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 Single Cell Hydrodynamic Stretching and Microsieve Filtration Reveal Genetic, Phenotypic and Treatment-Related Links to Cellular Deformability

Micromachines ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 486
Author(s):  
Fenfang Li ◽  
Igor Cima ◽  
Jess Honganh Vo ◽  
Min-Han Tan ◽  
Claus Dieter Ohl
Keyword(s):  
Single Cell ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Extensional Flow ◽  
Colorectal Cancer Cell Line ◽  
Mesenchymal Transition ◽  
Cellular Models ◽  
Cellular Deformability

Deformability is shown to correlate with the invasiveness and metastasis of cancer cells. Recent studies suggest epithelial-to-mesenchymal transition (EMT) might enable cancer metastasis. However, the correlation of EMT with cancer cell deformability has not been well elucidated. Cellular deformability could also help evaluate the drug response of cancer cells. Here, we combine hydrodynamic stretching and microsieve filtration to study cellular deformability in several cellular models. Hydrodynamic stretching uses extensional flow to rapidly quantify cellular deformability and size with high throughput at the single cell level. Microsieve filtration can rapidly estimate relative deformability in cellular populations. We show that colorectal cancer cell line RKO with the mesenchymal-like feature is more flexible than the epithelial-like HCT116. In another model, the breast epithelial cells MCF10A with deletion of the TP53 gene are also significantly more deformable compared to their isogenic wildtype counterpart, indicating a potential genetic link to cellular deformability. We also find that the drug docetaxel leads to an increase in the size of A549 lung cancer cells. The ability to associate mechanical properties of cancer cells with their phenotypes and genetics using single cell hydrodynamic stretching or the microsieve may help to deepen our understanding of the basic properties of cancer progression.

scholarly journals Resveratrol and Its Analogs: Potent Agents to Reverse Epithelial-to-Mesenchymal Transition in Tumors

2021 ◽  
Vol 11 ◽  
Author(s):  
Kaibo Guo ◽  
Yuqian Feng ◽  
Xueer Zheng ◽  
Leitao Sun ◽  
Harpreet S. Wasan ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Basement Membrane ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
Antiproliferative Effects ◽  
Invasion And Migration ◽  
And Migration

Epithelial-to-mesenchymal transition (EMT), a complicated program through which polarized epithelial cells acquire motile mesothelial traits, is regulated by tumor microenvironment. EMT is involved in tumor progression, invasion and metastasis via reconstructing the cytoskeleton and degrading the tumor basement membrane. Accumulating evidence shows that resveratrol, as a non-flavonoid polyphenol, can reverse EMT and inhibit invasion and migration of human tumors via diverse mechanisms and signaling pathways. In the present review, we will summarize the detailed mechanisms and pathways by which resveratrol and its analogs (e.g. Triacetyl resveratrol, 3,5,4’-Trimethoxystilbene) might regulate the EMT process in cancer cells to better understand their potential as novel anti-tumor agents. Resveratrol can also reverse chemoresistance via EMT inhibition and improvement of the antiproliferative effects of conventional treatments. Therefore, resveratrol and its analogs have the potential to become novel adjunctive agents to inhibit cancer metastasis, which might be partly related to their blocking of the EMT process.

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.

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 Noncoding RNAs in Tumor Epithelial-to-Mesenchymal Transition

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Ching-Wen Lin ◽  
Pei-Ying Lin ◽  
Pan-Chyr Yang
Keyword(s):  
Signaling Pathways ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Regulation Of Gene Expression ◽  
Noncoding Rnas ◽  
Protein Translation ◽  
Gene Expressions ◽  
Mesenchymal Transition

Epithelial-derived tumor cells acquire the capacity for epithelial-to-mesenchymal transition (EMT), which enables them to invade adjacent tissues and/or metastasize to distant organs. Cancer metastasis is the main cause of cancer-related death. Molecular mechanisms involved in the switch from an epithelial phenotype to mesenchymal status are complicated and are controlled by a variety of signaling pathways. Recently, a set of noncoding RNAs (ncRNAs), including miRNAs and long noncoding RNAs (lncRNAs), were found to modulate gene expressions at either transcriptional or posttranscriptional levels. These ncRNAs are involved in EMT through their interplay with EMT-related transcription factors (EMT-TFs) and EMT-associated signaling. Reciprocal regulatory interactions between lncRNAs and miRNAs further increase the complexity of the regulation of gene expression and protein translation. In this review, we discuss recent findings regarding EMT-regulating ncRNAs and their associated signaling pathways involved in cancer progression.

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.

