Abstract
Though the early integration of mesenchymal stem cells (MSCs) into tumor-associated stroma of cancer has been demonstrated, the functional contributions and underlying mechanisms of these cells to tumor growth and angiogenesis remain to be clarified. Using a xenograft model, human colorectal cancer cells, MSCs, and their cell mixture were introduced to a subcutaneous site of immunodeficient mice. The tumor growth rate and angiogenesis of each transplantation was then compared. We demonstrate that a variety of colorectal cancer cells, when mixed with otherwise non-tumorigenic MSCs, increase the tumor growth rate and angiogenesis more than that when mixed with carcinoma-associated fibroblasts or normal colonic fibroblasts. The secretion of interleukin-6 (IL-6) from MSCs increases the secretion of endothelin-1 (ET-1) in cancer cells, which induces the activation of Akt and ERK in endothelial cells, thereby enhancing their capacities for recruitment and angiogenesis to tumor. The IL-6/ET-1/Akt or ERK pathway of tumor-stroma interaction can be targeted by an antibody against IL-6 or Lentiviral-mediated RNAi against IL-6 in MSCs, by inhibition or knockdown of ET-1 in cancer cells, or by inhibition of ERK and Akt in host endothelial cells. These demonstrate that attempts to interrupt the interaction of MSCs and cancer cells help to abrogate angiogenesis and inhibit tumor growth in tumors formed by cancer cells admixed with MSCs. These data demonstrate that the tumor microenvironment, namely, MSCs-secreted IL-6, may enrich the proangiognic factors secreted by cancer cells to increase angiogenesis and tumor growth and that targeting this interaction may lead to novel therapeutic and preventive strategies.
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Abbreviations
- CAFs:
-
cancer-associated fibroblasts
- CM:
-
conditioned medium
- ET-1:
-
endothelin-1
- IL-6:
-
interleukin-6
- MSCs:
-
mesenchymal stem cells
- shRNA:
-
short hairpin RNA.
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Acknowledgements
National Science Council (99-3111-B-010-005-; 100-2321-B-010-022-), Taipei Veterans General Hospital (V99E1-011) and National Yang-Ming University, Ministry of Education. The study sponsors do not have a role in the study design, collection, analysis and interpretation of date.
Authors contributions: W-HH was involved inacquisition, analysis and interpretation of data, drafting of the manuscript. statistical analysis and paper revision. M-CC contributed in the study concept and design, analysis and interpretation of the data, drafting of the manuscript, statistical analysis and also in the paper revision. K-ST was involved also in acquisition of data, analysis and interpretation of data, drafting of the manuscript and statistical analysis. M-CH obtained funding, technical support and study supervision. H-LC also contributed in the study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content and obtained funding. S-CH was involved in the study concept and design, analysis and interpretation of the data, drafting of the manuscript, critical revision of the manuscript for important intellectual content and also obtained funding.
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Huang, WH., Chang, MC., Tsai, KS. et al. Mesenchymal stem cells promote growth and angiogenesis of tumors in mice. Oncogene 32, 4343–4354 (2013). https://doi.org/10.1038/onc.2012.458
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DOI: https://doi.org/10.1038/onc.2012.458
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