Proline-Rich Protein 11 Regulates Self-Renewal and Tumorigenicity of Gastric Cancer Stem Cells

Background/Aims: Gastric cancer is a highly aggressive tumor containing cancer stem cells (CSCs), which participate in tumor initiation, therapeutic resistance, and tumor relapse. Proline-rich protein 11 (PRR11) has been shown to be up-regulated in human cancers; however, its role in gastric CSCs is unknown. We hypothesize that PRR11 may affect tumorigenicity of gastric CSCs. In this study, we explored the biological function and regulation of PRR11 in gastric CSCs. Methods: Expression of PRR11 was evaluated in gastric CSC cell line by real-time quantitative PCR and western blot. The effect of PRR11 on tumorigenicity was examined by interference with gene expression using lentiviral vector-loaded shRNA. A xenograft tumor model using NOD/SCID mice was established to examine the role of PRR11 in tumor development. Results: Data showed that PRR11 was highly expressed in gastric CSCs. PRR11 was responsible for the maintenance of self-renewal and tumorigenicity of gastric CSCs, and overexpression of exogenous PRR11 could restore the self-renewal of gastric non-CSCs. Furthermore, interference with PRR11 altered the expression of stemness transcription factors. Interestingly, MAPK signaling controlled PRR11 expression by increasing PRR11 protein stability, and maintained gastric CSCs self-renewal in a PRR11 dependent manner. Conclusions: PRR11 regulated self-renewal and tumorigenicity of gastric CSCs through MAPK signaling, and could be used as a therapeutic target for gastric cancer.

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Proton pump inhibitor pantoprazole inhibits the proliferation, self-renewal and chemoresistance of gastric cancer stem cells via the EMT/β-catenin pathways

Oncology Reports ◽

10.3892/or.2016.5154 ◽

2016 ◽

Vol 36 (6) ◽

pp. 3207-3214 ◽

Cited By ~ 17

Author(s):

Shuitu Feng ◽

Zhigao Zheng ◽

Lihua Feng ◽

Lihong Yang ◽

Zuhong Chen ◽

...

Keyword(s):

Gastric Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Proton Pump Inhibitor ◽

Proton Pump ◽

Self Renewal ◽

Gastric Cancer Stem Cells

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Gastric Cancer Stem Cells: Current Insights into the Immune Microenvironment and Therapeutic Targets

Biomedicines ◽

10.3390/biomedicines8010007 ◽

2020 ◽

Vol 8 (1) ◽

pp. 7 ◽

Cited By ~ 3

Author(s):

Lingfeng Fu ◽

Luke Bu ◽

Tadahito Yasuda ◽

Mayu Koiwa ◽

Takahiko Akiyama ◽

...

Keyword(s):

Gastric Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Chemotherapy Resistance ◽

Immune Microenvironment ◽

Self Renewal ◽

Current Review ◽

Gastric Cancer Stem Cells ◽

Novel Therapeutic Strategies ◽

The Relationship

Gastric cancer (GC) is a leading cause of cancer-related death worldwide. Cancer stem cells (CSCs) are known to be involved in chemotherapy resistance and the development of metastases. Although CSCs harbor self-renewal and tumorigenic abilities, the immune microenvironment surrounding CSCs provides various factors and supports the maintenance of CSC properties. The current review summarizes the accumulating findings regarding the relationship between the immune microenvironment and gastric CSCs (GCSCs), which will support the possibility of developing novel therapeutic strategies for targeting GCSCs.

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STEM-14. THE WRAD COMPLEX REPRESENTS A THERAPEUTIC TARGET FOR CANCER STEM CELLS IN GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.088 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi23-vi24

Author(s):

Kelly Mitchell ◽

Joseph Alvarado ◽

Christopher Goins ◽

Steven Martinez ◽

Jonathan Macdonald ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Transcription Factors ◽

Cancer Stem Cells ◽

Molecular Mechanisms ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Self Renewal ◽