Galectin-3: A factotum in carcinogenesis bestowing an archery for prevention

Tumor Biology ◽  
2021 ◽  
Vol 43 (1) ◽  
pp. 77-96
Author(s):  
T. Jeethy Ram ◽  
Asha Lekshmi ◽  
Thara Somanathan ◽  
K. Sujathan
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Cellular Level ◽  
Clinical Samples ◽  
Innovative Strategy ◽  
Mesenchymal Transition ◽  
Galectin 3

Cancer metastasis and therapy resistance are the foremost hurdles in oncology at the moment. This review aims to pinpoint the functional aspects of a unique multifaceted glycosylated molecule in both intracellular and extracellular compartments of a cell namely galectin-3 along with its metastatic potential in different types of cancer. All materials reviewed here were collected through the search engines PubMed, Scopus, and Google scholar. Among the 15 galectins identified, the chimeric gal-3 plays an indispensable role in the differentiation, transformation, and multi-step process of tumor metastasis. It has been implicated in the molecular mechanisms that allow the cancer cells to survive in the intravascular milieu and promote tumor cell extravasation, ultimately leading to metastasis. Gal-3 has also been found to have a pivotal role in immune surveillance and pro-angiogenesis and several studies have pointed out the importance of gal-3 in establishing a resistant phenotype, particularly through the epithelial-mesenchymal transition process. Additionally, some recent findings suggest the use of gal-3 inhibitors in overcoming therapeutic resistance. All these reports suggest that the deregulation of these specific lectins at the cellular level could inhibit cancer progression and metastasis. A more systematic study of glycosylation in clinical samples along with the development of selective gal-3 antagonists inhibiting the activity of these molecules at the cellular level offers an innovative strategy for primary cancer prevention.

scholarly journals Ovalitenone Inhibits the Migration of Lung Cancer Cells via the Suppression of AKT/mTOR and Epithelial-to-Mesenchymal Transition

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 638
Author(s):  
Kittipong Sanookpan ◽  
Nongyao Nonpanya ◽  
Boonchoo Sritularak ◽  
Pithi Chanvorachote
Keyword(s):  
Lung Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Colony Formation ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
A549 Cells ◽  
Lung Cancer Cells ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Cancer metastasis is the major cause of about 90% of cancer deaths. As epithelial-to-mesenchymal transition (EMT) is known for potentiating metastasis, this study aimed to elucidate the effect of ovalitenone on the suppression of EMT and metastasis-related behaviors, including cell movement and growth under detached conditions, and cancer stem cells (CSCs), of lung cancer cells. Methods: Cell viability and cell proliferation were determined by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazo-liumbromide (MTT) and colony formation assays. Cell migration and invasion were analyzed using a wound-healing assay and Boyden chamber assay, respectively. Anchorage-independent cell growth was determined. Cell protrusions (filopodia) were detected by phalloidin-rhodamine staining. Cancer stem cell phenotypes were assessed by spheroid formation. The proteins involved in cell migration and EMT were evaluated by Western blot analysis and immunofluorescence staining. Results: Ovalitenone was used at concentrations of 0–200 μM. While it caused no cytotoxic effects on lung cancer H460 and A549 cells, ovalitenone significantly suppressed anchorage-independent growth, CSC-like phenotypes, colony formation, and the ability of the cancer to migrate and invade cells. The anti-migration activity was confirmed by the reduction of filopodia in the cells treated with ovalitenone. Interestingly, we found that ovalitenone could significantly decrease the levels of N-cadherin, snail, and slug, while it increased E-cadherin, indicating EMT suppression. Additionally, the regulatory signaling of focal adhesion kinase (FAK), ATP-dependent tyrosine kinase (AKT), the mammalian target of rapamycin (mTOR), and cell division cycle 42 (Cdc42) was suppressed by ovalitenone. Conclusions: The results suggest that ovalitenone suppresses EMT via suppression of the AKT/mTOR signaling pathway. In addition, ovalitenone exhibited potential for the suppression of CSC phenotypes. These data reveal the anti-metastasis potential of the compound and support the development of ovalitenone treatment for lung cancer therapy.

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.

scholarly journals Epithelial-to-Mesenchymal Transition Is Not a Major Modulating Factor in the Cytotoxic Response to Natural Products in Cancer Cell Lines

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5858
Author(s):  
Baris Kucukkaraduman ◽  
Ekin Gokce Cicek ◽  
Muhammad Waqas Akbar ◽  
Secil Demirkol Canli ◽  
Burcak Vural ◽  
...  
Keyword(s):  
Natural Products ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Epithelial To Mesenchymal Transition ◽  
Epigallocatechin Gallate ◽  
Cancer Cell Lines ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
Urolithin A

Numerous natural products exhibit antiproliferative activity against cancer cells by modulating various biological pathways. In this study, we investigated the potential use of eight natural compounds (apigenin, curcumin, epigallocatechin gallate, fisetin, forskolin, procyanidin B2, resveratrol, urolithin A) and two repurposed agents (fulvestrant and metformin) as chemotherapy enhancers and mesenchymal-to-epithelial (MET) inducers of cancer cells. Screening of these compounds in various colon, breast, and pancreatic cancer cell lines revealed anti-cancer activity for all compounds, with curcumin being the most effective among these in all cell lines. Although some of the natural products were able to induce MET in some cancer cell lines, the MET induction was not related to increased synergy with either 5-FU, irinotecan, gemcitabine, or gefitinib. When synergy was observed, for example with curcumin and irinotecan, this was unrelated to MET induction, as assessed by changes in E-cadherin and vimentin expression. Our results show that MET induction is compound and cell line specific, and that MET is not necessarily related to enhanced chemosensitivity.

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