scholarly journals Breast tumor cell-specific knockout of Twist1 inhibits cancer cell plasticity, dissemination, and lung metastasis in mice

2017 ◽  
Vol 114 (43) ◽  
pp. 11494-11499 ◽  
Author(s):  
Yixiang Xu ◽  
Dong-Kee Lee ◽  
Zhen Feng ◽  
Yan Xu ◽  
Wen Bu ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Lung Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Early Stage ◽  
Migration And Invasion ◽  
Small Subset ◽  
Cell Plasticity ◽  
Mesenchymal Transition

Twist1 is an epithelial–mesenchymal transition (EMT)-inducing transcription factor (TF) that promotes cell migration and invasion. To determine the intrinsic role of Twist1 in EMT and breast cancer initiation, growth, and metastasis, we developed mouse models with an oncogene-induced mammary tumor containing wild-type (WT) Twist1 or tumor cell-specific Twist1 knockout (Twist1TKO). Twist1 knockout showed no effects on tumor initiation and growth. In both models with early-stage tumor cells, Twist1, and mesenchymal markers were not expressed, and lung metastasis was absent. Twist1 expression was detected in ∼6% of the advanced WT tumor cells. Most of these Twist1+ cells coexpressed several other EMT-inducing TFs (Snail, Slug, Zeb2), lost ERα and luminal marker K8, acquired basal cell markers (K5, p63), and exhibited a partial EMT plasticity (E-cadherin+/vimentin+). In advanced Twist1TKO tumor cells, Twist1 knockout largely diminished the expression of the aforementioned EMT-inducing TFs and basal and mesenchymal markers, but maintained the expression of the luminal markers. Circulating tumor cells (CTCs) were commonly detected in mice with advanced WT tumors, but not in mice with advanced Twist1TKO tumors. Nearly all WT CTCs coexpressed Twist1 with other EMT-inducing TFs and both epithelial and mesenchymal markers. Mice with advanced WT tumors developed extensive lung metastasis consisting of luminal tumor cells with silenced Twist1 and mesenchymal marker expression. Mice with advanced Twist1TKO tumors developed very little lung metastasis. Therefore, Twist1 is required for the expression of other EMT-inducing TFs in a small subset of tumor cells. Together, they induce partial EMT, basal-like tumor progression, intravasation, and metastasis.

scholarly journals Downregulated lncRNA GAS5 and Upregulated miR-21 Lead to Epithelial–Mesenchymal Transition and Lung Metastasis of Osteosarcomas

2021 ◽  
Vol 9 ◽  
Author(s):  
Ying Wang ◽  
Xue Ren ◽  
Ye Yuan ◽  
Bao-Shan Yuan
Keyword(s):  
Lung Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Primary Site ◽  
Migration And Invasion ◽  
Epigenetic Factors ◽  
Osteosarcoma Cells ◽  
Mesenchymal Transition ◽  
Mediated Effects ◽  
The Status

Lung is the primary site of osteosarcoma metastasis, but the underlying genetic or epigenetic factors determining lung metastasis of osteosarcoma are unknown. In this study, we report the status of growth arrest specific 5 (GAS5) in lung metastatic osteosarcomas. GAS5 was generally downregulated in osteosarcoma patients (n = 24) compared to healthy controls (n = 10) and even more so in patients with lung metastatic disease(n = 11) compared to the patients without metastasis (n = 13). We also report a role of miR-21 in GAS5-mediated effects. Downregulation of GAS5 in hFOB 1.19 and U2OS osteosarcoma cells enhanced their migration and invasion, along with an upregulated epithelial–mesenchymal transition (EMT), as evidenced by downregulated E-cadherin and upregulated vimentin, ZEB1, and ZEB2. Downregulation of GAS5 also resulted in a significantly increased expression of miR-21. Moreover, downregulation of such elevated miR-21 was found to reverse the effects of GAS5 silencing. miR-21 was also found to be elevated in osteosarcoma patients with its levels particularly high in patients with lung metastasis. Our observations reveal a possible role of GAS5 and miR-21 in lung metastasis of osteosarcoma, presenting them as novel targets for therapy.

