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 The metabolic adaptation mechanism of metastatic organotropism

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Chao Wang ◽  
Daya Luo
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Cancer Metabolism ◽  
Cancer Metastasis ◽  
Tumour Microenvironment ◽  
Metabolic Adaptation ◽  
Adaptation Mechanism ◽  
Metastatic Sites ◽  
The Impact

AbstractMetastasis is a complex multistep cascade of cancer cell extravasation and invasion, in which metabolism plays an important role. Recently, a metabolic adaptation mechanism of cancer metastasis has been proposed as an emerging model of the interaction between cancer cells and the host microenvironment, revealing a deep and extensive relationship between cancer metabolism and cancer metastasis. However, research on how the host microenvironment affects cancer metabolism is mostly limited to the impact of the local tumour microenvironment at the primary site. There are few studies on how differences between the primary and secondary microenvironments promote metabolic changes during cancer progression or how secondary microenvironments affect cancer cell metastasis preference. Hence, we discuss how cancer cells adapt to and colonize in the metabolic microenvironments of different metastatic sites to establish a metastatic organotropism phenotype. The mechanism is expected to accelerate the research of cancer metabolism in the secondary microenvironment, and provides theoretical support for the generation of innovative therapeutic targets for clinical metastatic diseases.

Superparamagnetic nanoparticles targeting cancer cells invading the extracellular matrix.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3083-3083
Author(s):  
Samar Elachy ◽  
Wegdan Ramadan ◽  
Remon Kalsa ◽  
Nihad Abou El Azm ◽  
Tamer Refaat ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Hela Cell ◽  
Cancer Cells ◽  
Cell Lines ◽  
Collagen Type ◽  
Blue Staining ◽  
Hela Cell Lines ◽  
The Matrix ◽  
Ecm Gel ◽  
Murine Sarcoma

3083 Background: Metastatic cancer cells secrete matrix metalloproteinases (MMP), which allow cancer cells to burrow their way to the nearby vasculature. Therefore, MMPs are potential targets for anticancer treatment. Nanoparticles (NPs) can be crafted to adhere to the ECM and subsequently be released in response to advance of invasive cells. The objective of the study is to elucidate the interaction of cancer cells in a three-dimensional culture, with functionalized SPIONS targeted to the extracellular matrix around them. Methods: SPIONS, 15-20 nm in size were functionalized using different coatings: ficoll 400, sucrose, lysine-arginine, dextran50,000. Cellular uptake studies using cervical adenocarcinoma HeLa cell lines were performed to determine the optimum formulation taken up by the cells, using electron microscopy and Prussian blue staining for optical microscopy. Two types of extracellular matrices were used: Rat-tail Collagen type I and ECM gel from Engelbreth-Holm-Swarm murine sarcoma with NPs embedded in them. To assess the capability of cells to invade the matrix, cells were grown on the surface of the matrices for 1 week To evaluate the ability to grow, expand and migrate inside the matrix, cells were embedded within the matrix and left for 14 days. Comparison was made in the presence or absence of SPIONS. Results: Sucrose-coated SPIONS were taken up the best by HeLa cell lines as evaluated by MRI. MMP-1 Secretion allowed HeLa cell invasion of collagen type-1 matrix unidirectionally. Cells could adhere, proliferate, differentiate and migrate in the absence of SPIONS. Cells positive for MMP-9 invaded ECM gel from Engelbreth-Hol-Swarm murine sarcoma matrix also only in the absence of SPIONS. Cells that were found engulfing SPIONS showed morphological features of apoptosis as nuclear pyknosis and karryorhexis. Conclusions: Targeting NPs to the ECM surrounding cancer cells that have developed a metastatic potential represents an attractive platform for cancer therapeutics. The findings show a great promise for development of new theranostic agents, that can be directed to the tumor environment using external magnetic fields, with subsequent suppression of invasion and even destroying malignant cells.

scholarly journals Chemotherapy-induced collagen IV drives cancer cell invasion through activation of Src/FAK signaling

2021 ◽  
Author(s):  
Jackson P. Fatherree ◽  
Justinne R. Guarin ◽  
Rachel A. McGinn ◽  
Stephen P. Naber ◽  
Madeleine J. Oudin
Keyword(s):  
Breast Cancer ◽  
Extracellular Matrix ◽  
Cancer Cells ◽  
Collagen Iv ◽  
Metastatic Recurrence ◽  
Decellularized Extracellular Matrix ◽  
Basement Membrane Protein ◽  
Tandem Mass Tag ◽  
Treatment Naïve ◽  
Metastatic Sites

