Cancer cell niche factors secreted from cancer-associated fibroblast by loss of H3K27me3

Gut ◽  
2019 ◽  
Vol 69 (2) ◽  
pp. 243-251 ◽  
Author(s):  
Masahiro Maeda ◽  
Hideyuki Takeshima ◽  
Naoko Iida ◽  
Naoko Hattori ◽  
Satoshi Yamashita ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cell ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Stem Cell Niche ◽  
Therapeutic Targets ◽  
Prognostic Impact ◽  
Cell Growth And Migration ◽  
Cell Niche

ObjectiveCancer-associated fibroblasts (CAFs), a major component of cancer stroma, can confer aggressive properties to cancer cells by secreting multiple factors. Their phenotypes are stably maintained, but the mechanisms are not fully understood. We aimed to show the critical role of epigenetic changes in CAFs in maintaining their tumour-promoting capacity and to show the validity of the epigenomic approach in identifying therapeutic targets from CAFs to starve cancer cells.DesignTwelve pairs of primary gastric CAFs and their corresponding non-CAFs (NCAFs) were established from surgical specimens. Genome-wide DNA methylation and H3K27me3 analyses were conducted by BeadArray 450K and ChIP-on-Chip, respectively. Functions of potential a therapeutic target were analysed by inhibiting it, and prognostic impact was assessed in a database.ResultsCAFs had diverse and distinct DNA methylation and H3K27me3 patterns compared with NCAFs. Loss of H3K27me3, but not DNA methylation, in CAFs was enriched for genes involved in stem cell niche, cell growth, tissue development and stromal–epithelial interactions, such asWNT5A,GREM1,NOGandIGF2. Among these, we revealed that WNT5A, which had been considered to be derived from cancer cells, was highly expressed in cancer stromal fibroblasts, and was associated with poor prognosis. Inhibition of secreted WNT5A from CAFs suppressed cancer cell growth and migration.ConclusionsH3K27me3 plays a crucial role in defining tumour-promoting capacities of CAFs, and multiple stem cell niche factors were secreted from CAFs due to loss of H3K27me3. The validity of the epigenetic approach to uncover therapeutic targets for cancer-starving therapy was demonstrated.

scholarly journals Understanding the Influence of Substrate When Growing Tumorspheres

2020 ◽  
Author(s):  
Lucía Benítez ◽  
Lucas Barberis ◽  
Luciano Vellón ◽  
Carlos Alberto Condat
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Growth Factors ◽  
Cell Growth ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Stem Cell Niche ◽  
Cell Number ◽  
Hard Substrate ◽  
Cell Niche

Abstract Background: Cancer stem cells are important for the development of many solid tumors. These cells receive promoting and inhibitory signals that depend on the nature of their environment (their niche) and determine cell dynamics. Mechanical stresses are crucial to the initiation and interpretation of these signals. Methods: A two-population mathematical model of tumorsphere growth is used to interpret the results of a series of experiments recently carried out in Tianjin, China, and extract information about the intraspecific and interspecific interactions between cancer stem cell and differentiated cancer cell populations. Results: The model allows us to reconstruct the time evolution of the cancer stem cell fraction, which was not directly measured. We find that, in the presence of stem cell growth factors, the interspecific cooperation between cancer stem cells and differentiated cancer cells induces a positive feedback loop that determines growth, independently of substrate hardness. In a frustrated attempt to reconstitute the stem cell niche, the number of cancer stem cells increases continuously with a reproduction rate that is enhanced by a hard substrate. For growth on soft agar, intraspecific interactions are always inhibitory, but on hard agar the interactions between stem cells are collaborative while those between differentiated cells are strongly inhibitory. Evidence also suggests that a hard substrate brings about a large fraction of asymmetric stem cell divisions. In the absence of stem cell growth factors, the barrier to differentiation is broken and overall growth is faster, even if the stem cell number is conserved. Conclusions: Our interpretation of the experimental results validates the centrality of the concept of stem cell niche when tumor growth is fueled by cancer stem cells. Niche memory is found to be responsible for the characteristic population dynamics observed in tumorspheres. A specific condition for the growth of the cancer stem cell number is also obtained.

scholarly journals The metabolically-modulated stem cell niche: a dynamic scenario regulating cancer cell phenotype and resistance to therapy

