Distinct epigenetic regulation of tumor suppressor genes in putative cancer stem cells of solid tumors

Abstract Pediatric glioblastoma (pGBM) are incurable brain tumors with overall poor prognosis and response to treatments due to molecular and epigenetic heterogeneity. In particular, the MYCN subtype of pGBM are a highly aggressive form of GBM with a dismal median survival of only 14 months. Furthermore, this subtype is enriched with loss of the tumor suppressor genes TP53 and PTEN, leading to aberrantly active PI3K-AKT signaling pathway and DNA-checkpoint abnormalities. Here, we report the generation of a novel syngeneic mouse model that recapitulates the features of the MYCN subtype of pGBM. We isolated Sox2-Cre neural stem cells from C57BL/6 mice and transduced inverted retroviral-cassettes of the murine Mycn oncogene simultaneously with shRNA targeting tumor suppressor genes p53 and Pten. Retroviral-cassettes are flanked by tandem LoxP sites arranged so that Cre recombinase expression inverts the cassettes in frame allowing for MYCN protein expression and loss of the P53/PTEN proteins. Transgene activation is accompanied with selectable cell surface markers and fluorescent tags enabling for fluorescent activated cell sorting (FACS) of the desired cell populations. Neural stem cells with MYCN protein expression and concurrent silencing of P53 and PTEN protein (NPP cells) result in significantly increased proliferation and activation of PI3K-AKT pathway as compared to control neural stem cells and have. Injection of NPP cells into the forebrain of immune competent C57BL/6 mice result in the formation of invasive high-grade gliomas with a lethal phenotype at ~50 days post injection. Using several next generation brain penetrant small molecule inhibitors of the PI3K-AKT pathway, we show inhibition of tumorigenesis in vitro. Moreover, we have identified several novel mechanisms of PI3KAKT treatment resistance and are currently identifying therapies that may overcome this resistance through RNA seq analysis. In summary, well defined genetic drivers of GBM can lead to informed mouse model generation to test promising therapies.

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NF1 in Solid Tumors: The Unknown Soldier of Tumor Suppressor Genes?

Genetics & Molecular Medicine ◽

10.33425/2689-1077.1004 ◽

2019 ◽

Vol 1 (1) ◽

Author(s):

Leslie L Lin ◽

Khalil Choucair ◽

Rayna Patel ◽

Rakan S Albalawy ◽

Susan M Morand ◽

...

Keyword(s):

Tumor Suppressor ◽

Solid Tumors ◽

Tumor Suppressor Genes ◽

Suppressor Genes

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Quantification of Chlorogenic Acid and Vanillin from Coffee Peel Extract and its Effect on α-Amylase Activity, Immunoregulation, Mitochondrial Oxidative Stress, and Tumor Suppressor Gene Expression Levels in H2O2-Induced Human Mesenchymal Stem Cells

Frontiers in Pharmacology ◽

10.3389/fphar.2021.760242 ◽

2021 ◽

Vol 12 ◽

Author(s):

Heba Khalil Alyahya ◽

Pandurangan Subash-Babu ◽

Ahmad Mohammad Salamatullah ◽

Khizar Hayat ◽

Nawal Albader ◽

...

