scholarly journals Extracellular Matrix Remodeling by Fibroblast-MMP14 Regulates Melanoma Growth

2021 ◽  
Vol 22 (22) ◽  
pp. 12276
Author(s):  
Elke Pach ◽  
Maike Kümper ◽  
Julia E. Fromme ◽  
Jan Zamek ◽  
Fabian Metzen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Progression ◽  
De Novo ◽  
Proteolytic Enzymes ◽  
Melanoma Cells ◽  
Dermal Fibroblasts ◽  
Collagen I ◽  
Collagenolytic Activity ◽  
The Matrix ◽  
Melanoma Growth

Maintaining a balanced state in remodeling the extracellular matrix is crucial for tissue homeostasis, and this process is altered during skin cancer progression. In melanoma, several proteolytic enzymes are expressed in a time and compartmentalized manner to support tumor progression by generating a permissive environment. One of these proteases is the matrix metalloproteinase 14 (MMP14). We could previously show that deletion of MMP14 in dermal fibroblasts results in the generation of a fibrotic-like skin in which melanoma growth is impaired. That was primarily due to collagen I accumulation due to lack of the collagenolytic activity of MMP14. However, as well as collagen I processing, MMP14 can also process several extracellular matrices. We investigated extracellular matrix alterations occurring in the MMP14-deleted fibroblasts that can contribute to the modulation of melanoma growth. The matrix deposited by cultured MMP14-deleted fibroblast displayed an antiproliferative and anti-migratory effect on melanoma cells in vitro. Analysis of the secreted and deposited-decellularized fibroblast’s matrix identified a few altered proteins, among which the most significantly changed was collagen XIV. This collagen was increased because of post-translational events, while de novo synthesis was unchanged. Collagen XIV as a substrate was not pro-proliferative, pro-migratory, or adhesive, suggesting a negative regulatory role on melanoma cells. Consistent with that, increasing collagen XIV concentration in wild-type fibroblast-matrix led to reduced melanoma proliferation, migration, and adhesion. In support of its anti-tumor activity, enhanced accumulation of collagen XIV was detected in peritumoral areas of melanoma grown in mice with the fibroblast’s deletion of MMP14. In advanced human melanoma samples, we detected reduced expression of collagen XIV compared to benign nevi, which showed a robust expression of this molecule around melanocytic nests. This study shows that loss of fibroblast-MMP14 affects melanoma growth through altering the peritumoral extracellular matrix (ECM) composition, with collagen XIV being a modulator of melanoma progression and a new proteolytic substrate to MMP14.

scholarly journals LPS Counter Regulates RNA Expression of Extracellular Proteases and Their Inhibitors in Murine Macrophages

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Andreas Hald ◽  
Birgitte Rønø ◽  
Leif R. Lund ◽  
Kristoffer L. Egerod
Keyword(s):  
Extracellular Matrix ◽  
Matrix Metalloproteinase ◽  
Serine Proteases ◽  
Gene Expression Regulation ◽  
Proteolytic Enzymes ◽  
Matrix Degradation ◽  
Extracellular Proteases ◽  
The Matrix ◽  
Matrix Metabolism ◽  
Temporal Expression Pattern

Besides their evident importance in host defense, macrophages have been shown to play a detrimental role in different pathological conditions, including chronic inflammation, atherosclerosis, and cancer. Regardless of the exact situation, macrophage activation and migration are intimately connected to extracellular matrix degradation. This process is accomplished by multiple proteolytic enzymes, including serine proteases and members of the matrix metalloproteinase family. In this study, we have utilized qPCR arrays to simultaneously analyze the temporal expression pattern of a range of genes involved in extracellular matrix metabolism in the mouse derived-macrophage cell line RAW 264.7 following stimulation with LPS. Our results revealed that LPS induces the expression of matrix metalloproteinases while at the same time decreased the expression of matrix metalloproteinase inhibitors. The opposite scenario was found for the genes encoding serine proteases, which were downregulated while their inhibitors were upregulated. In addition, intergenic comparison of the expression levels of related proteases revealed large differences in their basal expression level. These data highlight the complexity of the gene expression regulation implicated in macrophage-dependent matrix degradation and furthermore emphasize the value of qPCR array techniques for the investigation of the complex regulation of the matrix degradome.

