scholarly journals Extracellular matrix guidance of autophagy: a mechanism regulating cancer growth

Open Biology ◽  
2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Carolyn G. Chen ◽  
Renato V. Iozzo
Keyword(s):  
Extracellular Matrix ◽  
Cancer Progression ◽  
Dynamic Network ◽  
Cellular Reprogramming ◽  
Tissue Homeostasis ◽  
Cancer Growth ◽  
Signalling Cascades ◽  
The Matrix ◽  
Intracellular Process ◽  
Cellular Pathways

The extracellular matrix (ECM) exists as a dynamic network of biophysical and biochemical factors that maintain tissue homeostasis. Given its sensitivity to changes in the intra- and extracellular space, the plasticity of the ECM can be pathological in driving disease through aberrant matrix remodelling. In particular, cancer uses the matrix for its proliferation, angiogenesis, cellular reprogramming and metastatic spread. An emerging field of matrix biology focuses on proteoglycans that regulate autophagy, an intracellular process that plays both critical and contextual roles in cancer. Here, we review the most prominent autophagic modulators from the matrix and the current understanding of the cellular pathways and signalling cascades that mechanistically drive their autophagic function. We then critically assess how their autophagic functions influence tumorigenesis, emphasizing the complexities and stage-dependent nature of this relationship in cancer. We highlight novel emerging data on immunoglobulin-containing and proline-rich receptor-1, heparanase and thrombospondin 1 in autophagy and cancer. Finally, we further discuss the pro- and anti-autophagic modulators originating from the ECM, as well as how these proteoglycans and other matrix constituents specifically influence cancer progression.

Extracellular matrix: the gatekeeper of tumor angiogenesis

2019 ◽  
Vol 47 (5) ◽  
pp. 1543-1555 ◽  
Author(s):  
Maurizio Mongiat ◽  
Simone Buraschi ◽  
Eva Andreuzzi ◽  
Thomas Neill ◽  
Renato V. Iozzo
Keyword(s):  
Extracellular Matrix ◽  
Tumor Angiogenesis ◽  
Signaling Cascades ◽  
Cancer Growth ◽  
Cell Behavior ◽  
Metastatic Progression ◽  
Surface Receptors ◽  
The Matrix ◽  
Multiple Signaling

Abstract The extracellular matrix is a network of secreted macromolecules that provides a harmonious meshwork for the growth and homeostatic development of organisms. It conveys multiple signaling cascades affecting specific surface receptors that impact cell behavior. During cancer growth, this bioactive meshwork is remodeled and enriched in newly formed blood vessels, which provide nutrients and oxygen to the growing tumor cells. Remodeling of the tumor microenvironment leads to the formation of bioactive fragments that may have a distinct function from their parent molecules, and the balance among these factors directly influence cell viability and metastatic progression. Indeed, the matrix acts as a gatekeeper by regulating the access of cancer cells to nutrients. Here, we will critically evaluate the role of selected matrix constituents in regulating tumor angiogenesis and provide up-to-date information concerning their primary mechanisms of action.

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 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 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 Extracellular Matrix Influencing HGF/c-MET Signaling Pathway: Impact on Cancer Progression

2018 ◽  
Vol 19 (11) ◽  
pp. 3300 ◽  
Author(s):  
Heydi Noriega-Guerra ◽  
Vanessa Freitas
Keyword(s):  
Extracellular Matrix ◽  
Tumor Cell ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Cell Communication ◽  
Dynamic Network ◽  
Cell Types ◽  
Bioactive Molecules ◽  
Matricellular Proteins ◽  
Cellular Processes

The extracellular matrix (ECM) is a crucial component of the tumor microenvironment involved in numerous cellular processes that contribute to cancer progression. It is acknowledged that tumor–stromal cell communication is driven by a complex and dynamic network of cytokines, growth factors and proteases. Thus, the ECM works as a reservoir for bioactive molecules that modulate tumor cell behavior. The hepatocyte growth factor (HGF) produced by tumor and stromal cells acts as a multifunctional cytokine and activates the c-MET receptor, which is expressed in different tumor cell types. The HGF/c-MET signaling pathway is associated with several cellular processes, such as proliferation, survival, motility, angiogenesis, invasion and metastasis. Moreover, c-MET activation can be promoted by several ECM components, including proteoglycans and glycoproteins that act as bridging molecules and/or signal co-receptors. In contrast, c-MET activation can be inhibited by proteoglycans, matricellular proteins and/or proteases that bind and sequester HGF away from the cell surface. Therefore, understanding the effects of ECM components on HGF and c-MET may provide opportunities for novel therapeutic strategies. Here, we give a short overview of how certain ECM components regulate the distribution and activation of HGF and c-MET.

scholarly journals Regulation of the Extracellular Matrix by Ciliary Machinery

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 278 ◽  
Author(s):  
Collins I ◽  
Wann A.K.T
Keyword(s):  
Extracellular Matrix ◽  
Primary Cilium ◽  
Indirect Evidence ◽  
Tissue Homeostasis ◽  
Cell Behaviour ◽  
Structural Support ◽  
Cellular Processes ◽  
Cellular Signalling ◽  
The Matrix

