Skip to main content

Advertisement

SpringerLink
Log in

Downregulation of CXCR7 inhibits proliferative capacity and stem cell-like properties in breast cancer stem cells

  • Original Article
  • Published:
Tumor Biology

Abstract

Breast cancer stem cells (bCSCs) are considered an obstacle in breast cancer therapy because they exhibit long-term proliferative potential, phenotypic plasticity and high resistance to the current therapeutics. CXC chemokine receptor type 7 (CXCR7), which provides a growth advantage to breast cancer cells, has recently been demonstrated to play an important role in the maintenance of stem cell-like properties in the CSCs of glioblastoma and lung cancer, yet its role in bCSCs remains elusive. In this study, CD44+/CD24low bCSC-enriched cells (bCSCs for short) were isolated from MCF-7 cells, and CXCR7 was stably knocked down in bCSCs via lentivirus-mediated transduction with CXCR7 short hairpin RNA (shRNA). Knockdown of CXCR7 in bCSCs decreased the proportion of CD44+/CD24low cells, and markedly reduced the clonogenicity of the cells. Moreover, silencing of CXCR7 downregulated the expression of stem cell markers, such as aldehyde dehydrogenase 1 (ALDH1), Oct4, and Nanog. In addition, CXCR7 silencing in bCSCs suppressed cell proliferation and G1/S transition in vitro, and delayed tumor growth in vivo in a xenograft mouse model. In situ immunohistochemical analysis revealed a reduction in Ki-67 expression and enhanced apoptosis in the xenograft tumors as a result of CXCR7 silencing. Furthermore, combined treatment with CXCR7 silencing and epirubicin displayed an outstanding anti-tumor effect compared with either single treatment. Our study demonstrates that CXCR7 plays a critical role in the maintenance of stem cell-like properties and promotion of growth in bCSCs, and suggests that CXCR7 may be a candidate target for bCSCs in breast cancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Soerjomataram I, Lortet-Tieulent J, Parkin DM, Ferlay J, Mathers C, Forman D, et al. Global burden of cancer in 2008: a systematic analysis of disability-adjusted life-years in 12 world regions. Lancet. 2012;380(9856):1840–50.

    Article  PubMed  Google Scholar 

  2. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.

    Article  CAS  PubMed  Google Scholar 

  3. Smalley M, Piggott L, Clarkson R. Breast cancer stem cells: obstacles to therapy. Cancer Lett. 2013;338(1):57–62.

    Article  CAS  PubMed  Google Scholar 

  4. Lobo NA, Shimono Y, Qian D, Clarke MF. The biology of cancer stem cells. Annu Rev Cell Dev Biol. 2007;23:675–99.

    Article  CAS  PubMed  Google Scholar 

  5. Phillips TM, McBride WH, Pajonk F. The response of CD24(−/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst. 2006;98(24):1777–85.

    Article  PubMed  Google Scholar 

  6. Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, MF W, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100(9):672–9.

    Article  CAS  PubMed  Google Scholar 

  7. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100(7):3983–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fillmore CM, Kuperwasser C. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res. 2008;10(2):R25.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1(5):555–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410(6824):50–6.

    Article  CAS  PubMed  Google Scholar 

  11. Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, et al. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem. 2005;280(42):35760–6.

