Contextual niche signals towards colorectal tumor progression by mesenchymal stem cell in the mouse xenograft model.
J Gastroenterol, 2015/9;50(9):962-74.
Nakagaki S[1], Arimura Y, Nagaishi K, Isshiki H, Nasuno M, Watanabe S, Idogawa M, Yamashita K, Naishiro Y, Adachi Y, Suzuki H, Fujimiya M, Imai K, Shinomura Y
Affiliations
PMID: 25680886DOI: 10.1007/s00535-015-1049-0
Impact factor: 6.772
Abstract
background: The role of mesenchymal stem/stromal cells (MSCs) in tumorigenesis remains controversial. This study aimed to determine whether heterotypic interactions between MSCs and colon cancer cells can supply contextual signals towards tumor progression.
methods: Xenografts consisting of co-implanted human colorectal cancer cells with rat MSCs in immunodeficient mice were evaluated by tumor progression, angiogenic profiles, and MSC fate. Furthermore, we investigated how MSCs function as a cancer cell niche by co-culture experiments in vitro.
results: Tumor growth progressed in two ways, either independent of or dependent on MSCs. Such cell line-specific dependency could not be explained by host immune competency. COLO 320 xenograft angiogenesis was MSC-dependent, but less dependent on vascular endothelial growth factor (VEGF), whereas HT-29 angiogenesis was not MSC-dependent, but was VEGF-dependent. MSCs and COLO 320 cells established a functional positive feedback loop that triggered formation of a cancer cell niche, leading to AKT activation. Subsequently, MSCs differentiated into pericytes that enhanced angiogenesis as a perivascular niche. In contrast, the MSC niche conferred an anti-proliferative property to HT-29 cells, through mesenchymal-epithelial transition resulting in p38 activation.
conclusions: In conclusion, MSCs demonstrate pleiotropic capabilities as a cancer cell or perivascular niche to modulate colorectal cancer cell fate in a cell line-dependent manner in a xenogeneic context.
MeSH terms
Animals; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Coculture Techniques; Colorectal Neoplasms; Disease Models, Animal; Disease Progression; Heterografts; Humans; In Situ Hybridization, Fluorescence; Mesenchymal Stem Cells; Mice; Microarray Analysis; Neoplastic Processes; Neovascularization, Pathologic; Rats; Real-Time Polymerase Chain Reaction; Signal Transduction; Stem Cell Niche; Transplantation, Heterologous
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