AbstractTriple-negative breast cancer (TNBC) is the most aggressive and deadly subtype of breast cancer, accounting for 30,000 cases annually in the US. While there are several clinical trials ongoing to identify new agents to treat TNBC, the majority of TNBC patients are treated with anthracycline- or taxane-based chemotherapies in the neoadjuvant setting, followed by surgical resection and adjuvant chemotherapy. While many patients respond well to this approach, as many as 25% will suffer local or metastatic recurrence within five years. Understanding the mechanisms that drive recurrence after chemotherapy treatment is critical to improving survival for patients with TNBC. It is well-established that the extracellular matrix, which provides structure and support to tissues, is a major driver of tumor growth, local invasion and dissemination of cancer cells to distant metastatic sites. In the present study, we show that decellularized extracellular matrix (dECM) obtained from chemotherapy-treated mice increases invasion of treatment-naïve breast cancer cells compared to vehicle-treated dECM. Using tandem-mass-tag proteomics, we further demonstrate that anthracycline- and taxane-based chemotherapies induce drug-specific changes in tumor ECM composition. We identify the basement membrane protein collagen IV as significantly upregulated in the ECM of chemotherapy-treated mice and patients treated with neoadjuvant chemotherapy. We show that collagen IV drives invasion via Src/FAK signaling and that inhibiting collagen IV-driven signaling decreases invasion in chemotherapy-treated dECM. These studies provide a novel mechanism by which chemotherapy may induce metastasis via effects on ECM composition.One Sentence SummaryChemotherapy alters the extracellular matrix of breast tumors leading to increased invasion of residual cancer cells.

scholarly journals Targeting the Tumor Microenvironment for Cancer Therapy

2013 ◽  
Vol 59 (1) ◽  
pp. 85-93 ◽  
Author(s):  
Nor Eddine Sounni ◽  
Agnès Noel
Keyword(s):  
Extracellular Matrix ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Local Environment ◽  
Tumor Stroma ◽  
Host Cells ◽  
Stromal Compartment ◽  
Tumor Infiltrate ◽  
Cellular Components

BACKGROUND With the emergence of the tumor microenvironment as an essential ingredient of cancer malignancy, therapies targeting the host compartment of tumors have begun to be designed and applied in the clinic. CONTENT The malignant features of cancer cells cannot be manifested without an important interplay between cancer cells and their local environment. The tumor infiltrate composed of immune cells, angiogenic vascular cells, lymphatic endothelial cells, and cancer-associated fibroblastic cells contributes actively to cancer progression. The ability to change these surroundings is an important property by which tumor cells are able to acquire some of the hallmark functions necessary for tumor growth and metastatic dissemination. Thus in the clinical setting the targeting of the tumor microenvironment to encapsulate or destroy cancer cells in their local environment has become mandatory. The variety of stromal cells, the complexity of the molecular components of the tumor stroma, and the similarity with normal tissue present huge challenges for therapies targeting the tumor microenvironment. These issues and their interplay are addressed in this review. After a decade of intensive clinical trials targeting cellular components of the tumor microenvironment, more recent investigations have shed light on the important role in cancer progression played by the noncellular stromal compartment composed of the extracellular matrix. SUMMARY A better understanding of how the tumor environment affects cancer progression should provide new targets for the isolation and destruction of cancer cells via interference with the complex crosstalk established between cancer cells, host cells, and their surrounding extracellular matrix.

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 Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis

2017 ◽  
Vol 45 (1) ◽  
pp. 229-236 ◽  
Author(s):  
Begum Erdogan ◽  
Donna J. Webb
Keyword(s):  
Extracellular Matrix ◽  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Migration And Invasion ◽  
Matrix Remodeling ◽  
Growth Factor Signaling ◽  
Cancer Associated Fibroblasts ◽  
Cell Migration And Invasion ◽  
Tumor Cell Migration

Cancer-associated fibroblasts (CAFs) are major components of the surrounding stroma of carcinomas that emerge in the tumor microenvironment as a result of signals derived from the cancer cells. Biochemical cross-talk between cancer cells and CAFs as well as mechanical remodeling of the stromal extracellular matrix (ECM) by CAFs are important contributors to tumor cell migration and invasion, which are critical for cancer progression from a primary tumor to metastatic disease. In this review, we discuss key paracrine signaling pathways between CAFs and cancer cells that promote cancer cell migration and invasion. In addition, we discuss physical changes that CAFs exert on the stromal ECM to facilitate migration and invasion of cancer cells.

