Journal
JOURNAL OF CELLULAR PHYSIOLOGY
Volume 236, Issue 4, Pages 3114-3128Publisher
WILEY
DOI: 10.1002/jcp.30080
Keywords
colon cancer stem cell; CXCR2 inhibitor; IL-8 peptide inhibitor; mesenchymal stem cell; stemness; tropism
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Funding
- National Natural Science Foundation of China [81873050]
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In cancer treatment, mesenchymal stem cells (MSCs) exhibit tropism towards colon cancer stem cells (CCSCs), particularly CD133(+)/CD44(+) cells. When recruited by CCSCs, BMSCs transform into cancer-associated fibroblasts and secrete more IL-8, resulting in increased stemness of CCSCs. Targeting the IL-8/CXCR2 pathway in BMSCs could potentially improve therapy targeting CCSCs.
In cancer treatment, the most attractive feature of mesenchymal stem cells (MSCs) is it's homing to tumor tissues. MSC is an important part of the colon cancer stem cell niche, but little research has been done on the tropism of human MSCs toward colon cancer stem cells (CCSCs). In this study, we first compared the effects of three tissue-derived MSCs (bone marrow, adipose tissue, and placenta) in vivo on colon tumor xenograft growth. Then, we analyzed the tropism of bone marrow-derived MSCs (BMSCs) toward normal intestinal epithelial cells (NCM460), parental colon cancer cells, CD133(-)/CD44(-,)and CD133(+)/CD44(+)colon cancer cells in vitro. Microarray analysis and in vitro experiments explored the mechanism of mediating the homing of BMSCs toward CCSCs. Compared with the parental and CD133(-)/CD44(-)colon cancer cells, CD133(+)/CD44(+)cells have a stronger ability to recruit BMSCs. In addition, BMSCs were significantly transformed into cancer-associated fibroblasts after being recruited by CCSCs. After coculture of BMSCs and CCSCs, the expression of interleukin (IL)-6, IL-8, IL-32, and CCL20 was significantly increased. Compared with parental strains, CD133(-)/CD44(-)cells, and NCM460, BMSC secreted significantly more IL-8 after coculture with CD133(+)/CD44(+)cells. Low concentration of IL-8 peptide inhibitors (100 ng/ml) and CXC receptor 2 (CXCR2) inhibitors have little effect on the migration of BMSCs, but can effectively weaken CCSC stemness and promote dormant CSCs in the coculture system to re-enter into the cell cycle. The endogenous IL-8 knockout in BMSCs or BMSCs loaded with IL-8 and/or CXCR2 inhibitors will make the therapy of BMSC targeting CCSCs function at its best.
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