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Chemotherapy-induced Dkk-1 expression by primary human mesenchymal stem cells is p53 dependent
Ian Hare1,2, Rebecca Evans3, James Fortney3
1Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, PO Box 9300, Morgantown, WV, USA. ihare@mix.wvu.edu.
Abstract:
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.
Insights
Mesenchymal stem cells (MSCs) release Dkk-1, a Wnt signaling inhibitor, after chemotherapy. This MSC-derived Dkk-1 may promote tumor growth, counteracting cancer treatment and suggesting Dkk-1 inhibition as a therapeutic strategy.
Area of Science:
- Oncology
- Stem Cell Biology
- Cancer Signaling
Background:
- Mesenchymal stem cells (MSCs) influence tumor microenvironments.
- Wnt signaling is implicated in tumorigenesis across various cancers.
- The interaction between MSCs, Wnt signaling, and chemotherapy response requires further elucidation.
Purpose of the Study:
- To investigate the effect of chemotherapy on MSCs' regulation of Wnt signaling.
- To determine the specific Wnt pathway molecules modulated by MSCs post-chemotherapy.
- To assess the potential implications of MSC-mediated Wnt signaling changes in cancer treatment.
Main Methods:
- Primary human MSCs were exposed to chemotherapy.
- Expression levels of Wnt pathway activators and inhibitors were analyzed.
- The role of p53 in MSC response to chemotherapy was evaluated.
Main Results:
- Chemotherapy exposure induced primary human MSCs to increase extracellular Dkk-1 expression.
- This induction was dependent on the p53 signaling pathway.
- Dkk-1 is a known promoter of tumor growth in multiple models.
Conclusions:
- MSC-derived Dkk-1, upregulated by chemotherapy, may counteract its anti-tumor effects.
- Targeting Dkk-1 pharmacologically could be a potential therapeutic strategy for patients undergoing chemotherapy for certain malignancies.
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