data analysis and integration. In this study, we show that combining Pan-Cancer expression data from The Cancer Genome Atlas (TCGA) with genomics, epigenomics and microenvironmental features from TCGA and other sources enables the identification of “landmark” matrisome genes and machine learning-based reconstruction of their regulatory networks in 74 clinical and molecular subtypes of human cancers and approx. 6700 patients. These results, enriched for prognostic genes and cross-validated markers at the protein level, unravel the role of genetic and epigenetic programs in governing the tumor matrisome and allow the prioritization of tumor-specific matrisome genes (and their regulators) for the development of novel therapeutic approaches. Full article

(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment)

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Review

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20 pages, 2370 KiB

Open AccessReview

Inflammation, Extracellular Matrix Remodeling, and Proteostasis in Tumor Microenvironment

by Marina Marozzi, Arianna Parnigoni, Aide Negri, Manuela Viola, Davide Vigetti, Alberto Passi, Evgenia Karousou and Federica Rizzi

Int. J. Mol. Sci. 2021, 22(15), 8102; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158102 - 28 Jul 2021

Cited by 53 | Viewed by 4498

Abstract

Cancer is a multifaceted and complex pathology characterized by uncontrolled cell proliferation and decreased apoptosis. Most cancers are recognized by an inflammatory environment rich in a myriad of factors produced by immune infiltrate cells that induce host cells to differentiate and to produce a matrix that is more favorable to tumor cells’ survival and metastasis. As a result, the extracellular matrix (ECM) is changed in terms of macromolecules content, degrading enzymes, and proteins. Altered ECM components, derived from remodeling processes, interact with a variety of surface receptors triggering intracellular signaling that, in turn, cancer cells exploit to their own benefit. This review aims to present the role of different aspects of ECM components in the tumor microenvironment. Particularly, we highlight the effect of pro- and inflammatory factors on ECM degrading enzymes, such as metalloproteases, and in a more detailed manner on hyaluronan metabolism and the signaling pathways triggered by the binding of hyaluronan with its receptors. In addition, we sought to explore the role of extracellular chaperones, especially of clusterin which is one of the most prominent in the extracellular space, in proteostasis and signaling transduction in the tumor microenvironment. Although the described tumor microenvironment components have different biological roles, they may engage common signaling pathways that favor tumor growth and metastasis. Full article

(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment)

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16 pages, 881 KiB

Open AccessReview

Immunodiagnostic Biomarkers for Hepatocellular Carcinoma (HCC): The First Step in Detection and Treatment

by Mengtao Xing, Xinzhi Wang, Robert A. Kirken, Ling He and Jian-Ying Zhang

Int. J. Mol. Sci. 2021, 22(11), 6139; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116139 - 07 Jun 2021

Cited by 18 | Viewed by 4690

Abstract

Hepatocellular carcinoma (HCC) exerts huge effects on the health burden of the world because of its high mortality and poor prognosis. HCC is often clinically detected late in patients. If HCC could be detected and treated earlier, the survival rate of patients will be greatly improved. Therefore, identifying specific biomarkers is urgent and important for HCC. The liver is also recognized as an immune organ. The occurrence of HCC is related to exacerbation of immune tolerance and/or immunosurveillance escape. The host immune system plays an important role in the recognition and targeting of tumor cells in cancer immunotherapy, as can be seen from the clinical success of immune checkpoint inhibitors and chimeric antigen receptor (CAR) T cells. Thus, there is a pressing medical need to discover immunodiagnostic biomarkers specific to HCC for understanding the pathological mechanisms of HCC, especially for immunotherapy targets. We have reviewed the existing literature to summarize the immunodiagnostic markers of HCC, including autoantibodies against tumor-associated antigens (TAAs) and exosomes, to provide new insights into HCC and early detection of this deadly cancer. Full article

(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment)

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41 pages, 4013 KiB

Open AccessReview

Hold on or Cut? Integrin- and MMP-Mediated Cell–Matrix Interactions in the Tumor Microenvironment

by Stephan Niland and Johannes A. Eble

Int. J. Mol. Sci. 2021, 22(1), 238; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010238 - 28 Dec 2020

Cited by 33 | Viewed by 5885

Abstract

The tumor microenvironment (TME) has become the focus of interest in cancer research and treatment. It includes the extracellular matrix (ECM) and ECM-modifying enzymes that are secreted by cancer and neighboring cells. The ECM serves both to anchor the tumor cells embedded in it and as a means of communication between the various cellular and non-cellular components of the TME. The cells of the TME modify their surrounding cancer-characteristic ECM. This in turn provides feedback to them via cellular receptors, thereby regulating, together with cytokines and exosomes, differentiation processes as well as tumor progression and spread. Matrix remodeling is accomplished by altering the repertoire of ECM components and by biophysical changes in stiffness and tension caused by ECM-crosslinking and ECM-degrading enzymes, in particular matrix metalloproteinases (MMPs). These can degrade ECM barriers or, by partial proteolysis, release soluble ECM fragments called matrikines, which influence cells inside and outside the TME. This review examines the changes in the ECM of the TME and the interaction between cells and the ECM, with a particular focus on MMPs. Full article

(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment)

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