Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Infiltrating bone marrow mesenchymal stem cells increase prostate cancer stem cell population and metastatic ability via secreting cytokines to suppress androgen receptor signaling

Abstract

Although the contribution of the bone marrow mesenchymal stem cells (BM-MSCs) in cancer progression is emerging, their potential roles in prostate cancer (PCa) remain unclear. Here, we showed that PCa cells could recruit BM-MSCs and consequently the metastatic ability of PCa cells was increased. We also found that the increased metastatic ability of PCa cells could be due to the increased PCa stem cell population. Mechanism dissection studies found that the upregulation of Chemokine ligand 5 (CCL5) expression in BM-MSCs and PCa cells, after MSCs infiltrated into the PCa cells, subsequently downregulated androgen receptor (AR) signaling, which was due to inhibition of AR nuclear translocation. Interruption of such signaling led to suppression of the BM-MSCs-induced PCa stem cell population increase and thereby inhibited the metastatic ability of PCa cells. The PCa stem cell increase then led to the upregulation of matrix metalloproteinase 9, ZEB-1, CD133 and CXCR4 molecules, and enhanced the metastatic ability of PCa cells. Therefore, we conclude that the BM-MSCs-mediated increased metastatic ability of PCa cells can be due to the PCa stem cell increase via alteration of the CCL5–AR signaling pathway. Together, these results uncover the important roles of BM-MSCs as key components in the prostate tumor microenvironment to promote PCa metastasis and may provide a new potential target to suppress PCa metastasis by blocking BM-MSCs infiltration into PCa.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Zhu P, Baek SH, Bourk EM, Ohgi KA, Garcia-Bassets I, Sanjo H et al. Macrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway. Cell 2006; 124: 615–629.

    Article  CAS  PubMed  Google Scholar 

  2. Zeng Y, Opeskin K, Goad J, Williams ED . Tumor-induced activation of lymphatic endothelial cells via vascular endothelial growth factor receptor-2 is critical for prostate cancer lymphatic metastasis. Cancer Res 2006; 66: 9566–9575.

    Article  CAS  PubMed  Google Scholar 

  3. Augsten M, Hagglof C, Olsson E, Stolz C, Tsagozis P, Levchenko T et al. CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth. Proc Natl Acad Sci USA 2009; 106: 3414–3419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 2011; 19: 257–272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449: 557–563.

    Article  CAS  PubMed  Google Scholar 

  6. Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S et al. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med 2011; 208: 2641–2655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Raaijmakers MH, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker JA et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 2010; 464: 852–857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Park D, Spencer JA, Koh BI, Kobayashi T, Fujisaki J, Clemens TL et al. Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Cell Stem Cell 2012; 10: 259–272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chong JJ, Chandrakanthan V, Xaymardan M, Asli NS, Li J, Ahmed I et al. Adult cardiac-resident MSC-like stem cells with a proepicardial origin. Cell Stem Cell 2011; 9: 527–540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lee CH, Shah B, Moioli EK, Mao JJ . CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model. J Clin Invest 2010; 120: 3340–3349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gao Y, Yao A, Zhang W, Lu S, Yu Y, Deng L et al. Human mesenchymal stem cells overexpressing pigment epithelium-derived factor inhibit hepatocellular carcinoma in nude mice. Oncogene 2010; 29: 2784–2794.

    Article  CAS  PubMed  Google Scholar 

  12. Yong RL, Shinojima N, Fueyo J, Gumin J, Vecil GG, Marini FC et al. Human bone marrow-derived mesenchymal stem cells for intravascular delivery of oncolytic adenovirus Delta24-RGD to human gliomas. Cancer Res 2009; 69: 8932–8940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Loebinger MR, Eddaoudi A, Davies D, Janes SM . Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res 2009; 69: 4134–4142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xu S, Menu E, De Becker A, Van Camp B, Vanderkerken K, Van Riet I . Bone marrow-derived mesenchymal stromal cells are attracted by multiple myeloma cell-produced chemokine CCL25 and favor myeloma cell growth in vitro and in vivo. Stem Cells 2012; 30: 266–279.

    Article  CAS  PubMed  Google Scholar 

  15. Goldstein RH, Reagan MR, Anderson K, Kaplan DL, Rosenblatt M . Human bone marrow-derived MSCs can home to orthotopic breast cancer tumors and promote bone metastasis. Cancer Res 2010; 70: 10044–10050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jodele S, Chantrain CF, Blavier L, Lutzko C, Crooks GM, Shimada H et al. The contribution of bone marrow-derived cells to the tumor vasculature in neuroblastoma is matrix metalloproteinase-9 dependent. Cancer Res 2005; 65: 3200–3208.

    Article  CAS  PubMed  Google Scholar 

  17. Charoenfuprasert S, Yang YY, Lee YC, Chao KC, Chu PY, Lai CR et al. Identification of salt-inducible kinase 3 as a novel tumor antigen associated with tumorigenesis of ovarian cancer. Oncogene 2011; 30: 3570–3584.

    Article  CAS  PubMed  Google Scholar 

  18. Rossi DJ, Jamieson CH, Weissman IL . Stems cells and the pathways to aging and cancer. Cell 2008; 132: 681–696.

    Article  CAS  PubMed  Google Scholar 

  19. Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ, Collins AT . CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci 2004; 117 (Pt 16): 3539–3545.

