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 Control of the Epithelial-to-Mesenchymal Transition and Cancer Metastasis by Autophagy-Dependent SNAI1 Degradation

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 129 ◽  
Author(s):  
Sahib Zada ◽  
Jin Hwang ◽  
Mahmoud Ahmed ◽  
Trang Lai ◽  
Trang Pham ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Nuclear Translocation ◽  
Degradation Process ◽  
Mesenchymal Transition ◽  
Invasion And Migration

Autophagy, an intracellular degradation process, is essential for maintaining cell homeostasis by removing damaged organelles and proteins under various conditions of stress. In cancer, autophagy has conflicting functions. It plays a key role in protecting against cancerous transformation by maintaining genomic stability against genotoxic components, leading to cancerous transformation. It can also promote cancer cell survival by supplying minimal amounts of nutrients during cancer progression. However, the molecular mechanisms underlying how autophagy regulates the epithelial-to-mesenchymal transition (EMT) and cancer metastasis are unknown. Here, we show that starvation-induced autophagy promotes Snail (SNAI1) degradation and inhibits EMT and metastasis in cancer cells. Interestingly, SNAI1 proteins were physically associated and colocalized with LC3 and SQSTM1 in cancer cells. We also found a significant decrease in the levels of EMT and metastatic proteins under starvation conditions. Furthermore, ATG7 knockdown inhibited autophagy-induced SNAI1 degradation in the cytoplasm, which was associated with a decrease in SNAI1 nuclear translocation. Moreover, cancer cell invasion and migration were significantly inhibited by starvation-induced autophagy. These findings suggest that autophagy-dependent SNAI1 degradation could specifically regulate EMT and cancer metastasis during tumorigenesis.

scholarly journals Molecular Mechanisms of Epithelial to Mesenchymal Transition Regulated by ERK5 Signaling

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 183
Author(s):  
Akshita B. Bhatt ◽  
Saloni Patel ◽  
Margarite D. Matossian ◽  
Deniz A. Ucar ◽  
Lucio Miele ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Progression ◽  
Cell Invasion ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
Mesenchymal Transition

Extracellular signal-regulated kinase (ERK5) is an essential regulator of cancer progression, tumor relapse, and poor patient survival. Epithelial to mesenchymal transition (EMT) is a complex oncogenic process, which drives cell invasion, stemness, and metastases. Activators of ERK5, including mitogen-activated protein kinase 5 (MEK5), tumor necrosis factor α (TNF-α), and transforming growth factor-β (TGF-β), are known to induce EMT and metastases in breast, lung, colorectal, and other cancers. Several downstream targets of the ERK5 pathway, such as myocyte-specific enhancer factor 2c (MEF2C), activator protein-1 (AP-1), focal adhesion kinase (FAK), and c-Myc, play a critical role in the regulation of EMT transcription factors SNAIL, SLUG, and β-catenin. Moreover, ERK5 activation increases the release of extracellular matrix metalloproteinases (MMPs), facilitating breakdown of the extracellular matrix (ECM) and local tumor invasion. Targeting the ERK5 signaling pathway using small molecule inhibitors, microRNAs, and knockdown approaches decreases EMT, cell invasion, and metastases via several mechanisms. The focus of the current review is to highlight the mechanisms which are known to mediate cancer EMT via ERK5 signaling. Several therapeutic approaches that can be undertaken to target the ERK5 pathway and inhibit or reverse EMT and metastases are discussed.

scholarly journals The Recruitment of Neutrophils to the Tumor Microenvironment Is Regulated by Multiple Mediators

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuvasree SenGupta ◽  
Lauren E. Hein ◽  
Carole A. Parent
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Current Knowledge ◽  
Extracellular Vesicle ◽  
Immune Defense ◽  
Mesenchymal Transition ◽  
Chemotactic Factors

