scholarly journals Cell Heterogeneity and Phenotypic Plasticity in Metastasis Formation: The Case of Colon Cancer

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1368 ◽  
Author(s):  
Miriam Teeuwssen ◽  
Riccardo Fodde
Keyword(s):  
Colon Cancer ◽  
Phenotypic Plasticity ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Genetic Alterations ◽  
Primary Site ◽  
Metastasis Formation ◽  
Mesenchymal Transition ◽  
Intermediate Phenotypes

The adenoma-to-carcinoma progression in colon cancer is driven by a sequential accumulation of genetic alterations at specific tumor suppressors and oncogenes. In contrast, the multistage route from the primary site to metastasis formation is underlined by phenotypic plasticity, i.e., the capacity of disseminated tumor cells to undergo transiently and reversible transformations in order to adapt to the ever-changing environmental contexts. Notwithstanding the considerable body of evidence in support of the role played by epithelial-to-mesenchymal transition (EMT)/mesenchymal-to-epithelial transition (MET) in metastasis, its rate-limiting function, the detailed underlying cellular and molecular mechanisms, and the extension of the necessary morphologic and epigenetic changes are still a matter of debate. Rather than leading to a complete epithelial or mesenchymal state, the EMT/MET-program generates migrating cancer cells displaying intermediate phenotypes featuring both epithelial and mesenchymal characteristics. In this review, we will address the role of colon cancer heterogeneity and phenotypic plasticity in metastasis formation and the contribution of EMT to these processes. The alleged role of hybrid epithelial/mesenchymal (E/M) in collective and/or single-cell migration during local dissemination at the primary site and more systemic spreading will also be highlighted.

Role of Epithelial-to-Mesenchymal Transition in Inflammatory Bowel Disease

2018 ◽  
Vol 13 (5) ◽  
pp. 659-668 ◽  
Author(s):  
Sara Lovisa ◽  
Giannicola Genovese ◽  
Silvio Danese
Keyword(s):  
Inflammatory Bowel Disease ◽  
Wound Healing ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Clinical Manifestations ◽  
Mesenchymal Transition ◽  
Intestinal Fibrosis ◽  
Inflammatory Bowel

Abstract Intestinal fibrosis is an inevitable complication in patients with inflammatory bowel disease [IBD], occurring in its two major clinical manifestations: ulcerative colitis and Crohn’s disease. Fibrosis represents the final outcome of the host reaction to persistent inflammation, which triggers a prolonged wound healing response resulting in the excessive deposition of extracellular matrix, eventually leading to intestinal dysfunction. The process of epithelial-to-mesenchymal transition [EMT] represents an embryonic program relaunched during wound healing, fibrosis and cancer. Here we discuss the initial observations and the most recent findings highlighting the role of EMT in IBD-associated intestinal fibrosis and fistulae formation. In addition, we briefly review knowledge on the cognate process of endothelial-to-mesenchymal transition [EndMT]. Understanding EMT functionality and the molecular mechanisms underlying the activation of this mesenchymal programme will permit designing new therapeutic strategies to halt the fibrogenic response in the intestine.

scholarly journals The Key Role of Epithelial to Mesenchymal Transition (EMT) in Hypertensive Kidney Disease

2019 ◽  
Vol 20 (14) ◽  
pp. 3567 ◽  
Author(s):  
Teresa Seccia ◽  
Brasilina Caroccia ◽  
Maria Piazza ◽  
Gian Paolo Rossi
Keyword(s):  
Kidney Disease ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Renal Diseases ◽  
Hypertensive Nephropathy ◽  
Mesenchymal Transition ◽  
Afferent Arterioles ◽  
Stage Renal Disease ◽  
End Stage