Cell Cycle ◽  
2014 ◽  
Vol 13 (20) ◽  
pp. 3169-3175 ◽  
Author(s):  
Elisabetta Rovida ◽  
Silvia Peppicelli ◽  
Silvia Bono ◽  
Francesca Bianchini ◽  
Ignazia Tusa ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Cell ◽  
Stem Cell Niche ◽  
Cell Phenotype ◽  
Resistance To Therapy ◽  
Dynamic Scenario ◽  
Cell Niche

scholarly journals Cyclophilin B as a co-regulator of prolactin-induced gene expression and function in breast cancer cells

2010 ◽  
Vol 44 (6) ◽  
pp. 319-329 ◽  
Author(s):  
Feng Fang ◽  
Jiamao Zheng ◽  
Traci L Galbaugh ◽  
Alyson A Fiorillo ◽  
Elizabeth E Hjort ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cell Growth And Migration ◽  
Cyclophilin B ◽  
And Migration

The effects of prolactin (PRL) during the pathogenesis of breast cancer are mediated in part though Stat5 activity enhanced by its interaction with its transcriptional inducer, the prolyl isomerase cyclophilin B (CypB). We have demonstrated that knockdown of CypB decreases cell growth, proliferation, and migration, and CypB expression is associated with malignant progression of breast cancer. In this study, we examined the effect of CypB knockdown on PRL signaling in breast cancer cells. CypB knockdown with two independent siRNAs was shown to impair PRL-induced reporter expression in breast cancer cell line. cDNA microarray analysis was performed on these cells to assess the effect of CypB reduction, and revealed a significant decrease in PRL-induced endogenous gene expression in two breast cancer cell lines. Parallel functional assays revealed corresponding alterations of both anchorage-independent cell growth and cell motility of breast cancer cells. Our results demonstrate that CypB expression levels significantly modulate PRL-induced function in breast cancer cells ultimately resulting in enhanced levels of PRL-responsive gene expression, cell growth, and migration. Given the increasingly appreciated role of PRL in the pathogenesis of breast cancer, the actions of CypB detailed here are of biological significance.

Microenvironment of macula flava in the human vocal fold as a stem cell niche

2016 ◽  
Vol 130 (7) ◽  
pp. 656-661 ◽  
Author(s):  
K Sato ◽  
S Chitose ◽  
T Kurita ◽  
H Umeno
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Cell Growth ◽  
Mesenchymal Stem Cell ◽  
Growth Medium ◽  
Stem Cell Niche ◽  
Vocal Fold ◽  
Colony Forming Unit ◽  
Cell Niche

AbstractBackground:There is growing evidence that the cells in the maculae flavae are tissue stem cells of the human vocal fold mucosa, and that the maculae flavae are a candidate for a stem cell niche. The role of microenvironment in the maculae flavae of the human vocal fold mucosa was investigated.Method:Anterior maculae flavae from six surgical specimens were cultured in a mesenchymal stem cell growth medium or a Dulbecco's modified Eagle's medium.Results:Using mesenchymal stem cell growth medium, the subcultured cells formed a colony-forming unit, and cell division reflected asymmetric self-renewal. This indicates that these cells are mesenchymal stem cells or stromal stem cells in the bone marrow. Using Dulbecco's modified Eagle's medium, the subcultured cells showed symmetric cell division without a colony-forming unit.Conclusion:A proper microenvironment in the maculae flavae of the human vocal fold mucosa is necessary to be effective as a stem cell niche that maintains the stemness of the contained tissue stem cells.

scholarly journals Novel Clofarabine-Based Combinations with Polyphenols Epigenetically Reactivate Retinoic Acid Receptor Beta, Inhibit Cell Growth, and Induce Apoptosis of Breast Cancer Cells

2018 ◽  
Vol 19 (12) ◽  
pp. 3970 ◽  
Author(s):  
Katarzyna Lubecka ◽  
Agnieszka Kaufman-Szymczyk ◽  
Barbara Cebula-Obrzut ◽  
Piotr Smolewski ◽  
Janusz Szemraj ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Retinoic Acid ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Retinoic Acid Receptor ◽  
Retinoic Acid Receptor Beta ◽  
Receptor Beta