scholarly journals Matrix Metalloproteinases in Cerebrovascular Disease

1998 ◽  
Vol 18 (11) ◽  
pp. 1163-1172 ◽  
Author(s):  
Sheila Mun-Bryce ◽  
Gary A. Rosenberg
Keyword(s):  
Extracellular Matrix ◽  
Matrix Metalloproteinases ◽  
Serine Proteases ◽  
Capillary Permeability ◽  
Proteolytic Enzymes ◽  
Cellular Damage ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Intracerebral Injection ◽  
Type Iv Collagenase ◽  
The Matrix

Cerebral ischemia and intracerebral hemorrhage cause extensive damage to neurons, disrupt the extracellular matrix, and increase capillary permeability. Multiple substrates participate in the cellular damage, including free radicals and proteases. Matrix metalloproteinases and serine proteases are two classes of proteases that are normally present in brain in latent forms, but once activated, contribute to the injury process. These enzymes have a unique role in the remodeling of the extracellular matrix and in the modulation of the capillary permeability. Intracerebral injection of the matrix metalloproteinase, type IV collagenase, attacks the basal lamina around the capillary and opens the blood—brain barrier, Extracellular matrix-degrading proteases are induced by immediate early genes and cytokines, and regulated by growth factors. Activity of the matrix metalloproteinases is tightly controlled by activation mechanisms and tissue inhibitors of metalloproteinases. During ischemia and hemorrhage, multiple matrix metalloproteinases and serine proteases are produced along with their inhibitors. These proteolytic enzymes are involved in the delayed injury that accompanies the neuroinflammatory response. Synthetic inhibitors to metalloproteinases reduce proteolytic tissue damage, and may limit secondary neuroinflammation.

scholarly journals Glycation by glyoxal leads to profound changes in the behavior of dermal fibroblasts

2021 ◽  
Vol 9 (1) ◽  
pp. e002091
Author(s):  
Cécile Guillon ◽  
Sandra Ferraro ◽  
Sophie Clément ◽  
Marielle Bouschbacher ◽  
Dominique Sigaudo-Roussel ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Wound Healing ◽  
Type I Collagen ◽  
Human Fibroblasts ◽  
Dermal Fibroblasts ◽  
Collagen I ◽  
Type I ◽  
Pronounced Increase ◽  
Chronic Hyperglycemia ◽  
Collagen Secretion

IntroductionDiabetes is a worldwide health problem that is associated with severe complications. Advanced Glycation End products (AGEs) such as Nε-(carboxymethyl)lysine, which result from chronic hyperglycemia, accumulate in the skin of patients with diabetes. The effect of AGEs on fibroblast functionality and their impact on wound healing are still poorly understood.Research design and methodsTo investigate this, we treated cultured human fibroblasts with 0.6 mM glyoxal to induce acute glycation. The behavior of fibroblasts was analyzed by time-lapse monolayer wounding healing assay, seahorse technology and atomic force microscopy. Production of extracellular matrix was studied by transmission electronic microscopy and western blot. Lipid metabolism was investigated by staining of lipid droplets (LDs) with BODIPY 493/503.ResultsWe found that the proliferative and migratory capacities of the cells were greatly reduced by glycation, which could be explained by an increase in fibroblast tensile strength. Measurement of the cellular energy balance did not indicate that there was a change in the rate of oxygen consumption of the fibroblasts. Assessment of collagen I revealed that glyoxal did not influence type I collagen secretion although it did disrupt collagen I maturation and it prevented its deposition in the extracellular matrix. We noted a pronounced increase in the number of LDs after glyoxal treatment. AMPK phosphorylation was reduced by glyoxal treatment but it was not responsible for the accumulation of LDs.ConclusionGlyoxal promotes a change in fibroblast behavior in favor of lipogenic activity that could be involved in delaying wound healing.

scholarly journals Metalloproteinases in Ovarian Cancer

2021 ◽  
Vol 22 (7) ◽  
pp. 3403
Author(s):  
Preston Carey ◽  
Ethan Low ◽  
Elizabeth Harper ◽  
M. Sharon Stack
Keyword(s):  
Ovarian Cancer ◽  
Extracellular Matrix ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Ovarian Cancer Cells ◽  
Age Related ◽  
The Matrix ◽  
Interaction Stress

