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Extracellular Matrix in the Tumor Microenvironment 2.0
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Extracellular Matrix in the Tumor Microenvironment 2.0

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 (15 March 2023) | Viewed by 6488

Special Issue Editors

Prof. Dr. Martin Götte

E-Mail Website
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
Special Issues, Collections and Topics in MDPI journals
Dr. Gertraud Orend

E-Mail Website
Guest Editor
The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d'Hématologie et d'Immunologie, 1 Place de l'Hôpital, 67091 Strasbourg, France
Interests: tumor microenvironment; TME

Special Issue Information

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
Dr. Gertraud Orend
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 short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
  • collagen
  • proteoglycans
  • heparanase
  • integrins
  • MMPs
  • stem cell niche
  • matrix stiffness
  • immune cells
  • angiogenesis

Published Papers (3 papers)

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Research

13 pages, 1032 KiB  
Article
Endocan Promotes Pro-Tumorigenic Signaling in Lung Cancer Cells: Modulation of Cell Proliferation, Migration and lncRNAs H19 and HULC Expression
by Federica Aliquò, Aurelio Minuti, Angela Avenoso, Giuseppe Mandraffino, Giuseppe Maurizio Campo, Salvatore Campo, Angela D‘Ascola and Michele Scuruchi
Int. J. Mol. Sci. 2023, 24(9), 8178; https://doi.org/10.3390/ijms24098178 - 03 May 2023
Cited by 1 | Viewed by 1486
Abstract
Endocan is a circulating proteoglycan secreted by several cell lines and identified as a potential biomarker of inflammation and angiogenesis. Endocan-increased expression has been found in a broad spectrum of human tumors, including lung cancer, and is associated with a poor prognosis. To [...] Read more.
Endocan is a circulating proteoglycan secreted by several cell lines and identified as a potential biomarker of inflammation and angiogenesis. Endocan-increased expression has been found in a broad spectrum of human tumors, including lung cancer, and is associated with a poor prognosis. To elucidate the possible mechanism, this study aimed to investigate the role of endocan in non-small-cell lung carcinoma (NSCLC) using an in vitro model of cultured cells. Endocan expression was knocked down by using a specific small interfering RNA. The effects of endocan knockdown have been evaluated on VEGF-A, VEGFR-2, HIF-1α, the long non-coding RNAs H19 and HULC expression, and AKT and ERK 1/2 degree of activation. Cell migration and proliferation have been studied as well. VEGF-A, VEGFR-2, HIF-1α, and the long non-coding RNAs H19 and HULC expression were significantly affected by endocan knockdown. These effects correlated with a reduction of cell migration and proliferation and of AKT and ERK 1/2 activation. Our findings suggest that endocan promotes a more aggressive cancer cell phenotype in NSCLC. Full article
(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment 2.0)
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11 pages, 888 KiB  
Article
Autoreactivity against Denatured Type III Collagen Is Significantly Decreased in Serum from Patients with Cancer Compared to Healthy Controls
by Christina Jensen, Patryk Drobinski, Jeppe Thorlacius-Ussing, Morten A. Karsdal, Anne-Christine Bay-Jensen and Nicholas Willumsen
Int. J. Mol. Sci. 2023, 24(8), 7067; https://doi.org/10.3390/ijms24087067 - 11 Apr 2023
Cited by 1 | Viewed by 1441
Abstract
Autoantibodies have the potential as cancer biomarkers as they may associate with the outcome and immune-related adverse events (irAEs) following immunotherapy. Cancer and other fibroinflammatory diseases, such as rheumatoid arthritis (RA), are associated with excessive collagen turnover leading to collagen triple helix unfolding [...] Read more.