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 Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2795
Author(s):  
Sofia Papanikolaou ◽  
Aikaterini Vourda ◽  
Spyros Syggelos ◽  
Kostis Gyftopoulos
Keyword(s):  
Prostate Cancer ◽  
Cancer Therapy ◽  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Tumor ◽  
Therapy Resistance ◽  
Cellular Process ◽  
Cell Plasticity ◽  
Mesenchymal Transition

Prostate cancer, the second most common malignancy in men, is characterized by high heterogeneity that poses several therapeutic challenges. Epithelial–mesenchymal transition (EMT) is a dynamic, reversible cellular process which is essential in normal embryonic morphogenesis and wound healing. However, the cellular changes that are induced by EMT suggest that it may also play a central role in tumor progression, invasion, metastasis, and resistance to current therapeutic options. These changes include enhanced motility and loss of cell–cell adhesion that form a more aggressive cellular phenotype. Moreover, the reverse process (MET) is a necessary element of the metastatic tumor process. It is highly probable that this cell plasticity reflects a hybrid state between epithelial and mesenchymal status. In this review, we describe the underlying key mechanisms of the EMT-induced phenotype modulation that contribute to prostate tumor aggressiveness and cancer therapy resistance, in an effort to provide a framework of this complex cellular process.

scholarly journals SPNS2 Downregulation Induces EMT and Promotes Colorectal Cancer Metastasis via Activating AKT Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Lei Lv ◽  
Qiyi Yi ◽  
Ying Yan ◽  
Fengmei Chao ◽  
Ming Li
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Migration And Invasion ◽  
Akt Inhibitor ◽  
Colon Adenoma ◽  
Mesenchymal Transition

Spinster homologue 2 (SPNS2), a transporter of S1P (sphingosine-1-phosphate), has been reported to mediate immune response, vascular development, and pathologic processes of diseases such as cancer via S1P signaling pathways. However, its biological functions and expression profile in colorectal cancer (CRC) is elusive. In this study, we disclosed that SPNS2 expression, which was regulated by copy number variation and DNA methylation of its promoter, was dramatically upregulated in colon adenoma and CRC compared to normal tissues. However, its expression was lower in CRC than in colon adenoma, and low expression of SPN2 correlated with advanced T/M/N stage and poor prognosis in CRC. Ectopic expression of SPNS2 inhibited cell proliferation, migration, epithelial–mesenchymal transition (EMT), invasion, and metastasis in CRC cell lines, while silencing SPNS2 had the opposite effects. Meanwhile, measuring the intracellular and extracellular level of S1P after overexpression of SPNS2 pinpointed a S1P-independent model of SPNS2. Mechanically, SPNS2 led to PTEN upregulation and inactivation of Akt. Moreover, AKT inhibitor (MK2206) abrogated SPNS2 knockdown-induced promoting effects on the migration and invasion, while AKT activator (SC79) reversed the repression of migration and invasion by SPNS2 overexpression in CRC cells, confirming the pivotal role of AKT for SPNS2’s function. Collectively, our study demonstrated the suppressor role of SPNS2 during CRC metastasis, providing new insights into the pathology and molecular mechanisms of CRC progression.

scholarly journals MicroRNA-1246 Suppresses the Metastasis of Breast Cancer Cells by Targeting the DRAK1A/PGRN Axis to Prevent the Epithelial-Mesenchymal Transition

2021 ◽  
Author(s):  
Pan Wang ◽  
Wenju Chen ◽  
Yaqiong Zhang ◽  
Qianyi Zhong ◽  
Zhaoyun Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Tnbc Cell ◽  
Novel Target