Proteases play a crucial role in the progression and metastasis of ovarian cancer. Pericellular protein degradation and fragmentation along with remodeling of the extracellular matrix (ECM) is accomplished by numerous proteases that are present in the ovarian tumor microenvironment. Several proteolytic processes have been linked to cancer progression, particularly those facilitated by the matrix metalloproteinase (MMP) family. These proteases have been linked to enhanced migratory ability, extracellular matrix breakdown, and development of support systems for tumors. Several studies have reported the direct involvement of MMPs with ovarian cancer, as well as their mechanisms of action in the tumor microenvironment. MMPs play a key role in upregulating transcription factors, as well as the breakdown of structural proteins like collagen. Proteolytic mechanisms have been shown to enhance the ability of ovarian cancer cells to migrate and adhere to secondary sites allowing for efficient metastasis. Furthermore, angiogenesis for tumor growth and development of metastatic implants is influenced by upregulation of certain proteases, including MMPs. While proteases are produced normally in vivo, they can be upregulated by cancer-associated mutations, tumor–microenvironment interaction, stress-induced catecholamine production, and age-related pathologies. This review outlines the important role of proteases throughout ovarian cancer progression and metastasis.

scholarly journals The liver metastatic niche: modelling the extracellular matrix in metastasis

2021 ◽  
Vol 14 (4) ◽  
Author(s):  
James Drew ◽  
Laura M. Machesky
Keyword(s):  
Extracellular Matrix ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Stochastic Dynamic ◽  
Niche Modelling ◽  
Dynamic Interactions ◽  
Liver Support ◽  
Technical Developments ◽  
The Matrix ◽  
Metastatic Sites

ABSTRACT Dissemination of malignant cells from primary tumours to metastatic sites is a key step in cancer progression. Disseminated tumour cells preferentially settle in specific target organs, and the success of such metastases depends on dynamic interactions between cancer cells and the microenvironments they encounter at secondary sites. Two emerging concepts concerning the biology of metastasis are that organ-specific microenvironments influence the fate of disseminated cancer cells, and that cancer cell-extracellular matrix interactions have important roles at all stages of the metastatic cascade. The extracellular matrix is the complex and dynamic non-cellular component of tissues that provides a physical scaffold and conveys essential adhesive and paracrine signals for a tissue's function. Here, we focus on how extracellular matrix dynamics contribute to liver metastases – a common and deadly event. We discuss how matrix components of the healthy and premetastatic liver support early seeding of disseminated cancer cells, and how the matrix derived from both cancer and liver contributes to the changes in niche composition as metastasis progresses. We also highlight the technical developments that are providing new insights into the stochastic, dynamic and multifaceted roles of the liver extracellular matrix in permitting and sustaining metastasis. An understanding of the contribution of the extracellular matrix to different stages of metastasis may well pave the way to targeted and effective therapies against metastatic disease.

scholarly journals Perturbation of human endothelial cells by thrombin or PMA changes the reactivity of their extracellular matrix towards platelets.

1987 ◽  
Vol 104 (3) ◽  
pp. 697-704 ◽  
Author(s):  
P G de Groot ◽  
J H Reinders ◽  
J J Sixma
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Von Willebrand Factor ◽  
De Novo ◽  
The Matrix ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Adhesion Of Platelets ◽  
De Novo Protein Synthesis