An epigenetic component, especially aberrant DNA methylation pattern, has been shown to be frequently involved in sporadic breast cancer development. A growing body of literature demonstrates that combination of agents, i.e. nucleoside analogues with dietary phytochemicals, may provide enhanced therapeutic effects in epigenetic reprogramming of cancer cells. Clofarabine (2-chloro-2′-fluoro-2′-deoxyarabinosyladenine, ClF), a second-generation 2′-deoxyadenosine analogue, has numerous anti-cancer effects, including potential capacity to regulate epigenetic processes. Our present study is the first to investigate the combinatorial effects of ClF (used at IC50 concentration) with epigallocatechin-3-gallate (EGCG, tea catechin) or genistein (soy phytoestrogen), at physiological concentrations, on breast cancer cell growth, apoptosis, and epigenetic regulation of retinoic acid receptor beta (RARB) transcriptional activity. In MCF7 and MDA-MB-231 cells, RARB promoter methylation and expression of RARB, modifiers of DNA methylation reaction (DNMT1, CDKN1A, TP53), and potential regulator of RARB transcription, PTEN, were estimated using methylation-sensitive restriction analysis (MSRA) and quantitative real-time polymerase chain reaction (qPCR), respectively. The combinatorial exposures synergistically or additively inhibited the growth and induced apoptosis of breast cancer cells, followed by RARB hypomethylation with concomitant multiple increase in RARB, PTEN, and CDKN1A transcript levels. Taken together, our results demonstrate the ability of ClF-based combinations with polyphenols to promote cancer cell death and reactivate DNA methylation-silenced tumor suppressor genes in breast cancer cells with different invasive potential.

scholarly journals LncRNA ASAP1-IT1 Enhances Cancer Cell Stemness via Regulating miR-509-3p/YAP1 Axis in NSCLC

2021 ◽  
Author(s):  
Yantao Liu ◽  
Yuping Yang ◽  
Lingli Zhang ◽  
Jiaqiang Lin ◽  
Bin Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Growth ◽  
Cancer Stem Cells ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Qrt Pcr

Abstract Background: Non-small cell lung cancer (NSCLC) is a major cause of cancer-related death worldwide, and cancer stem cell is mainly responsible for the poor clinical outcome of NSCLC. Although previous reports indicated long noncoding RNAs (lncRNAs) play important roles in cancer stemness maintain, the underlying causes mechanisms remain is still mysterious. Our study aims to investigate the role of ASAP1 Intronic Transcript 1 (ASAP1-IT1) in cancer cell stemness of NSCLC. Methods: qRT-PCR analysis the expression of ASAP1-IT1 and microRNA-509-3p (miR-509-3p) in NSCLC tissues, cancer cells and spheres of cancer cells-derived cancer stem cells. Knockdown of ASAP1-IT1 or overexpression of miR-509-3p in NSCLC cells by infection or transfection. Sphere formation and colony formation detects NSCLC stem cell-like properties and tumor growth in vitro. Luciferase reporter assays, RNA immunoprecitation (RIP) and qRT-PCR assays analyzed the interaction between lncRNA and miRNA, qRT-PCR and Western blot detect ASAP1-IT1/miR-509-3p axis's regulation on the expression of regulated genes. NSCLC xenograft mice model validates ASAP1-IT1 role in NSCLC stemness and tumor growth in vivo. Results: ASAP1-IT1 was up-regulated in NSCLC tissues, cancer cells, and in spheres of A549-derived cancer stem cells. Downregulated ASAP1-IT1 or miR-509-3p significantly decreased cell colony formation and stem cell-like properties of A549-dereived stem cells with decreased expression of stem cell biomarkers SOX2, CD34, and CD133, and suppressing the expression of cell growth-related genes, Cyclin A1, Cyclin B1, and PCNA. Furthermore, knockdown of ASAP1-IT1 or overexpression of miR-509-3p repressed tumor growth in nude mice via reducing expression of tumorigenic genes. ASAP1-IT1 was found to interact with miR-509-3p. Moreover, overexpression of ASAP1-IT1 blocked miR-509-3p mediated regulation of stem cell-like properties, cell growth, and cell apoptosis of A549-dereived stem cells both in vitro and in vivo. Finally, the level of YAP1 was regulated by ASAP1-IT1 and miR-509-3p.Conclusions: YAP1-involved ASAP1-IT1/miR-509-3p axis promoted NSCLC progression by regulating cancer cell stemness，and targeting related signaling is a promising therapeutic strategy to overcome NSCLC stemness.

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