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Suppressor ◽

Chlorogenic Acid ◽

Tumor Suppressor Genes ◽

Human Mesenchymal Stem Cells ◽

Total Polyphenol ◽

Suppressor Genes ◽

Mitochondrial Oxidative Stress

Background: Polyphenols and flavonoid-rich foods help in arresting reactive oxygen species development and protecting DNA from oxidative damage. Coffee peel (CP) preparations are consumed as beverages, and their total polyphenol or flavonoid content and their effect on oxidative stress–induced human mesenchymal stem cells (hMSCs) are poorly understood.Method: We prepared hot water extracts of CP (CPE) and quantified the amount of total polyphenol and flavonoid using HPLC analysis. In addition, CPE have been studied for their α-amylase inhibitory effect and beneficial effects in oxidative stress–induced hMSCs.Results: The obtained results show that the availability of chlorogenic acid, vanillin, and salicylic acid levels in CPE is more favorable for enhancing cell growth, nuclear integrity, and mitochondrial efficiency which is confirmed by propidium iodide staining and JC-1 staining. CPE treatment to hMSCs for 48 h reduced oxidative stress by decreasing mRNA expression levels of LPO and NOX-4 and in increasing antioxidant CYP1A, GSH, GSK-3β, and GPX mRNA expressions. Decreased pro-inflammatory (TNF-α, NF-κβ, IL-1β, TLR-4) and increased tumor suppressor genes (except Bcl-2) such as Cdkn2A, p53 expressions have been observed.Conclusions: The availability of CGA in CPs effectively reduced mitochondrial oxidative stress, reduced pro-inflammatory cytokines, and increased tumor suppressor genes.

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Role of tumor suppressor genes in the cancer-associated reprogramming of human induced pluripotent stem cells

Stem Cell Research & Therapy ◽

10.1186/scrt447 ◽

2014 ◽

Vol 5 (2) ◽

pp. 58 ◽

Cited By ~ 11

Author(s):

Ying-Chu Lin ◽

Yoshinobu Murayama ◽

Koichiro Hashimoto ◽

Yukio Nakamura ◽

Chang-Shin Lin ◽

...

Keyword(s):

Stem Cells ◽

Tumor Suppressor ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Tumor Suppressor Genes ◽

Suppressor Genes ◽

Induced Pluripotent

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The role of miR-17-92 cluster in the expression of tumor suppressor genes in unrestricted somatic stem cells

Biologicals ◽

10.1016/j.biologicals.2017.02.006 ◽

2017 ◽

Vol 46 ◽

pp. 143-147 ◽

Cited By ~ 4

Author(s):

Rezvan Tavakoli ◽

Saeid Vakilian ◽

Lida Langroudi ◽

Ehsan Arefian ◽

Mehdi Sahmani ◽

...

Keyword(s):

Stem Cells ◽

Tumor Suppressor ◽

Tumor Suppressor Genes ◽

Somatic Stem Cells ◽

Suppressor Genes ◽

Unrestricted Somatic Stem Cells

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Trial in progress abstract phase I trial of 5-aza-4’-thio-2’-deoxycytidine (Aza-TdC) in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.tps3148 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. TPS3148-TPS3148

Author(s):

M. Cecilia Monge B. ◽

Geraldine Helen O'Sullivan Coyne ◽

Richard Piekarz ◽

Naoko Takebe ◽

Ashley Bruns ◽

...

Keyword(s):

Tumor Suppressor ◽

Solid Tumors ◽

Dose Level ◽

Standard Therapy ◽

Tumor Suppressor Genes ◽

Dna Methyltransferase ◽

Objective Response ◽

Tumor Xenograft ◽

Advanced Solid Tumors ◽

Suppressor Genes

TPS3148 Background: The nucleoside analog 5-aza-4’-thio-2’-deoxycytidine (Aza-TdC) inhibits DNA methyltransferase 1 (DNMT1), a methyltransferase involved in methylation-mediated silencing of tumor suppressor genes. Attenuation of DNA methylation via DNMT1 inhibitors results in reactivation of silenced tumor suppressor genes and can lead to tumor growth arrest and apoptosis. The DNMT1 inhibitors decitabine and 5-azacytdine are currently FDA-approved for use in myelodysplastic syndromes and are also used in patients with acute myeloid leukemia. Relative to these compounds, Aza-TdC exhibits enhanced stability and incorporation into DNA and has shown improved preclinical antitumor activity in both leukemia and solid tumor xenograft models. This study seeks to evaluate the safety and maximum tolerated dose (MTD) of oral Aza-TdC in patients with advanced solid tumors. Secondary study objectives include assessing objective response by RECIST 1.1, pharmacokinetic (PK) analysis, and examining re-expression of tumor suppressor genes inhibited by methylation in circulating tumor cells (CTCs). Methods: Patients are treated with Aza-TdC on days 1-5 and 8-12 of each 21-day cycle. The study follows Simon accelerated titration design 3, with 100% dose increments and 1 patient per dose level. Accelerated titration will continue until 1 patient experiences a dose-limiting toxicity (DLT) or 2 patients experience drug-related grade 2 toxicity at any dose level, after which, a 3 + 3 dose escalation design will be used. Blood samples are collected for PK and CTC analyses. An MTD expansion cohort is planned, in which tumor biopsies will be collected for further pharmacodynamic assessments. Patients included in this study must be ≥18 years old and have histologically documented solid tumors that have progressed on standard therapy and for which there is no other standard therapy available. Dose level 3 has been completed without any DLTs; enrollment to dose level 4 began in February 2019. Funded by NCI Contract No. HHSN261200800001E. Clinical trial information: NCT03366116.