Stem Cell Maintenance ◽

Cell Maintenance

Abstract Glioblastoma (GBM) progression and resistance to conventional therapies is driven in part by cells within the tumor with stem cell properties including quiescence, self-renewal and drug efflux potential. It is thought that eliminating these cancer stem cells (CSCs) is a key component to successful clinical management of GBM. However, currently, few known molecular mechanisms driving CSCs can be exploited for therapeutic development. Core transcription factors such as SOX2, OLIG2, OCT4 and NANOG maintain the CSC state in GBM. Our laboratory recently uncovered a self-renewal signaling axis involving RBBP5 that is necessary and sufficient for CSC maintenance through driving expression of these core stem cell maintenance transcription factors. RBBP5 is a component of the WRAD complex, which promotes Lys4 methylation of histone H3 to positively regulate transcription. We hypothesized that targeting RBBP5 could be a means to disrupt epigenetic programs that maintain CSCs in stemness transcriptional states. We found that genetic and pharmacologic inhibition of the WRAD complex reduced CSC growth, self-renewal and tumor initiation potential. WRAD inhibitors partially dissembled the WRAD complex and reduced H3K4 trimethylation both globally and at the promoters of key stem cell maintenance transcription factors. Using a CSC reporter system, we demonstrated that WRAD complex inhibition decreased growth of SOX2/OCT4 expressing CSCs in a concentration-dependent manner as quantified by live imaging. Overall, our studies assess the function of the WRAD complex and the effect of WRAD complex inhibitors in preclinical models and specifically on the stem cell state for the first time in GBM. Studying the functions of the WRAD complex in CSCs may improve understanding of GBM pathogenesis and elucidate how CSCs survive despite aggressive chemotherapy and radiation. Our ongoing studies aim to develop brain penetrant inhibitors targeting the WRAD complex as an anti-CSC strategy that could potentially synergize with standard of care treatments.

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The TGF- β Family Member Growth Differentiation Factor 15 (GDF15) Regulates the Self-Renewal of Multiple Myeloma Cancer Stem Cells

Blood ◽

10.1182/blood.v118.21.2954.2954 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2954-2954

Author(s):

Toshihiko Tanno ◽

Akil Merchant ◽

Jasmin R. Agarwal ◽

Qiuju Wang ◽

William Matsui

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Bone Marrow ◽

Cancer Stem Cells ◽

The Self ◽

Disease Stage ◽

Dependent Manner ◽

Self Renewal ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor

Abstract Abstract 2954 Multiple myeloma (MM) cancer stem cells (CSCs) possess both enhanced tumorigenic potential and relative drug resistance suggesting they play a major role in disease relapse and progression. Therefore, a better understanding of the processes regulating MM CSCs may lead to the development of novel therapies that prevent tumor regrowth and improve long-term outcomes. Normal stem cells are tightly regulated by factors within the local microenvironment that include both soluble factors and direct contact with accessory cells. However, external factors regulating MM CSCs have not been identified. Recent studies have demonstrated that stromal cells in the MM bone marrow microenvironment secrete growth differentiation factor 15 (GDF15), a member of the TGF-b family. We initially studied the role of this cytokine in the pathogenesis of MM by examining circulating GDF15 levels in MM patients. Compared to healthy volunteers, we found that median GDF15 levels were significantly increased in MM patients (821 vs. 390 pg/ml; n=16; p<0.05) and increased with disease stage (Stage II=585 pg/ml, Stage III=1, 004 pg/ml). To examine the functional effects of GDF15 on MM cells, we cultured human MM cell lines (NCI-H929, RPMI 8226) with recombinant GDF15 and found that it induced the expansion of isolated CD138neg MM CSCs in a dose-dependent manner but had little impact on the growth of CD138+ plasma cells (Fig). Furthermore, GDF15 enhanced clonogenic myeloma growth as evidenced by increased colony formation that was maintained during serial replating, a surrogate for self-renewal. This effect appeared to be GDF15 specific since it could be blocked using anti-GDF15 antibody. Similarly, GDF15 treatment increased the in vitro clonogenic growth of MM CSCs from primary clinical bone marrow specimens. We also investigated the down-stream cellular pathways potentially mediating the effects of GDF15 and found that it activates the AKT signaling pathway known to improve the self-renewal of embryonic (ES) and normal hematopoietic stem cells. GDF15 also induced expression of the SOX2 transcription factor known to be upregulated in CD138neg MM CSCs. Since SOX2 is required for the self-renewal of ES cells and the generation of induced pluripotent stem (iPS) cells, its induction by GDF15 may also increase the self-renewal of MM CSCs. GDF15 is the first soluble factor identified that regulates MM CSCs, and its effects are mediated by the activation of highly conserved self-renewal programs. Disclosures: No relevant conflicts of interest to declare.