Accumulating evidence indicates that epithelial-to-mesenchymal transition (EMT), originally described as a key process for organ development and metastasis budding in cancer, plays a key role in the development of renal fibrosis in several diseases, including hypertensive nephroangiosclerosis. We herein reviewed the concept of EMT and its role in renal diseases, with particular focus on hypertensive kidney disease, the second leading cause of end-stage renal disease after diabetes mellitus. After discussing the pathophysiology of hypertensive nephropathy, the ‘classic’ view of hypertensive nephrosclerosis entailing hyalinization, and sclerosis of interlobular and afferent arterioles, we examined the changes occurring in the glomerulus and tubulo-interstitium and the studies that investigated the role of EMT and its molecular mechanisms in hypertensive kidney disease. Finally, we examined the reasons why some studies failed to provide solid evidence for renal EMT in hypertension.

scholarly journals ADAM 17 and Epithelial-to-Mesenchymal Transition: The Evolving Story and Its Link to Fibrosis and Cancer

2021 ◽  
Vol 10 (15) ◽  
pp. 3373
Author(s):  
Margherita Sisto ◽  
Domenico Ribatti ◽  
Sabrina Lisi
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Tumour Progression ◽  
Smooth Muscle Actin ◽  
Mesenchymal Transition ◽  
Inflammatory Conditions ◽  
Fibrotic Process ◽  
Factor Α ◽  
Necrosis Factor

For decades, metalloproteinase 17 (ADAM17) has been the goal of wide investigation. Since its discovery as the tumour necrosis factor-α convertase, it has been studied as the main drug target, especially in the context of inflammatory conditions and tumour. In fact, evidence is mounting to support a key role of ADAM17 in the induction of the proliferation, migration and progression of tumour cells and the trigger of the pro-fibrotic process during chronic inflammatory conditions; this occurs, probably, through the activation of epithelial-to-mesenchymal transition (EMT). EMT is a central morphologic conversion that occurs in adults during wound healing, tumour progression and organ fibrosis. EMT is characterised by the disassembly of cell–cell contacts, remodelling of the actin cytoskeleton and separation of cells, and generates fibroblast-like cells that express mesenchymal markers and have migratory properties. This transition is characterised by loss of epithelial proteins such as E-cadherin and the acquisition of new mesenchymal markers, including vimentin and a-smooth muscle actin. The present review discusses the current understanding of molecular mechanisms involved in ADAM17-dependent EMT in order to individuate innovative therapeutic strategies using ADAM17-related pathways.

scholarly journals WNK3 promotes the invasiveness of glioma cell lines under hypoxia by inducing the epithelial-to-mesenchymal transition

2021 ◽  
Vol 12 (1) ◽  
pp. 320-329
Author(s):  
Yue Wang ◽  
Bingbing Wu ◽  
Shengrong Long ◽  
QiangLiu ◽  
Guangyu Li
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Low Grade ◽  
Glioma Invasion ◽  
Mesenchymal Transition ◽  
Hypoxic Conditions ◽  
Immunohistochemistry Analysis ◽  
Hypoxic Environment ◽  
U87 Cells

Abstract Background The primary features of malignant glioma include high rates of mortality and recurrence, uncontrollable invasiveness, strong angiogenesis, and widespread hypoxia. The hypoxic microenvironment is an important factor affecting the malignant progression of glioma. However, the molecular mechanisms underlying glioma adaption in hypoxic microenvironments are poorly understood. Objective The work presented in this paper focuses on the role of WNK3 gene in glioma invasion under hypoxic conditions. Furthermore, we aim to explore its role in epithelial-to-mesenchymal transition (EMT). Methods ShRNA targeting WNK3 transfection was used to knockdown the WNK3 expression in U87 cells. We used western blot analysis to detect the relative expression of proteins in U87 cells. The effect of WNK3 on cell migration was explored using a transwell assay in the U87 cell line. We also evaluated WNK3 expression levels in glioma samples by immunohistochemistry analysis. Results WNK3 expression was significantly higher in high-grade (III and IV) gliomas than in low-grade (I and II) gliomas. WNK3 expression was up-regulated in U87 cells when cultured in a hypoxic environment in addition; WNK3 knockdown inhibited the invasion of U87 glioma cells by regulating the EMT, especially under hypoxic conditions. Conclusion These findings suggested that WNK3 plays an important role in the hypoxic microenvironment of glioma and might also be a candidate for therapeutic application in the treatment of glioma.