Neutrophils sense and migrate towards chemotactic factors released at sites of infection/inflammation and contain the affected area using a variety of effector mechanisms. Aside from these established immune defense functions, neutrophils are emerging as one of the key tumor-infiltrating immune cells that influence cancer progression and metastasis. Neutrophil recruitment to the tumor microenvironment (TME) is mediated by multiple mediators including cytokines, chemokines, lipids, and growth factors that are secreted from cancer cells and cancer-associated stromal cells. However, the molecular mechanisms that underlie the expression and secretion of the different mediators from cancer cells and how neutrophils integrate these signals to reach and invade tumors remain unclear. Here, we discuss the possible role of the epithelial to mesenchymal transition (EMT) program, which is a well-established promoter of malignant potential in cancer, in regulating the expression and secretion of these key mediators. We also summarize and review our current understanding of the machineries that potentially control the secretion of the mediators from cancer cells, including the exocytic trafficking pathways, secretory autophagy, and extracellular vesicle-mediated secretion. We further reflect on possible mechanisms by which different mediators collaborate by integrating their signaling network, and particularly focus on TGF-β, a cytokine that is highly expressed in invasive tumors, and CXCR2 ligands, which are crucial neutrophil recruiting chemokines. Finally, we highlight gaps in the field and the need to expand current knowledge of the secretory machineries and cross-talks among mediators to develop novel neutrophil targeting strategies as effective therapeutic options in the treatment of cancer.

scholarly journals A Perspective on the Development of TGF-β Inhibitors for Cancer Treatment

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 743 ◽  
Author(s):  
Linh Huynh ◽  
Christopher Hipolito ◽  
Peter ten Dijke
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Clinical Status ◽  
Tumor Promoter ◽  
Receptor Interaction ◽  
Type I ◽  
Mesenchymal Transition ◽  
Β Receptor

Transforming growth factor (TGF)-β is a secreted multifunctional cytokine that signals via plasma membrane TGF-β type I and type II receptors and intercellular SMAD transcriptional effectors. Aberrant inter- and intracellular TGF-β signaling can contribute to cancer progression. In normal cells and early stages of cancer, TGF-β can stimulate epithelial growth arrest and elicit a tumor suppressor function. However, in late stages of cancer, when the cytostatic effects of TGF-β in cancer cells are blocked, TGF-β signaling can act as tumor promoter by its ability to stimulate epithelial-to-mesenchymal transition of cancer cells, by stimulating angiogenesis, and by promoting evasion of immune responses. In this review, we will discuss the rationale and challenges of targeting TGF-β signaling in cancer and summarize the clinical status of TGF-β signaling inhibitors that interfere with TGF−β bioavailability, TGF-β/receptor interaction, or TGF-β receptor kinase function. Moreover, we will discuss targeting of TGF-β signaling modulators and downstream effectors as well as alternative approaches by using promising technologies that may lead to entirely new classes of drugs.

scholarly journals Sterculic Acid Alters Adhesion Molecules Expression and Extracellular Matrix Compounds to Regulate Migration of Lung Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4370
Author(s):  
Rafael Pelaez ◽  
Rodrigo Ochoa ◽  
Ana Pariente ◽  
Angela Villanueva-Martínez ◽  
Álvaro Pérez-Sala ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Cancer Cells ◽  
Adhesion Molecules ◽  
Epithelial To Mesenchymal Transition ◽  
Sterculic Acid ◽  
Main Function ◽  
Cyclopropenoid Fatty Acid ◽  
Mesenchymal Transition ◽  
Migration Capacity

Sterculic acid (SA) is a cyclopropenoid fatty acid isolated from Sterculia foetida seeds. This molecule is a well-known inhibitor of SCD1 enzyme, also known as ∆9-desaturase, which main function is related to lipid metabolism. However, recent studies have demonstrated that it also modifies many other pathways and the underlying gene expression. SCD overexpression, or up-regulated activity, has been associated with tumor aggressiveness and poor prognosis in many cancer types. Scd1 down-regulation, with different inhibitors or molecular strategies, reduces tumor cell survival and cell proliferation, as well as the chemoresistance associated with cancer stem cell presence. However, SA effects over cancer cell migration and extracellular matrix or adhesion molecules have not been described in cancer cells up to now. We used different migration assays and qPCR gene expression analysis to evaluate the effects of SA treatment in cancer cells. The results reveal that SA induces tumoral cell death at high doses, but we also observed that lower SA-treatments induce cell adhesion-migration capacity reduction as a result of modifications in the expression of genes related to integrins and extracellular matrix compounds. Overall, the functional and transcriptomic findings suggest that SA could represent a new inhibitor activity of epithelial to mesenchymal transition.