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Abstract 1623: Epigenetic regulation of tumor suppressor genes in esophageal cancer by berries

10.1158/1538-7445.am2012-1623 ◽

2012 ◽

Author(s):

Yi-Wen Huang ◽

Chieh-Ti Kuo ◽

Fei Gu ◽

Li-Shu Wang ◽

Gary D. Stoner

Keyword(s):

Esophageal Cancer ◽

Tumor Suppressor ◽

Epigenetic Regulation ◽

Tumor Suppressor Genes ◽

Suppressor Genes

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Human Umbilical Cord Matrix Mesenchymal Stem Cells Suppress the Growth of Breast Cancer by Expression of Tumor Suppressor Genes

PLoS ONE ◽

10.1371/journal.pone.0123756 ◽

2015 ◽

Vol 10 (5) ◽

pp. e0123756 ◽

Cited By ~ 11

Author(s):

Naomi Ohta ◽

Susumu Ishiguro ◽

Atsushi Kawabata ◽

Deepthi Uppalapati ◽

Marla Pyle ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Suppressor ◽

Umbilical Cord ◽

Tumor Suppressor Genes ◽

Human Umbilical Cord ◽

Suppressor Genes ◽

Umbilical Cord Matrix

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Long-term expansion enhances the expression of tumor suppressor genes in human bone marrow-derived mesenchymal stem cells

Science and Technology Development Journal ◽

10.32508/stdj.v22i1.1661 ◽

2019 ◽

Vol 22 (1) ◽

pp. 136-142

Author(s):

Loan Thi Tung Dang ◽

Anh Thi Van Bui ◽

Nhat Chau Truong ◽

Huy Duc Van ◽

Phuc Van Pham

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Tumor Suppressor ◽

Tumor Suppressor Genes ◽

Human Bone ◽

Human Bone Marrow ◽

Differentiation Potential ◽

Suppressor Genes

Introduction: Mesenchymal stem cells (MSCs) are possibly the most potent type of stem cells for the treatment of many diseases since they possess many advantageous properties, such as abundant source, ease of isolation, and potential to differentiate and trans-differentiate into different types of cells. Although the therapeutic potential of expanded MSCs has been well proven, their biosafety features have not been fully understood. This study aimed to investigate some changes in phenotype and gene expression of bone marrow derived MSCs after long term expansion. Methods: In this study, expanded mesenchymal stem cells derived from human bone marrow (hBMSCs) were identified for their characteristics (which included morphology, immunophenotype, and differentiation potential) at passages 5, 10 and 15. Moreover, they were evaluated for the expression of various tumor suppressor genes (PTEN, p16, and p53) by real-time RT-PCR. Results: The results showed that the hBMSCs at passage 15 displayed a change in morphology and a slight reduction of the expression of CD44 and CD90, whereas their potential for adipogenic and osteogenic differentiation was maintained. Moreover, the expression of tumor suppressor genes in the hBMSCs increased after long-term culture. Conclusion: It could be assumed that prolonged cultures of more than 15 passages drove the hBMSCs into senescence phase. Cultured hBMSCs below passage 10 seemed to be more effective in application because their properties were still preserved.

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