Open AccessMesenchymal Stem Cells Cancel Azoxymethane‐Induced Tumor Initiation
Author(s) -
Nasuno Masanao,
Arimura Yoshiaki,
Nagaishi Kanna,
Isshiki Hiroyuki,
Onodera Kei,
Nakagaki Suguru,
Watanabe Shuhei,
Idogawa Masashi,
Yamashita Kentaro,
Naishiro Yasuyoshi,
Adachi Yasushi,
Suzuki Hiromu,
Fujimiya Mineko,
Imai Kohzoh,
Shinomura Yasuhisa
Publication year - 2014
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.1594
Subject(s) - azoxymethane , mesenchymal stem cell , carcinogenesis , biology , cancer research , wnt signaling pathway , stem cell , tumor initiation , cell cycle , aberrant crypt foci , microbiology and biotechnology , apoptosis , cancer , signal transduction , colorectal cancer , biochemistry , colonic disease , genetics
The role of mesenchymal stem cells (MSCs) in tumorigenesis remains controversial. Therefore, our goal was to determine whether exogenous MSCs possess intrinsic antineoplastic or proneoplastic properties in azoxymethane (AOM)‐induced carcinogenesis. Three in vivo models were studied: an AOM/dextran sulfate sodium colitis‐associated carcinoma model, an aberrant crypt foci model, and a model to assess the acute apoptotic response of a genotoxic carcinogen (AARGC). We also performed in vitro coculture experiments. As a result, we found that MSCs partially canceled AOM‐induced tumor initiation but not tumor promotion. Moreover, MSCs inhibited the AARGC in colonic epithelial cells because of the removal of O 6 ‐methylguanine (O 6 MeG) adducts through O 6 MeG‐DNA methyltransferase activation. Furthermore, MSCs broadly affected the cell‐cycle machinery, potentially leading to G1 arrest in vivo. Coculture of IEC‐6 rat intestinal cells with MSCs not only arrested the cell cycle at the G1 phase, but also induced apoptosis. The anti‐carcinogenetic properties of MSCs in vitro required transforming growth factor (TGF)‐β signaling because such properties were completely abrogated by absorption of TGF‐β under indirect coculture conditions. MSCs inhibited AOM‐induced tumor initiation by preventing the initiating cells from sustaining DNA insults and subsequently inducing G1 arrest in the initiated cells that escaped from the AARGC. Furthermore, tumor initiation perturbed by MSCs might potentially dysregulate WNT and TGF‐β‐Smad signaling pathways in subsequent tumorigenesis. Obtaining a better understanding of MSC functions in colon carcinogenesis is essential before commencing the broader clinical application of promising MSC‐based therapies for cancer‐prone patients with inflammatory bowel disease. S tem C ells 2014;32:913–925