Sox2 induces GBM cell stemness and tumor propagation by repressing TET2 and deregulating 5hmC and 5mC DNA modifications

Abstract DNA methylation is a reversible process catalyzed by the ten-eleven translocation (TET) family of enzymes (TET1, TET2, TET3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Altered patterns of 5hmC and 5mC are widely reported in human cancers and loss of 5hmC correlates with poor prognosis. Understanding the mechanisms leading to 5hmC loss and its role in oncogenesis will advance the development of epigenetic-based therapeutics. We show that TET2 loss associates with GBM stem cells and correlates with poor survival of GBM patients. We further identify a SOX2:miR-10b-5p:TET2 axis that represses TET2 expression, represses 5hmC, increases 5mC levels and induces GBM cell stemness and tumor-propagating potential. In vivo delivery of a miR-10b-5p inhibitor that normalizes TET2 expression and 5hmC levels inhibits tumor growth and prolongs survival of animals bearing pre-established orthotopic GBM xenografts. These findings highlight the importance of TET2 and 5hmC loss in Sox2-driven oncogenesis and their potential for therapeutic targeting.

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Let-7f miRNA regulates SDF-1α- and hypoxia-promoted migration of mesenchymal stem cells and attenuates mammary tumor growth upon exosomal release

Cell Death and Disease ◽

10.1038/s41419-021-03789-3 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Virginia Egea ◽

Kai Kessenbrock ◽

Devon Lawson ◽

Alexander Bartelt ◽

Christian Weber ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Growth ◽

Molecular Mechanisms ◽

Hypoxia Inducible Factor ◽

Human Mesenchymal Stem Cells ◽

Target Cells ◽

Autophagic Flux ◽

Stromal Cell Derived Factor

AbstractBone marrow-derived human mesenchymal stem cells (hMSCs) are recruited to damaged or inflamed tissues where they contribute to tissue repair. This multi-step process involves chemokine-directed invasion of hMSCs and on-site release of factors that influence target cells or tumor tissues. However, the underlying molecular mechanisms are largely unclear. Previously, we described that microRNA let-7f controls hMSC differentiation. Here, we investigated the role of let-7f in chemotactic invasion and paracrine anti-tumor effects. Incubation with stromal cell-derived factor-1α (SDF-1α) or inflammatory cytokines upregulated let-7f expression in hMSCs. Transfection of hMSCs with let-7f mimics enhanced CXCR4-dependent invasion by augmentation of pericellular proteolysis and release of matrix metalloproteinase-9. Hypoxia-induced stabilization of the hypoxia-inducible factor 1 alpha in hMSCs promoted cell invasion via let-7f and activation of autophagy. Dependent on its endogenous level, let-7f facilitated hMSC motility and invasion through regulation of the autophagic flux in these cells. In addition, secreted let-7f encapsulated in exosomes was increased upon upregulation of endogenous let-7f by treatment of the cells with SDF-1α, hypoxia, or induction of autophagy. In recipient 4T1 tumor cells, hMSC-derived exosomal let-7f attenuated proliferation and invasion. Moreover, implantation of 3D spheroids composed of hMSCs and 4T1 cells into a breast cancer mouse model demonstrated that hMSCs overexpressing let-7f inhibited tumor growth in vivo. Our findings provide evidence that let-7f is pivotal in the regulation of hMSC invasion in response to inflammation and hypoxia, suggesting that exosomal let-7f exhibits paracrine anti-tumor effects.

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ID: 1023 All-trans retinoic acid targets gastric cancer stem cells and inhibits patient-derived gastric carcinoma tumor growth

Biomedical Research and Therapy ◽

10.15419/bmrat.v4is.301 ◽

2017 ◽

Vol 4 (S) ◽

pp. 98

Author(s):

