Mesenchymal stem cells cancel azoxymethane-induced tumor initiation.
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.
Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University, Chuo-ku, Sapporo, Japan.
Masanao
M
Nasuno
Yoshiaki
Y
Arimura
Kanna
K
Nagaishi
Hiroyuki
H
Isshiki
Kei
K
Onodera
Suguru
S
Nakagaki
Shuhei
S
Watanabe
Masashi
M
Idogawa
Kentaro
K
Yamashita
Yasuyoshi
Y
Naishiro
Yasushi
Y
Adachi
Hiromu
H
Suzuki
Mineko
M
Fujimiya
Kohzoh
K
Imai
Yasuhisa
Y
Shinomura
D000818:Animals; D001397:Azoxymethane / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D016212:Transforming Growth Factor beta / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects
D002273:Carcinogens; D016212:Transforming Growth Factor beta; D001397:Azoxymethane
Azoxymethane; Chemoprevention; Colorectal cancer; Mesenchymal stem cells; Tumor initiation