THE ROLE OF GAIN-OF-FUNCTION MUTANT P53 IN CANCER STEM CELL-LIKE PROPERTIES IN OSTEOSARCOMA
Document Type
Presentation
Start Date
22-10-2010 10:45 AM
End Date
22-10-2010 12:00 PM
Description
INTRODUCTION: Osteosarcoma, the most common bone cancer, is the second highest cause of canceHelated death in children mainly due to its high metastatic and drug-resistant nature. Increasing evidence suggests that cancer stem cells (CSCs) are responsible for these properties and that the inadequacy of current treatments may result from our inability to target these cells. Approximately 50% of human osteosarcomas contain alterations in the tumor suppressor p53 gene, the majority of which are missense mutations which not only lose their wild-type p53 activity, but also show oncogenic phenotypes by their gain-of-function (GOF) activities. These include increased transformation, metastasis, and drug resistance, reminiscence of the CSC-like properties.
PURPOSE: Goal of this project is to identify genes commonly involved in both phenotypes in osteosarcoma cells in order to improve current treatments for osteosarcoma.
METHODS: Cells with CSC-like properties are enriched in spheres that grow in serum-and anchorage-independent conditions. We therefore used the sphere-forming assay to measure the CSC-property of several murine and human osteosarcoma cell lines with various p53 statuses. We also examined the effects of mutant p53 down-modulation on their sphere-and tumor-forming abilities.
RESULTS: Introducing GOF p53 mutants into a p53·1• osteosarcoma cell line MG63 increased its sphere formin~ ability, indicating their GOF activities. In contrast, down-modulation of a GOF mutant p53R17 H in a mouse osteosarcoma cell line attenuated the abilities of sphere formation and tumor initiation.
CONCLUSION: GOF p53 mutants contribute to the CSC-like properties, indicating the presence of a common pathway between mutant p53 GOF and CSC-like properties in osteosarcoma. Identifying genes commonly involved in these properties will be achieved by combining two screenings: the identification of genes responsible for sphere formation using a shRNA library, and the identification of genes involved in GOF activities using gene expression profile analyses. Completion of this project will help develop novel therapies targeting pathways that contribute to lethal characteristics of osteosarcoma.
Recommended Citation
Iyer, Swathi; Adhikari, Amit S.; Agarwal, Neeraj; and Iwakuma, Tomoo, "THE ROLE OF GAIN-OF-FUNCTION MUTANT P53 IN CANCER STEM CELL-LIKE PROPERTIES IN OSTEOSARCOMA" (2010). Dr. Joseph M. Moerschbaecher, III Graduate Research Day. 12.
https://digitalscholar.lsuhsc.edu/grad_rs/2010/poster1/12
THE ROLE OF GAIN-OF-FUNCTION MUTANT P53 IN CANCER STEM CELL-LIKE PROPERTIES IN OSTEOSARCOMA
INTRODUCTION: Osteosarcoma, the most common bone cancer, is the second highest cause of canceHelated death in children mainly due to its high metastatic and drug-resistant nature. Increasing evidence suggests that cancer stem cells (CSCs) are responsible for these properties and that the inadequacy of current treatments may result from our inability to target these cells. Approximately 50% of human osteosarcomas contain alterations in the tumor suppressor p53 gene, the majority of which are missense mutations which not only lose their wild-type p53 activity, but also show oncogenic phenotypes by their gain-of-function (GOF) activities. These include increased transformation, metastasis, and drug resistance, reminiscence of the CSC-like properties.
PURPOSE: Goal of this project is to identify genes commonly involved in both phenotypes in osteosarcoma cells in order to improve current treatments for osteosarcoma.
METHODS: Cells with CSC-like properties are enriched in spheres that grow in serum-and anchorage-independent conditions. We therefore used the sphere-forming assay to measure the CSC-property of several murine and human osteosarcoma cell lines with various p53 statuses. We also examined the effects of mutant p53 down-modulation on their sphere-and tumor-forming abilities.
RESULTS: Introducing GOF p53 mutants into a p53·1• osteosarcoma cell line MG63 increased its sphere formin~ ability, indicating their GOF activities. In contrast, down-modulation of a GOF mutant p53R17 H in a mouse osteosarcoma cell line attenuated the abilities of sphere formation and tumor initiation.
CONCLUSION: GOF p53 mutants contribute to the CSC-like properties, indicating the presence of a common pathway between mutant p53 GOF and CSC-like properties in osteosarcoma. Identifying genes commonly involved in these properties will be achieved by combining two screenings: the identification of genes responsible for sphere formation using a shRNA library, and the identification of genes involved in GOF activities using gene expression profile analyses. Completion of this project will help develop novel therapies targeting pathways that contribute to lethal characteristics of osteosarcoma.