P H Nguyen ◽

J Giraud ◽

C Staedel ◽

L Chambonnier ◽

P Dubus ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Cancer Stem Cells ◽

Gastric Carcinoma ◽

Tumor Growth ◽

Cell Cycle Progression ◽

3D Culture ◽

All Trans Retinoic Acid

Gastric carcinoma is the third leading cause of cancer-related death worldwide. This cancer, most of the time metastatic, is essentially treated by surgery associated with conventional chemotherapy, and has a poor prognosis. The existence of cancer stem cells (CSC) expressing CD44 and a high aldehyde dehydrogenase (ALDH) activity has recently been demonstrated in gastric carcinoma and has opened new perspectives to develop targeted therapy. In this study, we evaluated the effects of all-transretinoic acid (ATRA) on CSCs in human gastric carcinoma. ATRA effects were evaluated on the proliferation and tumorigenic properties of gastric carcinoma cells from patient-derived tumors and cell lines in conventional 2D cultures, in 3D culture systems (tumorsphere assay) and in mouse xenograft models. ATRA inhibited both tumorspheres initiation and growth in vitro, which was associated with a cell-cycle arrest through the upregulation of cyclin-dependent kinase (CDK) inhibitors and the downregulation of cell-cycle progression activators. More importantly, ATRA downregulated the expression of the CSC markers CD44 and ALDH as well as stemness genes such as Klf4 and Sox2 and induced differentiation of tumorspheres. Finally, 2 weeks of daily ATRA treatment were sufficient to inhibit gastric tumor progression in vivo, which was associated with a decrease in CD44, ALDH1, Ki67 and PCNA expression in the remaining tumor cells. Administration of ATRA appears to be a potent strategy to efficiently inhibit tumor growth and more importantly to target gastric CSCs in both intestinal and diffuse types of gastric carcinoma.

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Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo

Cancer Letters ◽

10.1016/j.canlet.2011.10.002 ◽

2012 ◽

Vol 315 (1) ◽

pp. 28-37 ◽

Cited By ~ 238

Author(s):

Wei Zhu ◽

Ling Huang ◽

Yahong Li ◽

Xu Zhang ◽

Jianmei Gu ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Tumor Growth ◽

Human Bone ◽

Human Bone Marrow ◽

Promote Tumor Growth ◽

Marrow Mesenchymal Stem Cells

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Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth in gallbladder cancer via upregulating the expression of NOX4, a poor prognosis factor, through IL-6-JAK-STAT3 signal pathway

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01742-4 ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Mu-Su Pan ◽

Hui Wang ◽

Kamar Hasan Ansari ◽

Xin-Ping Li ◽

Wei Sun ◽

...

Keyword(s):

Tumor Growth ◽

Gallbladder Cancer ◽

Molecular Mechanism ◽

Poor Prognosis ◽

Vasculogenic Mimicry ◽

Tube Formation ◽

Signal Pathway ◽

Cancer Associated Fibroblasts

Abstract Background Cancer-associated fibroblasts (CAFs) and vasculogenic mimicry (VM) play important roles in the occurrence and development of tumors. However, the relationship between CAFs and VM formation, especially in gallbladder cancer (GBC) has not been clarified. In this study, we investigated whether gallbladder CAFs (GCAFs) can promote VM formation and tumor growth and explored the underlying molecular mechanism. Methods A co-culture system of human GBC cells and fibroblasts or HUVECs was established. VM formation, proliferation, invasion, migration, tube formation assays, CD31-PAS double staining, optic/electron microscopy and tumor xenograft assay were used to detect VM formation and malignant phenotypes of 3-D co-culture matrices in vitro, as well as the VM formation and tumor growth of xenografts in vivo, respectively. Microarray analysis was used to analyze gene expression profile in GCAFs/NFs and VM (+)/VM (−) in vitro. QRT-PCR, western blotting, IHC and CIF were used to detected NOX4 expression in GCAFs/NFs, 3-D culture/co-culture matrices in vitro, the xenografts in vivo and human gallbladder tissue/stroma samples. The correlation between NOX4 expression and clinicopathological and prognostic factors of GBC patients was analyzed. And, the underlying molecular mechanism of GCAFs promoting VM formation and tumor growth in GBC was explored. Results GCAFs promote VM formation and tumor growth in GBC; and the finding was confirmed by facts that GCAFs induced proliferation, invasion, migration and tube formation of GBC cells in vitro, and promoted VM formation and tumor growth of xenografts in vivo. NOX4 is highly expressed in GBC and its stroma, which is the key gene for VM formation, and is correlated with tumor aggression and survival of GBC patients. The GBC patients with high NOX4 expression in tumor cells and stroma have a poor prognosis. The underlying molecular mechanism may be related to the upregulation of NOX4 expression through paracrine IL-6 mediated IL-6/JAK/STAT3 signaling pathway. Conclusions GCAFs promote VM formation and tumor growth in GBC via upregulating NOX4 expression through the activation of IL-6-JAK-STAT3 signal pathway. NOX4, as a VM-related gene in GBC, is overexpressed in GBC cells and GCAFs, which is related to aggression and unfavorable prognosis of GBC patients.

