scholarly journals Exploring the Crosstalk between Inflammation and Epithelial-Mesenchymal Transition in Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Indranil Chattopadhyay ◽  
Rangarao Ambati ◽  
Rohit Gundamaraju
Keyword(s):  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Cell ◽  
The Body ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Complex Interactions ◽  
Protein Encoding ◽  
Inflammatory Molecules ◽  
Encoding Genes

Tumor cells undergo invasion and metastasis through epithelial-to-mesenchymal cell transition (EMT) by activation of alterations in extracellular matrix (ECM) protein-encoding genes, enzymes responsible for the breakdown of ECM, and activation of genes that drive the transformation of the epithelial cell to the mesenchymal type. Inflammatory cytokines such as TGFβ, TNFα, IL-1, IL-6, and IL-8 activate transcription factors such as Smads, NF-κB, STAT3, Snail, Twist, and Zeb that drive EMT. EMT drives primary tumors to metastasize in different parts of the body. T and B cells, dendritic cells (DCs), and tumor-associated macrophages (TAMs) which are present in the tumor microenvironment induce EMT. The current review elucidates the interaction between EMT tumor cells and immune cells under the microenvironment. Such complex interactions provide a better understanding of tumor angiogenesis and metastasis and in defining the aggressiveness of the primary tumors. Anti-inflammatory molecules in this context may open new therapeutic options for the better treatment of tumor progression. Targeting EMT and the related mechanisms by utilizing natural compounds may be an important and safe therapeutic alternative in the treatment of tumor growth.

scholarly journals Epithelial-Mesenchymal Transition and Metastasis under the Control of Transforming Growth Factor β

2018 ◽  
Vol 19 (11) ◽  
pp. 3672 ◽  
Author(s):  
Yutaro Tsubakihara ◽  
Aristidis Moustakas
Keyword(s):  
Growth Factor ◽  
Tumor Cells ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β ◽  
Basement Membranes ◽  
The Body ◽  
Common Denominator ◽  
Adhesion Forces ◽  
Mesenchymal Transition

Metastasis of tumor cells from primary sites of malignancy to neighboring stromal tissue or distant localities entails in several instances, but not in every case, the epithelial-mesenchymal transition (EMT). EMT weakens the strong adhesion forces between differentiated epithelial cells so that carcinoma cells can achieve solitary or collective motility, which makes the EMT an intuitive mechanism for the initiation of tumor metastasis. EMT initiates after primary oncogenic events lead to secondary secretion of cytokines. The interaction between tumor-secreted cytokines and oncogenic stimuli facilitates EMT progression. A classic case of this mechanism is the cooperation between oncogenic Ras and the transforming growth factor β (TGFβ). The power of TGFβ to mediate EMT during metastasis depends on versatile signaling crosstalk and on the regulation of successive waves of expression of many other cytokines and the progressive remodeling of the extracellular matrix that facilitates motility through basement membranes. Since metastasis involves many organs in the body, whereas EMT affects carcinoma cell differentiation locally, it has frequently been debated whether EMT truly contributes to metastasis. Despite controversies, studies of circulating tumor cells, studies of acquired chemoresistance by metastatic cells, and several (but not all) metastatic animal models, support a link between EMT and metastasis, with TGFβ, often being a common denominator in this link. This article aims at discussing mechanistic cases where TGFβ signaling and EMT facilitate tumor cell dissemination.

scholarly journals Crotoxin Modulates Events Involved in Epithelial–Mesenchymal Transition in 3D Spheroid Model

Toxins ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 830
Author(s):  
Ellen Emi Kato ◽  
Sandra Coccuzzo Sampaio
Keyword(s):  
Tumor Cells ◽  
Type I Collagen ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Cancer ◽  
A549 Cells ◽  
The Body ◽  
Antitumor Action ◽  
Type I ◽  
Collagen Gels ◽  
Mesenchymal Transition

