scholarly journals Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs)

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5118
Author(s):  
Hamidreza Aboulkheyr Es ◽  
Thomas R Cox ◽  
Ehsan Sarafraz-Yazdi ◽  
Jean Paul Thiery ◽  
Majid Ebrahimi Warkiani
Keyword(s):  
Breast Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Carcinoma Cell ◽  
Positive Association ◽  
Carcinoma Cells ◽  
The Cancer Genome Atlas ◽  
Cancer Associated Fibroblasts ◽  
Breast Cancer Patients ◽  
Spheroid Formation ◽  
Mesenchymal Transition

The aim of this study was to assess the effects of pirfenidone (PFD) on promoting epithelial–mesenchymal-transition (EMT) and stemness features in breast carcinoma cells through targeting cancer-associated-fibroblasts (CAFs). Using The Cancer Genome Atlas (TCGA) database, we analyzed the association between stromal index, EMT, and stemness-related genes across 1084 breast cancer patients, identifying positive correlation between YAP1, EMT, and stemness genes in samples with a high-stromal index. We monitored carcinoma cell invasion and spheroid formation co-cultured with CAFs in a 3D microfluidic device, followed by exposing carcinoma cells, spheroids, and CAFs with PFD. We depicted a positive association between the high-stromal index and the expression of EMT and stemness genes. High YAP1 expression in samples correlated with more advanced EMT status and stromal index. Additionally, we found that CAFs promoted spheroid formation and induced the expression of YAP1, VIM, and CD44 in spheroids. Treatment with PFD reduced carcinoma cell migration and decreased the expression of these genes at the protein level. The cytokine profiling showed significant depletion of various EMT- and stemness-regulated cytokines, particularly IL8, CCL17, and TNF-beta. These data highlight the potential application of PFD on inhibiting EMT and stemness in carcinoma cells through the targeting of critical cytokines.

scholarly journals Inhibition of MIR4435-2HG on Invasion, Migration, and EMT of Gastric Carcinoma Cells by Mediating MiR-138-5p/Sox4 Axis

2021 ◽  
Vol 11 ◽  
Author(s):  
Li-Fei Gao ◽  
Wei Li ◽  
Ya-Gang Liu ◽  
Cui Zhang ◽  
Wei-Na Gao ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Tumor Growth ◽  
Epithelial Mesenchymal Transition ◽  
Carcinoma Cells ◽  
The Cancer Genome Atlas ◽  
Cell Counting ◽  
Pcr Analysis ◽  
Mesenchymal Transition ◽  
Qrt Pcr

BackgroundThe previous investigations have identified that long non-coding RNA (lncRNAs) act as crucial regulators in gastric carcinoma. However, the function of lncRNA MIR4435-2HG in the modulation of gastric carcinoma remains elusive. Here, we aimed to explore the role of MIR4435-2HG in gastric carcinoma.MethodThe Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were applied to select the differently expressed lncRNAs in gastric carcinoma. The qRT-PCR was applied to analyze MIR4435-2HG expression in carcinoma tissues and cell lines. The effect of MIR4435-2HG on proliferation, invasion, migration, and apoptosis of gastric carcinoma cells was detected by Cell Counting Kit-8 (CCK-8) assays, transwell assays, and flow cytometry in vitro. A subcutaneous tumor model was constructed to examine the tumor growth of gastric carcinoma cells after knocking out MIR4435-2HG. RNA immunoprecipitation and luciferase reporting assays were applied to evaluate the interaction of MIR4435-2HG, miR-138-5p, and Sox4.ResultsThe bioinformatics analysis based on TCGA and GEO databases indicated that MIR4435-2HG was obviously elevated in gastric carcinoma samples. The qRT-PCR analysis revealed that MIR4435-2HG was upregulated in clinical gastric carcinoma tissues and cells. The high expression of MIR4435-2HG is associated with the poor survival rate of patients. The knockout of MIR4435-2HG could repress the proliferation, invasion, migration, and epithelial–mesenchymal transition (EMT) and accelerate the apoptosis of gastric carcinoma cells. Moreover, the deletion of MIR4435-2HG was able to attenuate the tumor growth in vivo. Mechanically, we identified that MIR4435-2HG enhanced Sox4 expression by directly interacting with miR-138-5p as a competitive endogenous RNA (ceRNA) in gastric carcinoma cells, in which Sox4 was targeted by miR-138-5p.ConclusionMIR4435-2HG is elevated in gastric carcinoma cells and contributes to the growth, metastasis, and EMT of gastric carcinoma cells by targeting miR-138-5p/Sox4 axis. MIR4435-2HG may be applied as a potential therapeutic target in gastric carcinoma.

scholarly journals Machine learning reveals mesenchymal breast carcinoma cell adaptation in response to matrix stiffness