scholarly journals CRB3A Controls the Morphology and Cohesion of Cancer Cells through Ehm2/p114RhoGEF-Dependent Signaling

2015 ◽  
Vol 35 (19) ◽  
pp. 3423-3435 ◽  
Author(s):  
Elise Loie ◽  
Lucie E. Charrier ◽  
Kévin Sollier ◽  
Jean-Yves Masson ◽  
Patrick Laprise
Keyword(s):  
Epithelial Cell ◽  
Cancer Cells ◽  
Hela Cells ◽  
Cell Shape ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transmembrane Protein ◽  
Cell Polarization ◽  
Cell Periphery ◽  
Mesenchymal Transition

The transmembrane protein CRB3A controls epithelial cell polarization. Elucidating the molecular mechanisms of CRB3A function is essential as this protein prevents the epithelial-to-mesenchymal transition (EMT), which contributes to tumor progression. To investigate the functional impact of altered CRB3A expression in cancer cells, we expressed CRB3A in HeLa cells, which are devoid of endogenous CRB3A. While control HeLa cells display a patchy F-actin distribution, CRB3A-expressing cells form a circumferential actomyosin belt. This reorganization of the cytoskeleton is accompanied by a transition from an ameboid cell shape to an epithelial-cell-like morphology. In addition, CRB3A increases the cohesion of HeLa cells. To perform these functions, CRB3A recruits p114RhoGEF and its activator Ehm2 to the cell periphery using both functional motifs of its cytoplasmic tail and increases RhoA activation levels. ROCK1 and ROCK2 (ROCK1/2), which are critical effectors of RhoA, are also essential to modulate the cytoskeleton and cell shape downstream of CRB3A. Overall, our study highlights novel roles for CRB3A and deciphers the signaling pathway conferring to CRB3A the ability to fulfill these functions. Thereby, our data will facilitate further investigation of CRB3A functions and increase our understanding of the cellular defects associated with the loss of CRB3A expression in cancer cells.

scholarly journals FOXH1 promotes lung cancer progression by activating the Wnt/β-catenin signaling pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jun Zhang ◽  
Xian Zhang ◽  
Shasha Yang ◽  
Yanqiu Bao ◽  
Dongyuan Xu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Lung Cancer Cells ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Mesenchymal Transition

Abstract Background The expression of forkhead box protein H1 (FOXH1) is frequently upregulated in various cancers. However, the molecular mechanisms underlying the association between FOXH1 expression and lung cancer progression still remain poorly understood. Thus, the main objective of this study is to explore the role of FOXH1 in lung cancer. Methods The Cancer Genome Atlas dataset was used to investigate FOXH1 expression in lung cancer tissues, and the Kaplan–Meier plotter dataset was used to determine the role of FOXH1 in patient prognosis. A549 and PC9 cells were transfected with short hairpin RNA targeting FOXH1 mRNA. The Cell Counting Kit-8, colony formation, soft agar, wound healing, transwell invasion and flow cytometry assays were performed to evaluate proliferation, migration and invasion of lung cancer cells. Tumorigenicity was examined in a BALB/c nude mice model. Western blot analysis was performed to assess the molecular mechanisms, and β-catenin activity was measured by a luciferase reporter system assay. Results Higher expression level of FOXH1 was observed in tumor tissue than in normal tissue, and this was associated with poor overall survival. Knockdown of FOXH1 significantly inhibited lung cancer cell proliferation, migration, invasion, and cycle. In addition, the mouse xenograft model showed that knockdown of FOXH1 suppressed tumor growth in vivo. Further experiments revealed that FOXH1 depletion inhibited the epithelial-mesenchymal transition of lung cancer cells by downregulating the expression of mesenchymal markers (Snail, Slug, matrix metalloproteinase-2, N-cadherin, and Vimentin) and upregulating the expression of an epithelial marker (E-cadherin). Moreover, knockdown of FOXH1 significantly downregulated the activity of β-catenin and its downstream targets, p-GSK-3β and cyclin D1. Conclusion FOXH1 exerts oncogenic functions in lung cancer through regulation of the Wnt/β-catenin signaling pathway. FOXH1 might be a potential therapeutic target for patients with certain types of lung cancer.