Epithelial–mesenchymal transition (EMT) occurs in the early stages of embryonic development and plays a significant role in the migration and the differentiation of cells into various types of tissues of an organism. However, tumor cells, with altered form and function, use the EMT process to migrate and invade other tissues in the body. Several experimental (in vivo and in vitro) and clinical trial studies have shown the antitumor activity of crotoxin (CTX), a heterodimeric phospholipase A2 present in the Crotalus durissus terrificus venom. In this study, we show that CTX modulates the microenvironment of tumor cells. We have also evaluated the effect of CTX on the EMT process in the spheroid model. The invasion of type I collagen gels by heterospheroids (mix of MRC-5 and A549 cells constitutively prepared with 12.5 nM CTX), expression of EMT markers, and secretion of MMPs were analyzed. Western blotting analysis shows that CTX inhibits the expression of the mesenchymal markers, N-cadherin, α-SMA, and αv. This study provides evidence of CTX as a key modulator of the EMT process, and its antitumor action can be explored further for novel drug designing against metastatic cancer.

scholarly journals Key Characteristics of Circulating Tumor Cell Clusters and Implications for Cancer Metastases

2021 ◽  
Vol 10 (2) ◽  
Author(s):  
Yakov Perlov ◽  
Dean Lee
Keyword(s):  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Embryonic Stem ◽  
Metastatic Potential ◽  
Circulating Tumor Cell ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Metastatic Lesions ◽  
Key Characteristics ◽  
Single Ctcs

Primary tumors generate metastases by shedding tumor cells into the circulation; these circulating tumor cells (CTCs) implant at distant sites to develop into metastatic lesions. CTCs can travel either as clusters or as single CTCs. Previous studies revealed that the frequency of CTC clusters in a cancer patient positively correlates with the likelihood of developing metastatic lesions. Three key characteristics of CTC clusters - chemoresistance, reduced apoptosis, and epigenetically programmed stemness - enhance their metastatic potential relative to single CTCs: CTC clusters seem to be more resistant to chemotherapy due to their quiescent and necrotic cores, making drug penetration difficult. Their chemoresistance also correlates with specific molecular components of the extracellular matrix. CTC clusters suffer lower rates of apoptosis. This might be attributed to autocrine factors that protect against immune attack and the epithelial-mesenchymal transition. The DNA methylation landscape of CTC clusters closely resembles that of embryonic stem cells. It features hypomethylation of four critical transcription factors associated with stemness and hypermethylation of a set of pro-differentiation genes. Further research might focus on the interdependence of these three characteristics and whether they precede or follow the clustering of CTCs. The answers to these research questions will help drug developers define specific mechanisms that can curb the metastatic potential of CTC clusters.

scholarly journals Phenotypic Heterogeneity of Triple-Negative Breast Cancer Mediated by Epithelial–Mesenchymal Plasticity

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2188
Author(s):  
Barbora Kvokačková ◽  
Ján Remšík ◽  
Mohit Kumar Jolly ◽  
Karel Souček
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Intratumoral Heterogeneity ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Metastatic Colonization ◽  
Evolutionarily Conserved

Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma known for its unusually aggressive behavior and poor clinical outcome. Besides the lack of molecular targets for therapy and profound intratumoral heterogeneity, the relatively quick overt metastatic spread remains a major obstacle in effective clinical management. The metastatic colonization of distant sites by primary tumor cells is affected by the microenvironment, epigenetic state of particular subclones, and numerous other factors. One of the most prominent processes contributing to the intratumoral heterogeneity is an epithelial–mesenchymal transition (EMT), an evolutionarily conserved developmental program frequently hijacked by tumor cells, strengthening their motile and invasive features. In response to various intrinsic and extrinsic stimuli, malignant cells can revert the EMT state through the mesenchymal–epithelial transition (MET), a process that is believed to be critical for the establishment of macrometastasis at secondary sites. Notably, cancer cells rarely undergo complete EMT and rather exist in a continuum of E/M intermediate states, preserving high levels of plasticity, as demonstrated in primary tumors and, ultimately, in circulating tumor cells, representing a simplified element of the metastatic cascade. In this review, we focus on cellular drivers underlying EMT/MET phenotypic plasticity and its detrimental consequences in the context of TNBC cancer.

scholarly journals The role of miRNA in regulation of AXL, DAPK1, NFIB gene expression in breast cancer