scholarly journals SLUG and Truncated TAL1 Reduce Glioblastoma Stem Cell Growth Downstream of Notch1 and Define Distinct Vascular Subpopulations in Glioblastoma Multiforme

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5393
Author(s):  
Sophie Guelfi ◽  
Béatrice Orsetti ◽  
Virginie Deleuze ◽  
Valérie Rigau ◽  
Luc Bauchet ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Growth Factor Receptor ◽  
Treatment Resistance ◽  
Mesenchymal Transition ◽  
Glioblastoma Stem Cell ◽  
A Minor

Glioblastomas (GBM) are high-grade brain tumors, containing cells with distinct phenotypes and tumorigenic potentials, notably aggressive and treatment-resistant multipotent glioblastoma stem cells (GSC). The molecular mechanisms controlling GSC plasticity and growth have only partly been elucidated. Contact with endothelial cells and the Notch1 pathway control GSC proliferation and fate. We used three GSC cultures and glioma resections to examine the expression, regulation, and role of two transcription factors, SLUG (SNAI2) and TAL1 (SCL), involved in epithelial to mesenchymal transition (EMT), hematopoiesis, vascular identity, and treatment resistance in various cancers. In vitro, SLUG and a truncated isoform of TAL1 (TAL1-PP22) were strongly upregulated upon Notch1 activation in GSC, together with LMO2, a known cofactor of TAL1, which formed a complex with truncated TAL1. SLUG was also upregulated by TGF-β1 treatment and by co-culture with endothelial cells. In patient samples, the full-length isoform TAL1-PP42 was expressed in all glioma grades. In contrast, SLUG and truncated TAL1 were preferentially overexpressed in GBMs. SLUG and TAL1 are expressed in the tumor microenvironment by perivascular and endothelial cells, respectively, and to a minor extent, by a fraction of epidermal growth factor receptor (EGFR) -amplified GBM cells. Mechanistically, both SLUG and truncated TAL1 reduced GSC growth after their respective overexpression. Collectively, this study provides new evidence for the role of SLUG and TAL1 in regulating GSC plasticity and growth.

scholarly journals CXCL12/CXCR7/β-arrestin1 Biased Signal Promotes Epithelial-to-Mesenchymal Transition of Colorectal Cancer by Repressing Mirnas Through YAP1 Nuclear Translocation

2021 ◽  
Author(s):  
Mahan Si ◽  
Yujia Song ◽  
Xiaohui Wang ◽  
Dong Wang ◽  
Xiaohui Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Nuclear Translocation ◽  
Luciferase Assay ◽  
Mesenchymal Transition ◽  
Tumor Xenografts ◽  
Signal Activation