2021 ◽  
Vol 17 (7) ◽  
pp. e1009193
Author(s):  
Vlada S. Rozova ◽  
Ayad G. Anwer ◽  
Anna E. Guller ◽  
Hamidreza Aboulkheyr Es ◽  
Zahra Khabir ◽  
...  
Keyword(s):  
Machine Learning ◽  
Breast Carcinoma ◽  
Soft Tissues ◽  
Epithelial Mesenchymal Transition ◽  
Carcinoma Cell ◽  
Primary Tumour ◽  
Cluster Formation ◽  
Mesenchymal Transition ◽  
Organ Microenvironment ◽  
E Cadherin

Epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition (MET), are believed to play key roles in facilitating the metastatic cascade. Metastatic lesions often exhibit a similar epithelial-like state to that of the primary tumour, in particular, by forming carcinoma cell clusters via E-cadherin-mediated junctional complexes. However, the factors enabling mesenchymal-like micrometastatic cells to resume growth and reacquire an epithelial phenotype in the target organ microenvironment remain elusive. In this study, we developed a workflow using image-based cell profiling and machine learning to examine morphological, contextual and molecular states of individual breast carcinoma cells (MDA-MB-231). MDA-MB-231 heterogeneous response to the host organ microenvironment was modelled by substrates with controllable stiffness varying from 0.2kPa (soft tissues) to 64kPa (bone tissues). We identified 3 distinct morphological cell types (morphs) varying from compact round-shaped to flattened irregular-shaped cells with lamellipodia, predominantly populating 2-kPa and >16kPa substrates, respectively. These observations were accompanied by significant changes in E-cadherin and vimentin expression. Furthermore, we demonstrate that the bone-mimicking substrate (64kPa) induced multicellular cluster formation accompanied by E-cadherin cell surface localisation. MDA-MB-231 cells responded to different substrate stiffness by morphological adaptation, changes in proliferation rate and cytoskeleton markers, and cluster formation on bone-mimicking substrate. Our results suggest that the stiffest microenvironment can induce MET.

scholarly journals Harnessing Carcinoma Cell Plasticity Mediated by TGF-β Signaling

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3397
Author(s):  
Xuecong Wang ◽  
Jean Paul Thiery
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Carcinoma Cell ◽  
Therapy Resistance ◽  
Carcinoma Cells ◽  
Cell Plasticity ◽  
Mesenchymal Transition ◽  
Tgfβ Receptor ◽  
Receptor Signaling Pathway ◽  
Cancer Dissemination

Epithelial cell plasticity, a hallmark of carcinoma progression, results in local and distant cancer dissemination. Carcinoma cell plasticity can be achieved through epithelial–mesenchymal transition (EMT), with cells positioned seemingly indiscriminately across the spectrum of EMT phenotypes. Different degrees of plasticity are achieved by transcriptional regulation and feedback-loops, which confer carcinoma cells with unique properties of tumor propagation and therapy resistance. Decoding the molecular and cellular basis of EMT in carcinoma should enable the discovery of new therapeutic strategies against cancer. In this review, we discuss the different attributes of plasticity in carcinoma and highlight the role of the canonical TGFβ receptor signaling pathway in the acquisition of plasticity. We emphasize the potential stochasticity of stemness in carcinoma in relation to plasticity and provide data from recent clinical trials that seek to target plasticity.

scholarly journals Carbonic anhydrase IX from cancer-associated fibroblasts drives epithelial-mesenchymal transition in prostate carcinoma cells

Cell Cycle ◽  
2013 ◽  
Vol 12 (11) ◽  
pp. 1791-1801 ◽  
Author(s):  
Tania Fiaschi ◽  
Elisa Giannoni ◽  
Letizia Taddei ◽  
Paolo Cirri ◽  
Alberto Marini ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Prostate Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Carcinoma Cells ◽  
Carbonic Anhydrase Ix ◽  
Cancer Associated Fibroblasts ◽  
Mesenchymal Transition

scholarly journals Index of Cancer-Associated Fibroblasts Is Superior to the Epithelial–Mesenchymal Transition Score in Prognosis Prediction

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1718
Author(s):  
Ying-Chieh Ko ◽  
Ting-Yu Lai ◽  
Shu-Ching Hsu ◽  
Fu-Hui Wang ◽  
Sheng-Yao Su ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Meta Analysis ◽  
Transforming Growth Factor Β ◽  
Transcriptomic Analysis ◽  
The Cancer Genome Atlas ◽  
Cancer Associated Fibroblasts ◽  
Mesenchymal Transition ◽  
Cancer Subtypes ◽  
Prognosis Prediction