In this study we have examined the influence of perturbation of endothelial cells on the amounts of fibronectin and von Willebrand factor in their extracellular matrix and the consequences of a changed composition of the matrix on platelet adhesion. For this purpose, we have used an in vitro perfusion system with which we can investigate the interactions of platelets in flowing blood with cultured endothelial cells and their extracellular matrix (Sakariassen, K. S., P. A. M. M. Aarts, P. G. de Groot, W. P. M. Houdgk, and J. J. Sixma, 1983, J. Lab. Clin Med. 102:522-535). Treatment of endothelial cells with 0.1-1.0 U/ml thrombin for 2 h increased the reactivity of the extracellular matrix, isolated after the thrombin treatment, towards platelets by approximately 50%. The increased reactivity did not depend on de novo protein synthesis but was inhibited by 3-deazaadenosine, an inhibitor of phospholipid methylation, which also inhibits the stimulus-induced instantaneous release of von Willebrand factor from endothelial cells. However, no changes in the amounts of von Willebrand factor and fibronectin in the matrix were detected. Thrombin may change the organization of the matrix proteins, not the composition. When endothelial cells were perturbed with the phorbol ester PMA or thrombin for 3 d, the adhesion of platelets to the extracellular matrix of treated cells was strongly impaired. This impairment coincided with a decrease in the amounts of von Willebrand factor and fibronectin present in the matrix. These results indicate that, after perturbation, endothelial cells regulate the composition of their matrix, and that this regulation has consequences for the adhesion of platelets.

The collagen I sequence DGEA raises [Ca2+]i in dermal fibroblasts, modulation by extracellular matrix

1998 ◽  
Vol 16 ◽  
pp. S123
Author(s):  
A. Guignandon ◽  
P. Mineur ◽  
Ch.A. Lambert ◽  
B.V. Nusgens ◽  
Ch.M. Lapière
Keyword(s):  
Extracellular Matrix ◽  
Dermal Fibroblasts ◽  
Collagen I

Fibroblasts Derived From Human Adipose Stem Cells Produce More Effective Extracellular Matrix and Migrate Faster Compared to Primary Dermal Fibroblasts

2019 ◽  
Vol 40 (1) ◽  
pp. 108-117 ◽  
Author(s):  
Robert P Gersch ◽  
Jeffrey C Raum ◽  
Catherine Calvert ◽  
Ivona Percec
Keyword(s):  
Stem Cells ◽  
Extracellular Matrix ◽  
Wound Healing ◽  
Large Scale ◽  
De Novo ◽  
Scratch Test ◽  
Scar Tissue ◽  
Healing Time ◽  
Dermal Fibroblasts ◽  
Human Ascs

Abstract Background The efficacy of adipose-derived stem cells (ASCs) to improve wound healing has been extensively investigated. Unfortunately, no consistent reports have described significant improvements in healing time or outcomes in large-scale clinical trials utilizing human ASCs. Primarily, these studies examined undifferentiated ASCs as opposed to specific cells differentiated from ASCs. Objectives The authors sought to examine the properties of fibroblasts differentiated from human ASCs (dFib cells) compared with those of primary dermal fibroblasts. Methods ASCs were isolated from healthy female patients, differentiated into dFib cells, and compared with intra-patient primary dermal fibroblasts for morphology, extracellular matrix (ECM) marker expression, and cell migration employing qPCR, western blot, and scratch test assays. Results De novo differentiated fibroblasts produce higher levels of the healthy ECM markers Elastin, Fibronectin, and Collagen 1 compared with primary fibroblasts. In contrast, dFib cells have reduced expression of the scar tissue markers αSMA, Collagen 3, and MMP-1. Further, dFib cells close scratch defects more quickly than primary dermal fibroblasts (32 ± 12.85 hours vs 64 ± 13.85 hours, P < 0.01) in a scratch test assay. Conclusions These data suggest that fibroblasts newly differentiated from human ASCs migrate well and produce a robust ECM, the combination of which may contribute to improved wound healing, and thus should be further investigated.

Manipulating Cx43 expression triggers gene reprogramming events in dermal fibroblasts from oculodentodigital dysplasia patients

2015 ◽  
Vol 472 (1) ◽  
pp. 55-69 ◽  
Author(s):  
Jessica L. Esseltine ◽  
Qing Shao ◽  
Tao Huang ◽  
John J. Kelly ◽  
Jacinda Sampson ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Dermal Fibroblasts ◽  
Collagen I ◽  
Cx43 Expression ◽  
Associated Proteins ◽  
Oculodentodigital Dysplasia

We have investigated gene reprogramming events in dermal fibroblasts from oculodentodigital dysplasia (ODDD) patients. Patient fibroblasts contain less functional Cx43 which results in changes in the production of extracellular matrix (ECM)-associated proteins, collagen-I secretion, gel contraction and overall fibroblast function.

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