Abstract Background: CXCR7 is an atypical chemokine receptor that transmits biased signal independent of G-protein activation. However, whether CXCL12/CXCR7 biased signal activation plays an essential role in colorectal cancer (CRC) progression and metastasis remains obscure. Methods: The functional role of CXCL12/CXCR7 biased signal in CRC was investigated by RNA-sequencing, Transwell assay and in vivo tumor xenografts. YAP1 nuclear translocation and molecular mechanisms were determined by cell transfection, luciferase activity assay, immunofluorescence, coimmunoprecipitation and immunohistochemistry and RT-qPCR analysis.Results: In this study, CXCR7 CXCL12/overexpression promotes Epithelial-to-mesenchymal transition (EMT) and upregulates the expression of stem marker doublecortin-like kinase 1 (DCLK1) in CRC cells with concurrent repression of miR-124-3p and miR-188-5p. Further luciferase assay prove that these miRNAs could regulate EMT by direct targeting vimentin and DCLK1. More importantly, CXCL12/CXCR7/β-arrestin1-mediated biased signal induces YAP1 nuclear translocation, which functions as a transcriptional repressor by interacting with Yin Yang 1 (YY1) and recruiting YY1 to the promoter of miR-124-3p and miR-188-5p. Pharmacological inhibitor of YAP1 recapitulates the anti-tumorigenesis and anti-metastasis effects of YAP1 depletion upon CXCR7 activation in tumor xenografts. Clinically, the expression of CXCR7 was positively correlated with nuclear YAP1 levels and EMT markers. Conclusions: Our findings revealed the novel role of YAP1 nuclear translocation in promoting EMT of CRC by repressing miR-124-3p and miR-188-5p through CXCL12/CXCR7/β-arrestin1 biased signal activation. These findings highlight the potential of targeting YAP1 nuclear translocation in hampering CXCL12/CXCR7 biased signal-induced metastasis of CRC.

scholarly journals New Insights into Therapy-Induced Progression of Cancer

2020 ◽  
Vol 21 (21) ◽  
pp. 7872
Author(s):  
Polina V. Shnaider ◽  
Olga M. Ivanova ◽  
Irina K. Malyants ◽  
Ksenia S. Anufrieva ◽  
Ilya A. Semenov ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Acquired Resistance ◽  
Therapy Resistance ◽  
Genetic Alterations ◽  
Therapeutic Interventions ◽  
Molecular Response ◽  
Mesenchymal Transition ◽  
Third Line ◽  
Molecular Aspects

The malignant tumor is a complex heterogeneous set of cells functioning in a no less heterogeneous microenvironment. Like any dynamic system, cancerous tumors evolve and undergo changes in response to external influences, including therapy. Initially, most tumors are susceptible to treatment. However, remaining cancer cells may rapidly reestablish the tumor after a temporary remission. These new populations of malignant cells usually have increased resistance not only to the first-line agent, but also to the second- and third-line drugs, leading to a significant decrease in patient survival. Multiple studies describe the mechanism of acquired therapy resistance. In past decades, it became clear that, in addition to the simple selection of pre-existing resistant clones, therapy induces a highly complicated and tightly regulated molecular response that allows tumors to adapt to current and even subsequent therapeutic interventions. This review summarizes mechanisms of acquired resistance, such as secondary genetic alterations, impaired function of drug transporters, and autophagy. Moreover, we describe less obvious molecular aspects of therapy resistance in cancers, including epithelial-to-mesenchymal transition, cell cycle alterations, and the role of intercellular communication. Understanding these molecular mechanisms will be beneficial in finding novel therapeutic approaches for cancer therapy.

scholarly journals Defining the Role of GLI/Hedgehog Signaling in Chemoresistance: Implications in Therapeutic Approaches

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4746
Author(s):  
Jian Yi Chai ◽  
Vaisnevee Sugumar ◽  
Ahmed F. Alshanon ◽  
Won Fen Wong ◽  
Shin Yee Fung ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cancer Progression ◽  
Hedgehog Signaling ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Strategies ◽  
Cancer Treatments ◽  
Mesenchymal Transition ◽  
Hh Signaling

Insight into cancer signaling pathways is vital in the development of new cancer treatments to improve treatment efficacy. A relatively new but essential developmental signaling pathway, namely Hedgehog (Hh), has recently emerged as a major mediator of cancer progression and chemoresistance. The evolutionary conserved Hh signaling pathway requires an in-depth understanding of the paradigm of Hh signaling transduction, which is fundamental to provide the necessary means for the design of novel tools for treating cancer related to aberrant Hh signaling. This review will focus substantially on the canonical Hh signaling and the treatment strategies employed in different studies, with special emphasis on the molecular mechanisms and combination treatment in regard to Hh inhibitors and chemotherapeutics. We discuss our views based on Hh signaling’s role in regulating DNA repair machinery, autophagy, tumor microenvironment, drug inactivation, transporters, epithelial-to-mesenchymal transition, and cancer stem cells to promote chemoresistance. The understanding of this Achilles’ Heel in cancer may improve the therapeutic outcome for cancer therapy.

