Medical Oncology

, 33:113 | Cite as

Chemotherapy-induced Dkk-1 expression by primary human mesenchymal stem cells is p53 dependent

  • Ian Hare
  • Rebecca Evans
  • James Fortney
  • Blake Moses
  • Debbie Piktel
  • William Slone
  • Laura F. Gibson
Short Communication

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.

Keywords

Chemotherapy Wnt Signaling Tumor Microenvironment Dkk-1 Mesenchymal Stem Cell 

Notes

Acknowledgments

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.

Compliance with ethical standards

Conflict of interest

None.

Supplementary material

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References

  1. 1.
    Hare I, Gencheva M, Evans R, Fortney J, Piktel D, Vos JA, et al. In vitro expansion of bone marrow derived mesenchymal stem cells alters DNA double strand break repair of etoposide induced DNA Damage. Stem Cells Int. 2016;2016:8270464.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Gencheva M, Hare I, Kurian S, Fortney J, Piktel D, Wysolmerski R, et al. Bone marrow osteoblast vulnerability to chemotherapy. Eur J Haematol. 2013;90:469–78.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Rhee K-J, Lee JI, Eom YW. mesenchymal stem cell-mediated effects of tumor support or suppression. Int J Mol Sci. 2015;16:30015–33.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Sun Z, Wang S, Zhao RC. The roles of mesenchymal stem cells in tumor inflammatory microenvironment. J Hematol Oncol J Hematol Oncol. 2014;7:14.CrossRefPubMedGoogle Scholar
  6. 6.
    Macheda ML, Stacker SA. Importance of Wnt signaling in the tumor stroma microenvironment. Curr Cancer Drug Targets. 2008;8:454–65.CrossRefPubMedGoogle Scholar
  7. 7.
    Cruciat C-M, Niehrs C. Secreted and transmembrane wnt inhibitors and activators. Cold Spring Harb Perspect Biol. 2013;5:a015081.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Chen D, Liu S, Ma H, Liang X, Ma H, Yan X, et al. Paracrine factors from adipose-mesenchymal stem cells enhance metastatic capacity through Wnt signaling pathway in a colon cancer cell co-culture model. Cancer Cell Int. 2015;15:42.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Edwards CM, Edwards JR, Lwin ST, Esparza J, Oyajobi BO, McCluskey B, et al. Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumor burden in bone in vivo. Blood. 2008;111:2833–42.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Rellick SL, O’Leary H, Piktel D, Walton C, Fortney JE, Akers SM, et al. Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7:e30758.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Wang L, Clutter S, Benincosa J, Fortney J, Gibson LF. Activation of transforming growth factor-β1/p38/Smad3 signaling in stromal cells requires reactive oxygen species-mediated MMP-2 activity during bone marrow damage. Stem Cells. 2005;23:1122–34.CrossRefPubMedGoogle Scholar
  12. 12.
    Etheridge SL, Spencer GJ, Heath DJ, Genever PG. Expression profiling and functional analysis of wnt signaling mechanisms in mesenchymal stem cells. Stem Cells Dayt. Ohio. 2004;22:849–60.CrossRefGoogle Scholar
  13. 13.
    Niida A, Hiroko T, Kasai M, Furukawa Y, Nakamura Y, Suzuki Y, et al. DKK1, a negative regulator of Wnt signaling, is a target of the beta-catenin/TCF pathway. Oncogene. 2004;23:8520–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Moors M, Bose R, Johansson-Haque K, Edoff K, Okret S, Ceccatelli S. Dickkopf 1 mediates glucocorticoid-induced changes in human neural progenitor cell proliferation and differentiation. Toxicol Sci Off J Soc Toxicol. 2012;125:488–95.CrossRefGoogle Scholar
  15. 15.
    Wang J, Shou J, Chen X. Dickkopf-1, an inhibitor of the Wnt signaling pathway, is induced by p53. Oncogene. 2000;19:1843–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Roecklein BA, Torok-Storb B. Functionally distinct human marrow stromal cell lines immortalized by transduction with the human papilloma virus E6/E7 genes. Blood. 1995;85:997–1005.PubMedGoogle Scholar
  17. 17.
    Pommier Y, Leo E, Zhang H, Marchand C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol. 2010;17:421–33.CrossRefPubMedGoogle Scholar
  18. 18.
    Hall AG, Tilby MJ. Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies. Blood Rev. 1992;6:163–73.CrossRefPubMedGoogle Scholar
  19. 19.
    Longley DB, Harkin DP, Johnston PG. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3:330–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Chen L, Li M, Li Q, Wang C-J, Xie S-Q. DKK1 promotes hepatocellular carcinoma cell migration and invasion through β-catenin/MMP7 signaling pathway. Mol Cancer. 2013;12:157.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Yamabuki T, Takano A, Hayama S, Ishikawa N, Kato T, Miyamoto M, et al. Dikkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas. Cancer Res. 2007;67:2517–25.CrossRefPubMedGoogle Scholar
  22. 22.
    Sato N, Yamabuki T, Takano A, Koinuma J, Aragaki M, Masuda K, et al. Wnt inhibitor Dickkopf-1 as a target for passive cancer immunotherapy. Cancer Res. 2010;70:5326–36.CrossRefPubMedGoogle Scholar
  23. 23.
    Yaccoby S, Ling W, Zhan F, Walker R, Barlogie B, Shaughnessy JD. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood. 2007;109:2106–11.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Mikheev AM, Mikheeva SA, Rostomily R, Zarbl H. Dickkopf-1 activates cell death in MDA-MB435 melanoma cells. Biochem Biophys Res Commun. 2007;352:675–80.CrossRefPubMedGoogle Scholar
  25. 25.
    Qi L, Sun B, Liu Z, Li H, Gao J, Leng X. Dickkopf-1 inhibits epithelial-mesenchymal transition of colon cancer cells and contributes to colon cancer suppression. Cancer Sci. 2012;103:828–35.CrossRefPubMedGoogle Scholar
  26. 26.
    Colla S, Zhan F, Xiong W, Wu X, Xu H, Stephens O, et al. The oxidative stress response regulates DKK1 expression through the JNK signaling cascade in multiple myeloma plasma cells. Blood. 2007;109:4470–7.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Shou J, Ali-Osman F, Multani AS, Pathak S, Fedi P, Srivenugopal KS. Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNA. Oncogene. 2002;21:878–89.CrossRefPubMedGoogle Scholar
  28. 28.
    Xu H, Wu J, Chen B, Li M, Tian Y, He M, et al. Serum Dickkopf-1 (DKK1) is significantly lower in patients with lung cancer but is rapidly normalized after treatment. Am J Trans Res. 2014;6:850–6.Google Scholar
  29. 29.
    Iyer SP, Beck JT, Stewart AK, Shah J, Kelly KR, Isaacs R, et al. A Phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events. Br J Haematol. 2014;167:366–75.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences CenterWest Virginia University School of MedicineMorgantownUSA
  2. 2.Department of Microbiology, Immunology, and Cell Biology, Robert C. Byrd Health Sciences CenterWest Virginia University School of MedicineMorgantownUSA

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