In many solid tumors, tissue of the mesenchymal subtype is frequently associated with epithelial–mesenchymal transition (EMT), strong stromal infiltration, and poor prognosis. Emerging evidence from tumor ecosystem studies has revealed that the two main components of tumor stroma, namely, infiltrated immune cells and cancer-associated fibroblasts (CAFs), also express certain typical EMT genes and are not distinguishable from intrinsic tumor EMT, where bulk tissue is concerned. Transcriptomic analysis of xenograft tissues provides a unique advantage in dissecting genes of tumor (human) or stroma (murine) origins. By transcriptomic analysis of xenograft tissues, we found that oral squamous cell carcinoma (OSCC) tumor cells with a high EMT score, the computed mesenchymal likelihood based on the expression signature of canonical EMT markers, are associated with elevated stromal contents featured with fibronectin 1 (Fn1) and transforming growth factor-β (Tgfβ) axis gene expression. In conjugation with meta-analysis of these genes in clinical OSCC datasets, we further extracted a four-gene index, comprising FN1, TGFB2, TGFBR2, and TGFBI, as an indicator of CAF abundance. The CAF index is more powerful than the EMT score in predicting survival outcomes, not only for oral cancer but also for the cancer genome atlas (TCGA) pan-cancer cohort comprising 9356 patients from 32 cancer subtypes. Collectively, our results suggest that a further distinction and integration of the EMT score with the CAF index will enhance prognosis prediction, thus paving the way for curative medicine in clinical oncology.

scholarly journals A Novel Ferroptosis-Related Prognostic Signature Reveals Macrophage Infiltration and EMT Status in Bladder Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Yilin Yan ◽  
Jinming Cai ◽  
Zhengnan Huang ◽  
Xiangqian Cao ◽  
Pengfei Tang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Risk Score ◽  
Risk Model ◽  
Epithelial Mesenchymal Transition ◽  
Positive Association ◽  
Lipid Peroxides ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Mutation Rates ◽  
Mesenchymal Transition

Bladder cancer (BC) belongs to one of the most common and highly heterogeneous malignancies. Ferroptosis is a newly discovered regulated cell death (RCD), characterized by accumulation of toxic lipid peroxides, and plays a crucial role in tumor progression. Here, we conducted a comprehensive analysis on the transcriptomics data of ferroptosis-related genes in BC based on The Cancer Genome Atlas (TCGA) and three Gene Expression Omnibus (GEO) datasets. In our study, a 6-gene signature was identified based on the potential prognostic ferroptotic regulatory genes. Furthermore, our signature revealed a good independent prognostic ability in BC. Patients with low-risk score exhibited higher FGFR3 mutation rates while high risk score had a positive association with higher RB1 mutation rates. Meanwhile, higher proportions of macrophages were observed in high BC risk group simultaneously with four methods. Unexpectedly, the risk score showed a significant positive correlation with epithelial-mesenchymal transition (EMT) status. Functional assays indicated that CRYAB and SQLE knockdown was associated with attenuated invasion capacity. Our study revealed a ferroptosis-related risk model for predicting prognostic and BC progression. Our results indicate that targeting ferroptosis may be a therapeutic strategy for BC.

Pirfenidone reduces immune-suppressive capacity of cancer-associated fibroblasts through targeting CCL17 and TNF-beta

2020 ◽  
Vol 12 (7) ◽  
pp. 188-197 ◽  
Author(s):  
Hamidreza Aboulkheyr Es ◽  
Sareh Zhand ◽  
Jean Paul Thiery ◽  
Majid Ebrahimi Warkiani
Keyword(s):  
Breast Carcinoma ◽  
Immune Suppression ◽  
Positive Association ◽  
Carcinoma Cells ◽  
Cancer Associated Fibroblasts ◽  
Malignant Cells ◽  
Inhibitory Effects ◽  
Breast Carcinoma Cells ◽  
Suppressive Capacity ◽  
Downstream Analysis

Abstract Various factors in the tumor microenvironment (TME) regulate the expression of PD-L1 in carcinoma cells. The cancer-associated fibroblasts (CAFs) play a crucial role in regulating and rewiring TME to enhance their immune suppressive function and to favor the invasion of the malignant cells. Tumor progression may be retarded by targeting CAFs in the TME. Various studies highlighted the ability of targeting CAF with pirfenidone (PFD), leading to increased efficacy of chemotherapy. However, its potential for the reduction of immune-suppression capacity of CAFs remains to be elusive. Here, we assessed the effect of PFD on the expression of PD-L1 on CAF cells. Besides migration inhibitory effects of PFD on CAFs, the expression level of PD-L1 reduced in CAFs after treatment with PFD. The downstream analysis of released cytokines from CAFs showed that PFD significantly dropped the secretion of CCL17 and TNF-β, where a positive association between PFD-targeted proteins and PD-L1 was observed. These data suggest that the treatment of CAF within TME through the PFD may reduce the acquisition of CAF-mediated invasive and immune-suppressive capacity of breast carcinoma cells.

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