scholarly journals Simultaneous haploinsufficiency of Pten and Trp53 tumor suppressor genes accelerates tumorigenesis in a mouse model of prostate cancer

2009 ◽  
Vol 77 (1) ◽  
pp. 103-111 ◽  
Author(s):  
Suzana S. Couto ◽  
Mei Cao ◽  
Paulo C. Duarte ◽  
Whitney Banach-Petrosky ◽  
Shunyou Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Mouse Model ◽  
Tumor Suppressor Genes ◽  
Suppressor Genes

scholarly journals TMOD-18. TARGETING THE PI3K/AKT PATHWAY IN MYCN AMPLIFIED HIGH GRADE GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii231-ii232
Author(s):  
Katharine Halligan ◽  
Ann-Catherine Stanton ◽  
Matthew Halbert ◽  
Brian Golbourn ◽  
Stephen Mack ◽  
...  
Keyword(s):  
Stem Cells ◽  
Tumor Suppressor ◽  
Mouse Model ◽  
Protein Expression ◽  
Neural Stem Cells ◽  
Tumor Suppressor Genes ◽  
Akt Pathway ◽  
High Grade ◽  
Suppressor Genes ◽  
High Grade Gliomas

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.

Aneuploidy of Chromosome 9 and the Tumor Suppressor Genes p16INK4 and p15INK4B Detected by in situ Hybridization in Locally Advanced Prostate Cancer

2000 ◽  
Vol 38 (4) ◽  
pp. 475-482 ◽  
Author(s):  
Birgit Heidenreich ◽  
Axel Heidenreich ◽  
Andreas Sesterhenn ◽  
Shiv Srivastava ◽  
Judd W. Moul ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
In Situ Hybridization ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Advanced Prostate Cancer ◽  
Locally Advanced ◽  
Chromosome 9 ◽  
Locally Advanced Prostate Cancer ◽  
Suppressor Genes

A new CRISPR mediated intestinal tumor mouse model targeting four canonical tumor suppressor genes.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16064-e16064
Author(s):  
Hajime Kashima ◽  
Daniel Veronese-Paniagua ◽  
Anthony Fischer ◽  
Blair Madison ◽  
Deborah Rubin
Keyword(s):  
Tumor Suppressor ◽  
Mouse Model ◽  
Tumor Suppressor Genes ◽  
Rapid Development ◽  
Tumor Development ◽  
Intestinal Tumor ◽  
Intestinal Tumors ◽  
Suppressor Genes ◽  
Intestinal Tumorigenesis ◽  
Guide Rnas

e16064 Background: Mouse models of intestinal tumorigenesis have been developed and many of them involve mutations in the Apc gene. However, human intestinal tumors contain multiple additional sporadic mutations in tumor suppressor genes (TSGs). Our goal is to develop a novel mouse model of intestinal tumorigenesis that can recapitulate the natural history of mutations in diverse stages of tumor development. Methods: We used multiple guide RNAs to achieve random mutations in the canonical TSGs, Apc, Pten, Smad4, and Tp53. We generated transgenic (PPAS) mice that constitutively express the appropriate guide RNAs. Moreover, we achieved inducible Cas9 expression in icCas9N mice intestine using the Villin promoter to drive both a doxycycline-dependent activator and a doxycycline-inactivated repressor. We fed the doxycycline chow to PPAS:icCas9 double transgenic mice from the age of 6 to 8 weeks, and harvested intestine at 12 weeks. Results: We examined seven PPAS;icCas9 mice, and detected intestinal tumors in all the mice. Two mice had small intestinal tumor, three mice had colonic tumor, and two mice had tumors in both small and large intestine. The average number of tumors were 0.86, 1.57, 2.43 in small intestine, colon, and both respectively. We analyzed mutations in 11 tumors in 6 mice. The mutation patterns of Apc, Pten, Smad4 and Tp53 in tumors shared three distinct patterns. One was characterized by mutations in all four TSGs (n = 9). The second showed mutation in APC and Smad4 and Pten (n = 1). The third showed mutation only in Tp53 (n = 1). Normal intestine and colon in PPAS:icCas9 mice had no mutations. Conclusions: This model provides a powerful platform for modeling intestinal tumorigenesis driven by the canonical signaling pathway which are commonly dysregulated in colon cancer. This model provides a means for rapid development of intestinal tumors in mice, enabling an investigation of the relationship between novel candidate regulators of tumorigenesis and the canonical signaling pathways regulated by these four common TSGs. [Table: see text]

Two putative tumor suppressor genes on chromosome arm 8p may play different roles in prostate cancer

2001 ◽  
Vol 124 (1) ◽  
pp. 20-26 ◽  
Author(s):  
Kazuo Oba ◽  
Hideyasu Matsuyama ◽  
Satoru Yoshihiro ◽  
Fumio Kishi ◽  
Mutsuo Takahashi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Suppressor Genes ◽  
Putative Tumor Suppressor ◽  
Chromosome Arm

scholarly journals Activation of silenced tumor suppressor genes in prostate cancer cells by a novel energy restriction-mimetic agent

The Prostate ◽  
2012 ◽  
Vol 72 (16) ◽  
pp. 1767-1778 ◽  
Author(s):  
Hsiang-Yu Lin ◽  
Yi-Chiu Kuo ◽  
Yu-I Weng ◽  
I-Lu Lai ◽  
Tim H.-M. Huang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Tumor Suppressor Genes ◽  
Energy Restriction ◽  
Prostate Cancer Cells ◽  
Suppressor Genes

557 INDUCTION OF TUMOR SUPPRESSOR GENES IL24 AND IL32 BY MICRORNA-205 IN PROSTATE CANCER

2010 ◽  
Vol 183 (4S) ◽  
Author(s):  
Shahana Majid ◽  
Altaf Dar ◽  
Sharanjot Saini ◽  
Yi Chen ◽  
Varahram Shahryari ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Suppressor Genes
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