Contextual niche signals towards colorectal tumor progression by mesenchymal stem cell in the mouse xenograft model
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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.
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.
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.
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.
KeywordsMesenchymal stem cell Niche Pericyte Cancer-associated fibroblast Angiogenesis
Mesenchymal stem/stromal cells
Cancer-associated fibroblastic cells
C–C motif chemokine ligand 5
Vascular endothelial growth factor
Enhanced green fluorescence protein
α-Modified Eagle’s medium
Fetal bovine serum
Quantitative real-time reverse transcription PCR
Tumor microvessel density
Thymus cell antigen-1
Neural/glial antigen 2
α-Smooth muscle actin
Chemokine C-X-C motif ligand 12
C-X-C chemokine receptor type 4
Mitogen-activated protein kinases
Fluorescence-activated cell sorting
Analysis of variance
Platelet endothelial cell adhesion molecule-1
- Vegfr1 (Flt1)
Vascular endothelial growth factor receptor 1
Platelet-derived growth factor BB
Platelet-derived growth factor receptor-β
Vascular cell adhesion molecule-1
Chemokine (C–C motif) receptor 5
Very late antigen-4
We are very grateful to Ms. K. Fujii of First Department of Internal Medicine, for technical assistance, and Dr. Y. Sasaki of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, for critical comments. We are also thankful to Dr. M. Tsuji of Chromosome Science Labo Inc., for providing FISH probes and technical advice. This work was supported in part by Health and Labor Sciences Research Grants for research on intractable diseases from the Ministry of Health, Labour, and Welfare of Japan (K.I. and Y.A.).
Conflict of interest
The authors declare that they have no conflict of interest.
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