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Oncogenic transformation of mesenchymal stem cells decreases Nrf2 expression favoring in vivo tumor growth and poorer survival

Molecular Cancer ◽

10.1186/1476-4598-13-20 ◽

2014 ◽

Vol 13 (1) ◽

pp. 20 ◽

Cited By ~ 24

Author(s):

Juan M Funes ◽

Stephen Henderson ◽

Rachel Kaufman ◽

James M Flanagan ◽

Mathew Robson ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Growth ◽

Oncogenic Transformation ◽

Nrf2 Expression

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Direct evidence that natural killer cells in nonimmune spleen cell populations prevent tumor growth in vivo

Journal of Experimental Medicine ◽

10.1084/jem.149.5.1260 ◽

1979 ◽

Vol 149 (5) ◽

pp. 1260-1264 ◽

Cited By ~ 105

Author(s):

M Kasai ◽

JC Leclerc ◽

L McVay-Boudreau ◽

FW Shen ◽

H Cantor

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Tumor Growth ◽

Nk Cells ◽

Spleen Cell ◽

Cell Population ◽

The Body ◽

Nk Activity

Relatively large numbers of nonimmune spleen cells do not protect against the local growth of two lymphomas. However, this heterogeneous population of splenic lymphocytes contains a subset of cells that efficiently protects against in vivo tumor growth. This cell population (cell-surface phenotype Thyl.2(-)Ig(-)Ly5.1(+)) represents less than 5 percent of the spleen cell population and is responsible for in vitro NK-mediated lysis. Although these studies clearly and directly demonstrate that Ly5(+) NK cells selected from a heterogeneous lymphoid population from nonimmune mice can protect syngeneic mice against local in vivo growth of two different types of tumor cells (in contrast to other lymphocyte sets within the spleen), they do not directly bear upon the role of NK cells in immunosurveillance. They do indicate that highly enriched Ig(-)Thyl(-)Ly5(+) cells, which account for virtually all in vitro NK activity, can retard tumor growth in vivo. It is difficult to ascribe all anti-tumor surveillance activity to NK cells, because they probably do not recirculate freely throughout the various organ systems of the body. Perhaps NK ceils may play a role in prevention of neoplastic growth within discrete anatomic compartments where there is rapid differentiation of stem cells to mature progeny (e.g., bone marrow, spleen, and portions of the gastrointestinal tract)and may normally act to regulate the growth and differentiation of non-neoplastic stem cells. Long-term observation of chimeric mice repopulated with bone marrow from congenic or mutant donors expressing very low or very high NK activity may help to answer these questions.

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Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth

Leukemia ◽

10.1038/sj.leu.2404489 ◽

2006 ◽

Vol 21 (2) ◽

pp. 304-310 ◽

Cited By ~ 256

Author(s):

R Ramasamy ◽

E W-F Lam ◽

I Soeiro ◽

V Tisato ◽

D Bonnet ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Growth ◽

Tumor Cells ◽

Proliferation And Apoptosis

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Stemness-Attenuating miR-503-3p as a Paracrine Factor to Regulate Growth of Cancer Stem Cells

Stem Cells International ◽

10.1155/2018/4851949 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Minkoo Seo ◽

Seung Min Kim ◽

Eun Young Woo ◽

Ki-Cheol Han ◽

Eun Joo Park ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Tumor Growth ◽

Cellular Heterogeneity ◽

Paracrine Factor ◽

Adipose Stem Cell ◽

Self Renewal ◽

Human Adipose Stem Cell ◽

Pluripotency Genes

Cancer stem cells (CSCs) with self-renewal abilities endorse cellular heterogeneity, resulting in metastasis and recurrence. However, there are no promising therapeutics directed against CSCs. Herein, we found that miR-503-3p inhibited tumor growth via the regulation of CSC proliferation and self-renewal. miR-503-3p, isolated from human adipose stem cell- (ASC-) derived exosomes, suppressed initiation and progression of CSCs as determined by anchorage-dependent (colony formation) and anchorage-independent (tumorsphere formation) assays. The expression of pluripotency genes was significantly decreased in miR-503-3p-treated CSCs. Furthermore, xenografts, which received miR-503-3p, exhibited remarkably reduced tumor growth in vivo. Thus, miR-503-3p may function as a stemness-attenuating factor via cell-to-cell communications.

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