2018 ◽  
pp. 130-133
Author(s):  
И.В. Пронина ◽  
Е.А. Филиппова ◽  
С.С. Лукина ◽  
А.М. Бурденный ◽  
Т.П. Казубская ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Epithelial Mesenchymal Transition ◽  
Negative Regulator ◽  
Protein Coding ◽  
Mesenchymal Transition ◽  
Protein Encoding ◽  
Apoptotic Pathways ◽  
Encoding Genes

Рак молочной железы (РМЖ) характеризуется эпигенетическими нарушениями, которые приводят к нарушению регуляции экспрессии опухоль ассоциированных белок-кодирующих генов, что влияет на развитие опухоли. Цель исследования - поиск новых микроРНК, потенциально вовлеченных в регуляцию экспрессии 3 белок-кодирующих генов (AXL, DAPK1, NFIB), связанных с регуляцией апоптоза и эпителиально-мезенхимального перехода при РМЖ. Методом количественной ПЦР определены изменения экспрессии 3 белок-кодирующих генов (AXL, DAPK1, NFIB) и 3 микроРНК (miR-127-5p, -132-3р, -9-5p), предсказанных с помощью алгоритмов miRWalk 2.0 как регуляторные. Определены статистически значимые отрицательные корреляции между изменениями уровней экспрессии микроРНК и мРНК для следующих пар: miR-127-5p - DAPK1 (Rs = -0,503, p = 0,001) и miR-9-5p - DAPK1 (Rs = -0,335, p = 0,040). Таким образом, установлена потенциальная роль двух микроРНК в регуляции экспрессии гена DAPK1, активатора различных путей апоптоза и негативного регулятора ЭМП, что имеет фундаментальное значение и может найти применение для разработки таргетной терапии РМЖ. Breast cancer (BC) is characterized by epigenetic disorders, which lead to dysregulation of protein-coding gene expression; together these result in development of a tumor. The goal of the study was to search for new miRNAs that are potentially involved in regulation of the expression of three protein-encoding genes (AXL, DAPK1, NFIB) associated with regulation of apoptosis and the epithelial-mesenchymal transition in breast cancer. Quantitative PCR was used to determine changes in the expression of three protein-coding genes (AXL, DAPK1, NFIB) and three miRNAs (miR-127-5p, -132-3p, -9-5p) that had been predicted to be regulators by miRWalk 2.0 algorithms. Statistically significant negative correlations between changes in miRNA and mRNA expression were determined for the following pairs: miR-127-5p - DAPK1 (Rs = -0.503, p = 0.001) and miR-9-5p - DAPK1 (Rs = -0.335, p = 0.040). Therefore, the study showed a potential role of two miRNAs in regulation of the DAPK1 gene expression, an activator of various apoptotic pathways and a negative regulator of EMT. This result is fundamentally important and can be used to develop targeted therapies for breast cancer.

scholarly journals The functional activity of E-cadherin controls tumor cell metastasis at multiple steps

2020 ◽  
Vol 117 (11) ◽  
pp. 5931-5937 ◽  
Author(s):  
Tae-Young Na ◽  
Leslayann Schecterson ◽  
Alisha M. Mendonsa ◽  
Barry M. Gumbiner
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Functional Activity ◽  
Epithelial Mesenchymal Transition ◽  
Important Determinant ◽  
Three Dimensional ◽  
Metastatic Potential ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
E Cadherin

E-cadherin is a tumor suppressor protein, and the loss of its expression in association with the epithelial mesenchymal transition (EMT) occurs frequently during tumor metastasis. However, many metastases continue to express E-cadherin, and a full EMT is not always necessary for metastasis; also, positive roles for E-cadherin expression in metastasis have been reported. We hypothesize instead that changes in the functional activity of E-cadherin expressed on tumor cells in response to environmental factors is an important determinant of the ability of the tumor cells to metastasize. We find that E-cadherin expression persists in metastatic lung nodules and circulating tumor cells (CTCs) in two mouse models of mammary cancer: genetically modified MMTV-PyMT mice and orthotopically grafted 4T1 tumor cells. Importantly, monoclonal antibodies that bind to and activate E-cadherin at the cell surface reduce lung metastasis from endogenous genetically driven tumors and from tumor cell grafts. E-cadherin activation inhibits metastasis at multiple stages, including the accumulation of CTCs from the primary tumor and the extravasation of tumor cells from the vasculature. These activating mAbs increase cell adhesion and reduce cell invasion and migration in both cell culture and three-dimensional spheroids grown from primary tumors. Moreover, activating mAbs increased the frequency of apoptotic cells without affecting proliferation. Although the growth of the primary tumors was unaffected by activating mAbs, CTCs and tumor cells in metastatic nodules exhibited increased apoptosis. Thus, the functional state of E-cadherin is an important determinant of metastatic potential beyond whether the gene is expressed.