Abstract Objective. Breast cancer is one of the most common malignant and highly heterogeneous tumors in women. MicroRNAs (miRNAs), such as miR-1246, play important roles in various types of malignant cancers, including triple-negative breast cancer (TNBC). However, the biological role of miR-1246 in TNBC has not yet been fully elucidated. In this study, we studied the role of miR-1246 in the occurrence and development of TNBC and its mechanism of action.Methods. Cell Counting Kit-8 (CCK-8), wound healing, and Transwell assays were performed to observe the effects of miR-1246 on TNBC cell proliferation, migration, and invasion, respectively. The expression of epithelial-mesenchymal transition (EMT) markers was detected by western blotting. Dual luciferase reporter assays were performed to determine whether DYRK1A is a novel target of miR-1246. In addition, an immunoprecipitation experiment was performed to verify the binding of DYRK1A to PGRN. Rescue experiments were performed to determine whether DYRK1A is a novel target of miR-1246 and whether miR-1246 suppresses the metastasis of breast cancer cells by targeting the DRAK1A/PGRN axis to prevent the epithelial-mesenchymal transition.Results. Our results show that miR‑1246 suppresses the proliferation, migration, and invasion of TNBC cells and that DYRK1A is a novel target of miR-1246. MiR‑1246 plays a suppressive role in the regulation of the EMT of TNBC cells by targeting DYRK1A. DYRK1A mediates the metastasis of triple-negative breast cancer via activation of the EMT. We identified PGRN as a novel DYRK1A-interacting protein. DYRK1A and PGRN act together to regulate the occurrence and development of breast cancer through miR-1246.Conclusion. miR-1246 attenuates TNBC cell invasion and the EMT by targeting the DRAK1A/PGRN axis. Our data suggest that miR‑1246 may be used to develop novel early-stage diagnostic and therapeutic strategies for TNBC.

scholarly journals The Intimate Relationship among EMT, MET and TME: A T(ransdifferentiation) E(nhancing) M(ix) to Be Exploited for Therapeutic Purposes

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3674 ◽  
Author(s):  
Ralf Hass ◽  
Juliane von der Ohe ◽  
Hendrik Ungefroren
Keyword(s):  
Stem Cell ◽  
Phenotypic Plasticity ◽  
Tumor Cell ◽  
Epithelial Mesenchymal Transition ◽  
Resistance Mechanisms ◽  
Current Evidence ◽  
Cell Plasticity ◽  
New Paradigm ◽  
Mesenchymal Transition ◽  
Tumor Cell Plasticity

Intratumoral heterogeneity is considered the major cause of drug unresponsiveness in cancer and accumulating evidence implicates non-mutational resistance mechanisms rather than genetic mutations in its development. These non-mutational processes are largely driven by phenotypic plasticity, which is defined as the ability of a cell to reprogram and change its identity (phenotype switching). Tumor cell plasticity is characterized by the reactivation of developmental programs that are closely correlated with the acquisition of cancer stem cell properties and an enhanced potential for retrodifferentiation or transdifferentiation. A well-studied mechanism of phenotypic plasticity is the epithelial-mesenchymal transition (EMT). Current evidence suggests a complex interplay between EMT, genetic and epigenetic alterations, and clues from the tumor microenvironment in cell reprogramming. A deeper understanding of the connections between stem cell, epithelial–mesenchymal, and tumor-associated reprogramming events is crucial to develop novel therapies that mitigate cell plasticity and minimize the evolution of tumor heterogeneity, and hence drug resistance. Alternatively, vulnerabilities exposed by tumor cells when residing in a plastic or stem-like state may be exploited therapeutically, i.e., by converting them into less aggressive or even postmitotic cells. Tumor cell plasticity thus presents a new paradigm for understanding a cancer’s resistance to therapy and deciphering its underlying mechanisms.

scholarly journals New Actors Driving the Epithelial–Mesenchymal Transition in Cancer: The Role of Leptin

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1676
Author(s):  
Monserrat Olea-Flores ◽  
Juan C. Juárez-Cruz ◽  
Miriam D. Zuñiga-Eulogio ◽  
Erika Acosta ◽  
Eduardo García-Rodríguez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Epithelial Cancers ◽  
Patients With Cancer

Leptin is a hormone secreted mainly by adipocytes; physiologically, it participates in the control of appetite and energy expenditure. However, it has also been linked to tumor progression in different epithelial cancers. In this review, we describe the effect of leptin on epithelial–mesenchymal transition (EMT) markers in different study models, including in vitro, in vivo, and patient studies and in various types of cancer, including breast, prostate, lung, and ovarian cancer. The different studies report that leptin promotes the expression of mesenchymal markers and a decrease in epithelial markers, in addition to promoting EMT-related processes such as cell migration and invasion and poor prognosis in patients with cancer. Finally, we report that leptin has the greatest biological relevance in EMT and tumor progression in breast, lung, prostate, esophageal, and ovarian cancer. This relationship could be due to the key role played by the enriched tumor microenvironment in adipose tissue. Together, these findings demonstrate that leptin is a key biomolecule that drives EMT and metastasis in cancer.

scholarly journals MicroRNAs and Their Influence on the ZEB Family: Mechanistic Aspects and Therapeutic Applications in Cancer Therapy