scholarly journals Molecular Activation of the Kv11.1 Channel Reprograms EMT in Colon Cancer by Inhibiting TGFβ Signaling via Activation of Calcineurin

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6025
Author(s):  
Najmeh Eskandari ◽  
Vitalyi Senyuk ◽  
Jennifer Moore ◽  
Zane Kalik ◽  
Qiyue Luan ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Vital Role ◽  
Colon Cancer Cells ◽  
Strong Inhibition ◽  
Tgfβ Signaling ◽  
Mesenchymal Transition ◽  
Stimulation Of

Control of ionic gradients is critical to maintain cellular homeostasis in both physiological and pathological conditions, but the role of ion channels in cancer cells has not been studied thoroughly. In this work we demonstrated that activity of the Kv11.1 potassium channel plays a vital role in controlling the migration of colon cancer cells by reversing the epithelial-to-mesenchymal transition (EMT) into the mesenchymal-to-epithelial transition (MET). We discovered that pharmacological stimulation of the Kv11.1 channel with the activator molecule NS1643 produces a strong inhibition of colon cancer cell motility. In agreement with the reversal of EMT, NS1643 treatment leads to a depletion of mesenchymal markers such as SNAIL1, SLUG, TWIST, ZEB, N-cadherin, and c-Myc, while the epithelial marker E-cadherin was strongly upregulated. Investigating the mechanism linking Kv11.1 activity to reversal of EMT into MET revealed that stimulation of Kv11.1 produced a strong and fast inhibition of the TGFβ signaling. Application of NS1643 resulted in de-phosphorylation of the TGFβ downstream effectors R-SMADs by activation of the serine/threonine phosphatase PP2B (calcineurin). Consistent with the role of TGFβ in controlling cancer stemness, NS1643 also produced a strong inhibition of NANOG, SOX2, and OCT4 while arresting the cell cycle in G0/G1. Our data demonstrate that activation of the Kv11.1 channel reprograms EMT into MET by inhibiting TGFβ signaling, which results in inhibition of motility in colon cancer cells.

scholarly journals The Role of the Epicardium During Heart Development and Repair

2020 ◽  
Vol 126 (3) ◽  
pp. 377-394 ◽  
Author(s):  
Pearl Quijada ◽  
Michael A. Trembley ◽  
Eric M. Small
Keyword(s):  
Heart Development ◽  
Progenitor Cell ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Cardiac Injury ◽  
Single Layer ◽  
Mesenchymal Transition ◽  
Heart Repair ◽  
Heart Formation

The heart is lined by a single layer of mesothelial cells called the epicardium that provides important cellular contributions for embryonic heart formation. The epicardium harbors a population of progenitor cells that undergo epithelial-to-mesenchymal transition displaying characteristic conversion of planar epithelial cells into multipolar and invasive mesenchymal cells before differentiating into nonmyocyte cardiac lineages, such as vascular smooth muscle cells, pericytes, and fibroblasts. The epicardium is also a source of paracrine cues that are essential for fetal cardiac growth, coronary vessel patterning, and regenerative heart repair. Although the epicardium becomes dormant after birth, cardiac injury reactivates developmental gene programs that stimulate epithelial-to-mesenchymal transition; however, it is not clear how the epicardium contributes to disease progression or repair in the adult. In this review, we will summarize the molecular mechanisms that control epicardium-derived progenitor cell migration, and the functional contributions of the epicardium to heart formation and cardiomyopathy. Future perspectives will be presented to highlight emerging therapeutic strategies aimed at harnessing the regenerative potential of the fetal epicardium for cardiac repair.

Sign in / Sign up

Export Citation Format

Share Document