Chemotherapy-induced Dkk-1 expression by primary human mesenchymal stem cells is p53 dependent
Mesenchymal stem cells (MSCs) are abundant throughout the body and regulate signaling within tumor microenvironments. Wnt signaling is an extrinsically regulated pathway that has been shown to regulate tumorigenesis in many types of cancer. After evaluating a panel of Wnt activating and inhibiting molecules, we show that primary human MSCs increase the expression of Dkk-1, an inhibitor of Wnt signaling, into the extracellular environment following chemotherapy exposure in a p53-dependent manner. Dkk-1 has been shown to promote tumor growth in several models of malignancy, suggesting that MSC-derived Dkk-1 could counteract the intent of cytotoxic chemotherapy, and that pharmacologic inhibition of Dkk-1 in patients receiving chemotherapy treatment for certain malignancies may be warranted.
KeywordsChemotherapy Wnt Signaling Tumor Microenvironment Dkk-1 Mesenchymal Stem Cell
This work was funded by National Institutes of Health (NIH) R01 HL056888 (LFG), NIH P20 RR016440 (LFG), National Cancer Institute (NCI) RO1 CA134573 (LFG), WV CTR-IDEA NIH 1U54 GM104942, CoBRE P30GM103488, The Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program, and The WV Research Trust Fund. The authors would like to thank Dr. James Coad for providing de-identified bone marrow specimens.
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