    Article  CAS  PubMed  Google Scholar 

  20. Trerotola M, Rathore S, Goel HL, Li J, Alberti S, Piantelli M et al. CD133, Trop-2 and alpha2beta1 integrin surface receptors as markers of putative human prostate cancer stem cells. Am J Transl Res 2010; 2: 135–144.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Yu X, Lin Y, Yan X, Tian Q, Li L, Lin EH . CD133, stem cells, and cancer stem cells: myth or reality? Curr Colorectal Cancer Rep 2011; 7: 253–259.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Leis O, Eguiara A, Lopez-Arribillaga E, Alberdi MJ, Hernandez-Garcia S, Elorriaga K et al. Sox2 expression in breast tumours and activation in breast cancer stem cells. Oncogene 2012; 31: 1354–1365.

    Article  CAS  PubMed  Google Scholar 

  23. Kumar SM, Liu S, Lu H, Zhang H, Zhang PJ, Gimotty PA et al. Acquired cancer stem cell phenotypes through Oct4-mediated dedifferentiation. Oncogene 2012; 31: 4898–4911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rybak AP, He L, Kapoor A, Cutz JC, Tang D . Characterization of sphere-propagating cells with stem-like properties from DU145 prostate cancer cells. Biochim Biophys Acta 2011; 1813: 683–694.

    Article  CAS  PubMed  Google Scholar 

  25. Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, Garcia-Echeverria C et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci USA 2009; 106: 268–273.

    Article  CAS  PubMed  Google Scholar 

  26. Shi X, Gipp J, Bushman W . Anchorage-independent culture maintains prostate stem cells. Dev Biol 2007; 312: 396–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Malanchi I, Santamaria-Martinez A, Susanto E, Peng H, Lehr HA, Delaloye JF et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 2012; 481: 85–89.

    Article  CAS  Google Scholar 

  28. Kleeberger W, Bova GS, Nielsen ME, Herawi M, Chuang AY, Epstein JI et al. Roles for the stem cell associated intermediate filament Nestin in prostate cancer migration and metastasis. Cancer Res 2007; 67: 9199–9206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mak P, Leav I, Pursell B, Bae D, Yang X, Taglienti CA et al. ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading. Cancer Cell 2010; 17: 319–332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li YM, Pan Y, Wei Y, Cheng X, Zhou BP, Tan M et al. Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell 2004; 6: 459–469.

    Article  CAS  PubMed  Google Scholar 

  31. Wegiel B, Bjartell A, Tuomela J, Dizeyi N, Tinzl M, Helczynski L et al. Multiple cellular mechanisms related to cyclin A1 in prostate cancer invasion and metastasis. J Natl Cancer Inst 2008; 100: 1022–1036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cai C, He HH, Chen S, Coleman I, Wang H, Fang Z et al. Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1. Cancer cell 2011; 20: 457–471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dayyani F, Gallick GE, Logothetis CJ, Corn PG . Novel therapies for metastatic castrate-resistant prostate cancer. J Natl Cancer Inst 2011; 103: 1665–1675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Niu Y, Altuwaijri S, Lai KP, Wu CT, Ricke WA, Messing EM et al. Androgen receptor is a tumor suppressor and proliferator in prostate cancer. Proc Natl Acad Sci USA 2008; 105: 12182–12187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Niu Y, Altuwaijri S, Yeh S, Lai KP, Yu S, Chuang KH et al. Targeting the stromal androgen receptor in primary prostate tumors at earlier stages. Proc Natl Acad Sci USA 2008; 105: 12188–12193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee SO, Ma Z, Yeh CR, Luo J, Lin TH, Lai KP et al. New therapy targeting differential androgen receptor signaling in prostate cancer stem/progenitor vs. non-stem/progenitor cells. J Mol Cell Biol 2012; 5: 14–26.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Altuwaijri S, Wu CC, Niu YJ, Mizokami A, Chang HC, Chang C . Expression of human AR cDNA driven by its own promoter results in mild promotion, but not suppression, of growth in human prostate cancer PC-3 cells. Asian J Androl 2007; 9: 181–188.

    Article  CAS  PubMed  Google Scholar 

  38. Huang XP, Sun Z, Miyagi Y, McDonald Kinkaid H, Zhang L, Weisel RD et al. Differentiation of allogeneic mesenchymal stem cells induces immunogenicity and limits their long-term benefits for myocardial repair. Circulation 2010; 122: 2419–2429.

    Article  CAS  PubMed  Google Scholar 

  39. Auletta JJ, Deans RJ, Bartholomew AM . Emerging roles for multipotent, bone marrow-derived stromal cells in host defense. Blood 2012; 119: 1801–1809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu S, Ginestier C, Ou SJ, Clouthier SG, Patel SH, Monville F et al. Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res 2011; 71: 614–624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ye H, Cheng J, Tang Y, Liu Z, Xu C, Liu Y et al. Human bone marrow-derived mesenchymal stem cells produced TGFbeta contributes to progression and metastasis of prostate cancer. Cancer Invest 2012; 30: 513–518.

    Article  CAS  PubMed  Google Scholar 

  42. Delude C . Tumorigenesis: testing ground for cancer stem cells. Nature 2011; 480: S43–S45.

    Article  CAS  PubMed  Google Scholar 

  43. Sun Y, Wang BE, Leong KG, Yue P, Li L, Jhunjhunwala S et al. Androgen deprivation causes epithelial-mesenchymal transition in the prostate: implications for androgen-deprivation therapy. Cancer Res 2012; 72: 527–536.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Karen Wolf for help with the manuscript preparation. This work was supported by NIH Grants (CA122840 and CA256700), and Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH102-TD-B-111-004) to China Medical University, Taiwan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C Chang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Luo, J., Ok Lee, S., Liang, L. et al. Infiltrating bone marrow mesenchymal stem cells increase prostate cancer stem cell population and metastatic ability via secreting cytokines to suppress androgen receptor signaling. Oncogene 33, 2768–2778 (2014). https://doi.org/10.1038/onc.2013.233

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.233

Keywords

This article is cited by

Search

Quick links