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The self-renewal signaling pathways utilized by gastric cancer stem cells

Tumor Biology ◽

10.1177/1010428317697577 ◽

2017 ◽

Vol 39 (4) ◽

pp. 101042831769757 ◽

Cited By ~ 8

Author(s):

Ying Fu ◽

Hui Li ◽

Xishan Hao

Keyword(s):

Gastric Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Signaling Pathways ◽

The Self ◽

Self Renewal ◽

Gastric Cancer Stem Cells

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Wharton Jelly Stem Cells inhibits AGS Gastric Cancer Cells through Induction of Apoptosis and Modification of MAPK and NF‑κB Signaling Pathways

10.21203/rs.3.rs-142543/v1 ◽

2021 ◽

Author(s):

Samaneh Abbasi ◽

Reza Bazyar ◽

Mohammad Ali Saremi ◽

Gholamhoseen Alishiri ◽

Nasrin Seyyedsani ◽

...

Keyword(s):

Gastric Cancer ◽

Stem Cells ◽

Mrna Expression ◽

Cancer Cells ◽

Signaling Pathways ◽

Cell Line ◽

Mapk Signaling ◽

Dependent Manner ◽

Induction Of Apoptosis ◽

Mapk Signaling Pathways

Abstract Background and aim: Gastric cancer) GC) is one of the most common cancer with high mortality worldwide. The human Wharton's jelly stem cells (hWJSCs) can inhibit several cancer cells through several molecular pathways. Therefore, the present study aimed to investigate anticancer effects of hWJSCs conditioned medium (hWJSC-CM) and cell-free lysate (hWJSC-CL) against of GC cell line AGS and underlying signaling pathways. Methods: In this study, we evaluated the effects of hWJSC-CM and hWJSC-CL on viability, proliferation, migration, invasion, apoptosis, and MAPK and NF‑κB signaling pathways in AGS cells. Moreover, mRNA expression of genes involved in apoptosis (BAX, BCL2, SMAC, and SURVIVIN), as well as expression of proteins involved in NF-κB and MAPK signaling pathways were evaluated. Results: The obtained results showed that the hWJSC-CM and hWJSC-CL decreased viability, migration, and invasion of GC cell line AGS in a concentration and time dependent manner. We observed that the hWJSC-CM and hWJSC-CL induced apoptosis pathway through regulation of apoptosis involved genes mRNA expression. In addition, the hWJSC-CM and hWJSC-CL suppressed NF-κB signaling pathways as well as promoted MAPK signaling pathways. Conclusions: In general, our study suggested that the hWJSC-CM and hWJSC-CL inhibits proliferation and viability of GC cell line AGS through induction of apoptosis, as well as modification of NF-κB and MAPK signaling pathways.

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Overexpression of NRG1 promotes progression of gastric cancer by regulating the self-renewal of cancer stem cells

Journal of Gastroenterology ◽

10.1007/s00535-014-1008-1 ◽

2014 ◽

Vol 50 (6) ◽

pp. 645-656 ◽

Cited By ~ 16

Author(s):

Myoung-Eun Han ◽

Hyun-Jung Kim ◽

Dong Hoon Shin ◽

Sun-Hwi Hwang ◽

Chi-Dug Kang ◽

...

Keyword(s):

Gastric Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

The Self ◽

Self Renewal

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Radial percolation reveals that Cancer Stem Cells are trapped in the core of colonies

Papers in Physics ◽

10.4279/pip.130002 ◽

2021 ◽

Vol 13 ◽

pp. 130002

Author(s):

Lucas Barberis

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Tumor Development ◽

Simple Explanation ◽

Natural Conditions ◽

Self Renewal ◽

Agent Based ◽

The Core ◽

Differentiated Cells ◽

Signaling Mechanisms

Using geometrical arguments, it is shown that Cancer Stem Cells (CSCs) must be confined inside solid tumors under natural conditions. Aided by an agent-based model and percolation theory, the probability of a CSC being positioned at the border of a colony is estimated. This probability is estimated as a function of the CSC self-renewal probabilityps; i.e., the chance that a CSC remains undifferentiated after mitosis. In the most common situations ps is low, and most CSCs produce differentiated cells at a very low rate. Theresults presented here show that CSCs form a small core in the center of a cancer cell colony; they become quiescent due to the lack of space to proliferate, which stabilizestheir population size. This result provides a simple explanation for the CSC niche size, dispensing with the need for quorum sensing or other proposed signaling mechanisms. Italso supports the hypothesis that metastases are likely to start at the very beginning of tumor development.

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