Autoantibodies have the potential as cancer biomarkers as they may associate with the outcome and immune-related adverse events (irAEs) following immunotherapy. Cancer and other fibroinflammatory diseases, such as rheumatoid arthritis (RA), are associated with excessive collagen turnover leading to collagen triple helix unfolding and denaturation with exposure of immunodominant epitopes. In this study, we aimed to investigate the role of autoreactivity against denatured collagen in cancer. A technically robust assay to quantify autoantibodies against denatured type III collagen products (anti-dCol3) was developed and then measured in pretreatment serum from 223 cancer patients and 33 age-matched controls. Moreover, the association between anti-dCol3 levels and type III collagen degradation (C3M) and formation (PRO-C3) was investigated. Anti-dCol3 levels were significantly lower in patients with bladder (p = 0.0007), breast (p = 0.0002), colorectal (p < 0.0001), head and neck (p = 0.0005), kidney (p = 0.005), liver (p = 0.030), lung (p = 0.0004), melanoma (p < 0.0001), ovarian (p < 0.0001), pancreatic (p < 0.0001), prostate (p < 0.0001), and stomach cancers (p < 0.0001) compared to controls. High anti-dCol3 levels were associated with type III collagen degradation (C3M, p = 0.0002) but not type III collagen formation (PRO-C3, p = 0.26). Cancer patients with different solid tumor types have downregulated levels of circulating autoantibodies against denatured type III collagen compared to controls, suggesting that autoreactivity against unhealthy type III collagen may be important for tumor control and eradication. This autoimmunity biomarker may have the potential for studying the close relationship between autoimmunity and cancer. Full article
(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment 2.0)
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22 pages, 3143 KiB  
Article
The Cell Surface Heparan Sulfate Proteoglycan Syndecan-3 Promotes Ovarian Cancer Pathogenesis
by Lara Hillemeyer, Nancy Adriana Espinoza-Sanchez, Burkhard Greve, Nourhan Hassan, Anca Chelariu-Raicu, Ludwig Kiesel and Martin Götte
Int. J. Mol. Sci. 2022, 23(10), 5793; https://doi.org/10.3390/ijms23105793 - 21 May 2022
Cited by 6 | Viewed by 2969
Abstract
Syndecans are transmembrane heparan sulfate proteoglycans that integrate signaling at the cell surface. By interacting with cytokines, signaling receptors, proteases, and extracellular matrix proteins, syndecans regulate cell proliferation, metastasis, angiogenesis, and inflammation. We analyzed public gene expression datasets to evaluate the dysregulation and [...] Read more.
Syndecans are transmembrane heparan sulfate proteoglycans that integrate signaling at the cell surface. By interacting with cytokines, signaling receptors, proteases, and extracellular matrix proteins, syndecans regulate cell proliferation, metastasis, angiogenesis, and inflammation. We analyzed public gene expression datasets to evaluate the dysregulation and potential prognostic impact of Syndecan-3 in ovarian cancer. Moreover, we performed functional in vitro analysis in syndecan-3-siRNA-treated SKOV3 and CAOV3 ovarian cancer cells. In silico analysis of public gene array datasets revealed that syndecan-3 mRNA expression was significantly increased 5.8-fold in ovarian cancer tissues (n = 744) and 3.4-fold in metastases (n = 44) compared with control tissue (n = 46), as independently confirmed in an RNAseq dataset on ovarian serous cystadenocarcinoma tissue (n = 374, controls: n = 133, 3.5-fold increase tumor vs. normal). Syndecan-3 siRNA knockdown impaired 3D spheroid growth and colony formation as stemness-related readouts in SKOV3 and CAOV3 cells. In SKOV3, but not in CAOV3 cells, syndecan-3 depletion reduced cell viability both under basal conditions and under chemotherapy with cisplatin, or cisplatin and paclitaxel. While analysis of the SIOVDB database did not reveal differences in Syndecan-3 expression between patients, sensitive, resistant or refractory to chemotherapy, KM Plotter analysis of 1435 ovarian cancer patients revealed that high syndecan-3 expression was associated with reduced survival in patients treated with taxol and platin. At the molecular level, a reduction in Stat3 activation and changes in the expression of Wnt and notch signaling constituents were observed. Our study suggests that up-regulation of syndecan-3 promotes the pathogenesis of ovarian cancer by modulating stemness-associated pathways. Full article
(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment 2.0)
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