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 Extracellular Matrix Alterations in Metastatic Processes

2019 ◽  
Vol 20 (19) ◽  
pp. 4947 ◽  
Author(s):  
Paolillo ◽  
Schinelli
Keyword(s):  
Extracellular Matrix ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Intercellular Junctions ◽  
Matrix Metalloproteases ◽  
Target Tissue ◽  
Epithelial Tumor ◽  
Mesenchymal Transition

The extracellular matrix (ECM) is a complex network of extracellular-secreted macromolecules, such as collagen, enzymes and glycoproteins, whose main functions deal with structural scaffolding and biochemical support of cells and tissues. ECM homeostasis is essential for organ development and functioning under physiological conditions, while its sustained modification or dysregulation can result in pathological conditions. During cancer progression, epithelial tumor cells may undergo epithelial-to-mesenchymal transition (EMT), a morphological and functional remodeling, that deeply alters tumor cell features, leading to loss of epithelial markers (i.e., E-cadherin), changes in cell polarity and intercellular junctions and increase of mesenchymal markers (i.e., N-cadherin, fibronectin and vimentin). This process enhances cancer cell detachment from the original tumor mass and invasiveness, which are necessary for metastasis onset, thus allowing cancer cells to enter the bloodstream or lymphatic flow and colonize distant sites. The mechanisms that lead to development of metastases in specific sites are still largely obscure but modifications occurring in target tissue ECM are being intensively studied. Matrix metalloproteases and several adhesion receptors, among which integrins play a key role, are involved in metastasis-linked ECM modifications. In addition, cells involved in the metastatic niche formation, like cancer associated fibroblasts (CAF) and tumor associated macrophages (TAM), have been found to play crucial roles in ECM alterations aimed at promoting cancer cells adhesion and growth. In this review we focus on molecular mechanisms of ECM modifications occurring during cancer progression and metastatic dissemination to distant sites, with special attention to lung, liver and bone. Moreover, the functional role of cells forming the tumor niche will also be reviewed in light of the most recent findings.

scholarly journals Towards a Better Understanding of the Relationships between Galectin-7, p53 and MMP-9 during Cancer Progression

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 879
Author(s):  
Yves St-Pierre
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
New Paradigm ◽  
Cancer Subtypes ◽  
Functional Relationships ◽  
Invasive Behavior ◽  
Cancer Field ◽  
The Matrix ◽  
Cancer Types

It has been almost 25 years since the discovery of galectin-7. This member of the galectin family has attracted interest from many working in the cancer field given its highly restricted expression profile in epithelial cells and the fact that cancers of epithelial origin (carcinoma) are among the most frequent and deadly cancer subtypes. Initially described as a p53-induced gene and associated with apoptosis, galectin-7 is now recognized as having a protumorigenic role in many cancer types. Several studies have indeed shown that galectin-7 is associated with aggressive behavior of cancer cells and induces expression of MMP-9, a member of the matrix metalloproteinases (MMP) family known to confer invasive behavior to cancer cells. It is therefore not surprising that many studies have examined its relationships with p53 and MMP-9. However, the relationships between galectin-7 and p53 and MMP-9 are not always clear. This is largely because p53 is often mutated in cancer cells and such mutations drastically change its functions and, consequently, its association with galectin-7. In this review, we discuss the functional relationships between galectin-7, p53 and MMP-9 and reconcile some apparently contradictory observations. A better understanding of these relationships will help to develop a working hypothesis and model that will provide the basis for further research in the hope of establishing a new paradigm for tackling the role of galectin-7 in cancer.

scholarly journals Collective cancer invasion forms an integrin-dependent radioresistant niche

2019 ◽  
Vol 217 (1) ◽  
Author(s):  
Anna Haeger ◽  
Stephanie Alexander ◽  
Manon Vullings ◽  
Fabian M.P. Kaiser ◽  
Cornelia Veelken ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Dna Damage ◽  
Clinical Trials ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Therapy Resistance ◽  
Mesenchymal Tumors ◽  
Dual Targeting ◽  
Extracellular Matrix Receptors

Cancer fatalities result from metastatic dissemination and therapy resistance, both processes that depend on signals from the tumor microenvironment. To identify how invasion and resistance programs cooperate, we used intravital microscopy of orthotopic sarcoma and melanoma xenografts. We demonstrate that these tumors invade collectively and that, specifically, cells within the invasion zone acquire increased resistance to radiotherapy, rapidly normalize DNA damage, and preferentially survive. Using a candidate-based approach to identify effectors of invasion-associated resistance, we targeted β1 and αVβ3/β5 integrins, essential extracellular matrix receptors in mesenchymal tumors, which mediate cancer progression and resistance. Combining radiotherapy with β1 or αV integrin monotargeting in invading tumors led to relapse and metastasis in 40–60% of the cohort, in line with recently failed clinical trials individually targeting integrins. However, when combined, anti-β1/αV integrin dual targeting achieved relapse-free radiosensitization and prevented metastatic escape. Collectively, invading cancer cells thus withstand radiotherapy and DNA damage by β1/αVβ3/β5 integrin cross-talk, but efficient radiosensitization can be achieved by multiple integrin targeting.

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