scholarly journals Epigenetic Regulation of Epithelial to Mesenchymal Transition in the Cancer Metastatic Cascade: Implications for Cancer Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Qiu-Luo Liu ◽  
Maochao Luo ◽  
Canhua Huang ◽  
Hai-Ning Chen ◽  
Zong-Guang Zhou
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Epigenetic Regulation ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Metastatic Cascade ◽  
Subsequent Transformation ◽  
Metastatic Cells

Metastasis is the end stage of cancer progression and the direct cause of most cancer-related deaths. The spreading of cancer cells from the primary site to distant organs is a multistep process known as the metastatic cascade, including local invasion, intravasation, survival in the circulation, extravasation, and colonization. Each of these steps is driven by the acquisition of genetic and/or epigenetic alterations within cancer cells, leading to subsequent transformation of metastatic cells. Epithelial–mesenchymal transition (EMT), a cellular process mediating the conversion of cell from epithelial to mesenchymal phenotype, and its reverse transformation, termed mesenchymal–epithelial transition (MET), together endow metastatic cells with traits needed to generate overt metastases in different scenarios. The dynamic shift between these two phenotypes and their transitional state, termed partial EMT, emphasizes the plasticity of EMT. Recent advances attributed this plasticity to epigenetic regulation, which has implications for the therapeutic targeting of cancer metastasis. In this review, we will discuss the association between epigenetic events and the multifaceted nature of EMT, which may provide insights into the steps of the cancer metastatic cascade.

Crosstalk of long non-coding RNAs and EMT: Searching the missing pieces of an incomplete puzzle for lung cancer therapy

2021 ◽  
Vol 21 ◽  
Author(s):  
Milad Ashrafizadeh ◽  
Md Shahinozzaman ◽  
Sima Orouei ◽  
Vahideh Zarrin ◽  
Kiavash Hushmandi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Lung Cancer Cells ◽  
Mesenchymal Transition ◽  
Life Threatening ◽  
Non Coding Rnas ◽  
Potential Factors

Background: Lung cancer is considered to be the first place among the cancer-related deaths worldwide and demands novel strategies in the treatment of this life-threatening disorder. The aim of this review is to explore regulation of epithelial-to-mesenchymal transition (EMT) by long non-coding RNAs (lncRNAs) in lung cancer. Introduction: LncRNAs can be considered as potential factors for targeting in cancer therapy, since they regulate a bunch of biological processes, e.g. cell proliferation, differentiation and apoptosis. The abnormal expression of lncRNAs occurs in different cancer cells. On the other hand, epithelial-to-mesenchymal transition (EMT) is a critical mechanism participating in migration and metastasis of cancer cells. Method: Different databases including Googlescholar, Pubmed and Sciencedirect were used for collecting articles using keywords such as “LncRNA”, “EMT”, and “Lung cancer”. Result: There are tumor-suppressing lncRNAs that can suppress EMT and metastasis of lung cancer cells. Expression of such lncRNAs undergoes down-regulation in lung cancer progression and restoring their expression is of importance in suppressing lung cancer migration. There are tumor-promoting lncRNAs triggering EMT in lung cancer and enhancing their migration. Conclusion: LncRNAs are potential regulators of EMT in lung cancer, and targeting them, both pharmacologically and genetically, can be of importance in controlling migration of lung cancer cells.

Sign in / Sign up

Export Citation Format

Share Document