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1040 ◽  
Author(s):  
Milad Ashrafizadeh ◽  
Hui Li Ang ◽  
Ebrahim Rahmani Moghadam ◽  
Shima Mohammadi ◽  
Vahideh Zarrin ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Therapy ◽  
Signaling Pathways ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Mesenchymal Transition ◽  
The Impact

Molecular signaling pathways involved in cancer have been intensively studied due to their crucial role in cancer cell growth and dissemination. Among them, zinc finger E-box binding homeobox-1 (ZEB1) and -2 (ZEB2) are molecules that play vital roles in signaling pathways to ensure the survival of tumor cells, particularly through enhancing cell proliferation, promoting cell migration and invasion, and triggering drug resistance. Importantly, ZEB proteins are regulated by microRNAs (miRs). In this review, we demonstrate the impact that miRs have on cancer therapy, through their targeting of ZEB proteins. MiRs are able to act as onco-suppressor factors and inhibit the malignancy of tumor cells through ZEB1/2 down-regulation. This can lead to an inhibition of epithelial-mesenchymal transition (EMT) mechanism, therefore reducing metastasis. Additionally, miRs are able to inhibit ZEB1/2-mediated drug resistance and immunosuppression. Additionally, we explore the upstream modulators of miRs such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as these regulators can influence the inhibitory effect of miRs on ZEB proteins and cancer progression.

Evaluation of risk recurrence in early breast cancer assessed by Oncotype DX and tumor cell dissemination to blood and bone marrow.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11516-e11516
Author(s):  
Bahriye Aktas ◽  
Agnes Bankfalvi ◽  
Martin Leonhard Heubner ◽  
Rainer Kimmig ◽  
Sabine Kasimir-Bauer
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Statistical Analysis ◽  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Early Stage ◽  
Data Set ◽  
Tissue Samples ◽  
Mesenchymal Transition ◽  
Genomic Test

e11516 Background: The OncotypeDX assay is a validated genomic test that predicts the likelihood of breast cancer (BC) recurrence, patients’ (pts) survival within 10 years of diagnosis and benefit of chemotherapy in early-stage, N0, ER-pos BC. In addition, disseminated tumor cells (DTC) in the bone marrow (BM) and circulating tumor cells (CTCs) in blood, especially stemness like tumor cells (slCTCs) including cells being able to perform epithelial-mesenchymal transition (EMT), have been associated with worse outcome in BC. Here we use OncotypeDX as well as the presence of DTCs, CTCs and slCTCs to evaluate the risk for recurrence in early BC pts. Methods: In total, 90 pts with newly diagnosed HER2-neg early stage BC received breast conserving surgery and sentinel lymphonodectomy. 17 pts were ER-/PR-, 12 pts ER+/PR-, 3 pts ER-/PR+ and 59 pts were ER+/PR+. Analysis of OncotypeDX and KI67 were performed. In case of G2 tumors, UPA and PAI1 were determined as further proliferation markers in tissue samples. Two BM aspirates from these patients were analyzed by immunocytochemistry for DTCs using the pan-cytokeratin antibody A45-B/B3. Furthermore, 2 x5 ml blood were analyzed for CTCs with the AdnaTest BreastCancer for the detection of EpCAM, MUC-1, HER-2, and beta-Actin transcripts. The recovered c-DNA was additionally multiplex tested for the presence of slCTCs using the AdnaTest EMT (multiplex RT-PCR for TWIST, AKT2, PI3K), and the AdnaTest TumorStemCell (ALDH1). Results: OncotypeDX was performed in 68/91 cases. 30/68 pts (44%) had a low RS, 29/68 pts (43%) an intermediate RS and 9/68 pts (13%) a high RS, respectively. BM aspiration could be performed in 70/91 pts with a positivity rate of 34% (24/70) for DTCs. CTCs were detected in 16/68 (25%) evaluable pts and slCTCs in 27/62 (44%) pts, respectively. In preliminary statistical analysis, KI67, PR and grading are showing association to RS as well as the presence of slCTCs. Tissue samples of patients with G2 tumors (N=65) underwent evaluation for UPA/PAI1analysis. Conclusions: Final statistical analysis for the complete data set including correlations to RS with all evaluable parameter will be available for presentation at the ASCO.

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