The primary cilium is an organelle involved in cellular signalling. Mutations affecting proteins involved in cilia assembly or function result in diseases known as ciliopathies, which cause a wide variety of phenotypes across multiple tissues. These mutations disrupt various cellular processes, including regulation of the extracellular matrix. The matrix is important for maintaining tissue homeostasis through influencing cell behaviour and providing structural support; therefore, the matrix changes observed in ciliopathies have been implicated in the pathogenesis of these diseases. Whilst many studies have associated the cilium with processes that regulate the matrix, exactly how these matrix changes arise is not well characterised. This review aims to bring together the direct and indirect evidence for ciliary regulation of matrix, in order to summarise the possible mechanisms by which the ciliary machinery could regulate the composition, secretion, remodelling and organisation of the matrix.

scholarly journals Fetal-like reversion in the regenerating intestine is regulated by mesenchymal Asporin

2021 ◽  
Author(s):  
Sharif Iqbal ◽  
Simon Andersson ◽  
Ernesta Nestaite ◽  
Nalle Pentinmikko ◽  
Ashish Kumar ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Tissue Regeneration ◽  
Tissue Repair ◽  
Ex Vivo ◽  
Cellular Reprogramming ◽  
Tissue Homeostasis ◽  
Epithelial Injury ◽  
Epithelial Regeneration ◽  
Tgfβ Signalling ◽  
Small Intestinal

Epithelial tissues undergo fetal-like cellular reprogramming to regenerate after damage1,2. Although the mesenchyme and the extracellular matrix (ECM) play critical roles in tissue homeostasis and regeneration2-5, their role in repurposing developmental programs in epithelium is unknown. To model epithelial regeneration, we culture intestinal epithelium on decellularized small intestinal scaffold (iECM), and identify Asporin (Aspn), an ECM bound proteoglycan, as a critical mediator of cellular reprogramming. Aspn is produced by the mesenchyme, and we show that its effect on epithelial Tgfβ-signalling via CD44 is critical for fetal-like conversion. Furthermore, we demonstrate that Aspn is transiently increased upon chemotherapy-induced damage and pivotal for a timely induction of the fetal-like state and tissue regeneration. In summary, we establish a platform for modelling epithelial injury responses ex vivo, and show that the mesenchymal Aspn-producing niche controls tissue repair by regulating epithelial fetal-like reprogramming.

scholarly journals Actin Cytoskeleton and Regulation of TGFβ Signaling: Exploring Their Links

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 336
Author(s):  
Roberta Melchionna ◽  
Paola Trono ◽  
Annalisa Tocci ◽  
Paola Nisticò
Keyword(s):  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Homeostasis ◽  
Actin Dynamics ◽  
Human Tissues ◽  
Cellular Functions ◽  
Tgfβ Signaling ◽  
Physical Mechanisms ◽  
And Function

Human tissues, to maintain their architecture and function, respond to injuries by activating intricate biochemical and physical mechanisms that regulates intercellular communication crucial in maintaining tissue homeostasis. Coordination of the communication occurs through the activity of different actin cytoskeletal regulators, physically connected to extracellular matrix through integrins, generating a platform of biochemical and biomechanical signaling that is deregulated in cancer. Among the major pathways, a controller of cellular functions is the cytokine transforming growth factor β (TGFβ), which remains a complex and central signaling network still to be interpreted and explained in cancer progression. Here, we discuss the link between actin dynamics and TGFβ signaling with the aim of exploring their aberrant interaction in cancer.

scholarly journals von Willebrand factor released from Weibel-Palade bodies binds more avidly to extracellular matrix than that secreted constitutively

Blood ◽  
1987 ◽  
Vol 69 (5) ◽  
pp. 1531-1534 ◽  
Author(s):  
LA Sporn ◽  
VJ Marder ◽  
DD Wagner
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Von Willebrand Factor ◽  
Immunofluorescent Staining ◽  
Cultured Endothelial Cells ◽  
Human Foreskin Fibroblasts ◽  
Platelet Binding ◽  
The Matrix ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Large multimers of von Willebrand factor (vWf) are released from the Weibel-Palade bodies of cultured endothelial cells following treatment with a secretagogue (Sporn et al, Cell 46:185, 1986). These multimers were shown by immunofluorescent staining to bind more extensively to the extracellular matrix of human foreskin fibroblasts than constitutively secreted vWf, which is composed predominantly of dimeric molecules. Increased binding of A23187-released vWf was not due to another component present in the releasate, since releasate from which vWf was adsorbed, when added together with constitutively secreted vWf, did not promote binding. When iodinated plasma vWf was overlaid onto the fibroblasts, the large forms bound preferentially to the matrix. These results indicated that the enhanced binding of the vWf released from the Weibel-Palade bodies was likely due to its large multimeric size. It appears that multivalency is an important component of vWf interaction with the extracellular matrix, just as has been shown for vWf interaction with platelets. The pool of vWf contained within the Weibel-Palade bodies, therefore, is not only especially suited for platelet binding, but also for interaction with the extracellular matrix.

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