Effect of Annexins Translocated in Extracellular Vesicles on Tumorigenesis

2020 ◽  
Vol 20 ◽  
Author(s):  
Qionghui Wu ◽  
Haidong Wei ◽  
Wenbo Meng ◽  
Xiaodong Xie ◽  
Zhenchang Zhang ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Immune Cell ◽  
Epithelial Mesenchymal Transition ◽  
Main Role ◽  
Tumor Cell Adhesion ◽  
Mesenchymal Transition ◽  
Calcium Dependent ◽  
Tumor Neovascularization

: Annexin, a calcium-dependent phospholipid binding protein, can affect tumor cell adhesion, proliferation, apoptosis, invasion and metastasis, as well as tumor neovascularization in different ways. Recent studies have shown that annexin exists not only as an intracellular protein in tumor cells, but also in different ways to be secret outside the cell as a “crosstalk” tool for tumor cells and tumor microenvironment, thus playing an important role in the development of tumors, such as participating in epithelial-mesenchymal transition, regulating immune cell behavior, promoting neovascularization and so on. The mechanism of annexin secretion in the form of extracellular vesicles and its specific role is still unclear. This paper summarizes the main role of annexin secreted into the extracellular space in the form of extracellular vesicles in tumorigenesis and drug resistance and analyzes its possible mechanism.

scholarly journals Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1102
Author(s):  
Alexander E. Kabakov ◽  
Anna O. Yakimova
Keyword(s):  
Heat Shock ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Liver Tumors ◽  
Oxygen Deficiency ◽  
Transarterial Embolization ◽  
Antiangiogenic Therapy ◽  
Adaptation To Hypoxia ◽  
Mesenchymal Transition

Within aggressive malignancies, there usually are the “hypoxic zones”—poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. Both the lack of oxygen by itself and the hypoxia-responsive phenotypic modulations render tumor cells more radioresistant, so that hypoxic tumors are a serious challenge for radiotherapy. An understanding of causes of the radioresistance of hypoxic tumors would help to develop novel ways for overcoming this challenge. Molecular targets for and various approaches to radiosensitizing hypoxic tumors are considered in the present review. It is here analyzed how the hypoxia-induced cellular responses involving hypoxia-inducible factor-1, heat shock transcription factor 1, heat shock proteins, glucose-regulated proteins, epigenetic regulators, autophagy, energy metabolism reprogramming, epithelial–mesenchymal transition and exosome generation contribute to the radioresistance of hypoxic tumors or may be inhibited for attenuating this radioresistance. The pretreatments with a multitarget inhibition of the cancer cell adaptation to hypoxia seem to be a promising approach to sensitizing hypoxic carcinomas, gliomas, lymphomas, sarcomas to radiotherapy and, also, liver tumors to radioembolization.

scholarly journals Epithelial-Mesenchymal Transition and MicroRNAs in Colorectal Cancer Chemoresistance to FOLFOX

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 75
Author(s):  
Paula I. Escalante ◽  
Luis A. Quiñones ◽  
Héctor R. Contreras
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Methylenetetrahydrofolate Reductase ◽  
Epithelial Mesenchymal Transition ◽  
Late Onset ◽  
Dihydropyrimidine Dehydrogenase ◽  
Acquired Resistance ◽  
Potential Effect ◽  
Mesenchymal Transition ◽  
Folfox Chemotherapy

The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Moreover, from pharmacogenomic research, it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), the DNA repair enzymes ERCC1, ERCC2, and XRCC1, and the phase 2 enzyme GSTP1 impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of DPYD, TYMS, ERCC1, and GSTP1. In this review, we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on the upregulation of DPYD, TYMS, MTHFR, ERCC1, ERCC2, XRCC1, and GSTP1 expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarker microRNAs could serve as tools for personalized medicine, and as potential therapeutic targets in the future.

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