Abstract 2222: Possible involvement of senescence bypass in mesenchymal stem cells for sarcomagenesis identified through a comparative gene expression profiling in rat sarcoma model
Authors: Honoki Kanya , Fujii Hiromasa , Kido Akira , Tsukamoto Shinji , Mori Toshio , Tanaka Yasuhito , Tsujiuchi Toshifumi 
Published: August 2015

Abstract
INTRODUCTION. Mesenchymal stem cells (MSCs) exist in a variety of tissues such as bone marrow and adipose tissue contributing tissue repair and maintenance, and have been used in clinical cell transplantation therapy. On the other hand, MSCs are also believed to be one of the cell of origins for certain sarcomas including osteosarcoma and malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma (MFH/UPS). To identify the signaling pathways that are involved in sarcoma pathogenesis, we compared gene expression profiles in rat osteosarcoma and MFH cells with those in syngeneic rat MSCs.
MATERIALS & METHODS. Rat osteosarcoma cell line COS1NR and MFH cell line MFH1NR, that were established in our laboratory from chemically induced tumors by 4-hydroxy(amino)-quinolin 1-oxide, and syngeneic rat MSCs isolated from rat femur bone marrow were used in this study. To investigate the difference of gene expression between sarcoma cells and MSCs, gene expression profiling was performed by Agilent array analysis. Data analysis was carried out using Agilent Feature Extraction software, analyzing pathways that were differentially expressed in sarcoma cells compared to MSCs.
RESULTS & DISCUSSION. Analysis of genes that characterize MSCs such as CD44, CD105, CD73 and CD90 showed higher expression in MSCs compared to sarcomas. Pathways involved in focal adhesion, cytokines, extracellular matrix-receptors and Wnt signaling were down-regulated in both sarcomas. In those factors, the genes involved in senescence acceleration in MSCs including Wnt4 and 5a, Lef1/tcf, β-catenin, p21Cip1, lysophosphatidic acid receptor 1 (LPAR1) are significantly down-regulated in both sarcomas. Meanwhile, DNA replication, cell cycle, mismatch repair, hedgehog signaling and metabolic pathways were up-regulated in both sarcomas and those include the genes involved in inhibiting senescence of MSCs such as DKK1, SOD1, FOXO4 and SIRT1. These results indicated that senescence factors for MSCs, which several previous reports suggested, such as Wnt pathways, p21Cip1 and CDKs-cyclins expression are mal-functionally regulated in sarcomas, and those have been suggested the involvement of cellular senescence in MSCs as the responses to oxidative stress and DNA damages. Taken together, acquiring the ability to bypassing senescence in MSCs is possibly involved in sarcomagenesis.
CONCLUSIONS. The current study suggests that the loss of senescence mechanism in MSCs might be involved in sarcomagenesis. Further study will clarify the critical pathways containing the driver genes in sarcoma development upon the data that current results indicated and targeting those genes and pathways will be beneficial to develop novel treatment for sarcomas.
Citation Format: Kanya Honoki, Hiromasa Fujii, Akira Kido, Shinji Tsukamoto, Toshio Mori, Yasuhito Tanaka, Toshifumi Tsujiuchi. Possible involvement of senescence bypass in mesenchymal stem cells for sarcomagenesis identified through a comparative gene expression profiling in rat sarcoma model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2222. doi:10.1158/1538-7445.AM2015-2222