    Article  CAS  PubMed  Google Scholar 

  12. Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med. 2006;203(9):2201–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Miao Z, Luker KE, Summers BC, Berahovich R, Bhojani MS, Rehemtulla A, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A. 2007;104(40):15735–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wani N, Nasser MW, Ahirwar DK, Zhao H, Miao Z, Shilo K, et al. C-X-C motif chemokine 12/C-X-C chemokine receptor type 7 signaling regulates breast cancer growth and metastasis by modulating the tumor microenvironment. Breast Cancer Res. 2014;16(3):R54.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hassan S, Ferrario C, Saragovi U, Quenneville L, Gaboury L, Baccarelli A, et al. The influence of tumor-host interactions in the stromal cell-derived factor-1/CXCR4 ligand/receptor axis in determining metastatic risk in breast cancer. Am J Pathol. 2009;175(1):66–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hattermann K, Holzenburg E, Hans F, Lucius R, Held-Feindt J, Mentlein R. Effects of the chemokine CXCL12 and combined internalization of its receptors CXCR4 and CXCR7 in human MCF-7 breast cancer cells. Cell Tissue Res. 2014;357(1):253–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li Q, Zhang A, Tao C, Li X, Jin P. The role of SDF-1-CXCR4/CXCR7 axis in biological behaviors of adipose tissue-derived mesenchymal stem cells in vitro. Biochem Biophys Res Commun. 2013;441(3):675–80.

    Article  CAS  PubMed  Google Scholar 

  18. Hernandez L, Magalhaes MA, Coniglio SJ, Condeelis JS, Segall JE. Opposing roles of CXCR4 and CXCR7 in breast cancer metastasis. Breast Cancer Res. 2011;13(6):R128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ribas R, Ghazoui Z, Gao Q, Pancholi S, Rani A, Dunbier A, et al. Identification of chemokine receptors as potential modulators of endocrine resistance in oestrogen receptor-positive breast cancers. Breast Cancer Res. 2014;16(5):447.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Walters MJ, Ebsworth K, Berahovich RD, Penfold ME, Liu SC, Al Omran R, et al. Inhibition of CXCR7 extends survival following irradiation of brain tumours in mice and rats. Br J Cancer. 2014;110(5):1179–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wu YC, Tang SJ, Sun GH, Sun, KH. CXCR7 mediates TGFbeta1-promoted EMT and tumor-initiating features in lung cancer. Oncogene 2015.

  22. Economopoulou P, Kaklamani VG, Siziopikou K. The role of cancer stem cells in breast cancer initiation and progression: potential cancer stem cell-directed therapies. Oncologist. 2012;17(11):1394–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu S, Wicha MS. Targeting breast cancer stem cells. J Clin Oncol. 2010;28(25):4006–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hattermann K, Held-Feindt J, Lucius R, Muerkoster SS, Penfold ME, Schall TJ, et al. The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects. Cancer Res. 2010;70(8):3299–308.

    Article  CAS  PubMed  Google Scholar 

  25. Boudot A, Kerdivel G, Habauzit D, Eeckhoute J, Le Dily F, Flouriot G, et al. Differential estrogen-regulation of CXCL12 chemokine receptors, CXCR4 and CXCR7, contributes to the growth effect of estrogens in breast cancer cells. PLoS One. 2011;6(6):e20898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kong L, Guo S, Liu C, Zhao Y, Feng C, Liu Y, et al. Overexpression of SDF-1 activates the NF-kappaB pathway to induce epithelial to mesenchymal transition and cancer stem cell-like phenotypes of breast cancer cells. Int J Oncol. 2016;48(3):1085–94.

    CAS  PubMed  Google Scholar 

  27. Shi G, Jin Y. Role of Oct4 in maintaining and regaining stem cell pluripotency. Stem Cell Res Ther. 2010;1(5):39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Saunders A, Faiola F, Wang J. Concise review: pursuing self-renewal and pluripotency with the stem cell factor Nanog. Stem Cells. 2013;31(7):1227–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu A, Yu X, Liu S. Pluripotency transcription factors and cancer stem cells: small genes make a big difference. Chin J Cancer. 2013;32(9):483–7.

    PubMed  PubMed Central  Google Scholar 

  30. Hattermann K, Mentlein R, Held-Feindt J. CXCL12 mediates apoptosis resistance in rat C6 glioma cells. Oncol Rep. 2012;27(5):1348–52.

    CAS  PubMed  Google Scholar 

  31. Heckmann D, Maier P, Laufs S, Li L, Sleeman JP, Trunk MJ, et al. The disparate twins: a comparative study of CXCR4 and CXCR7 in SDF-1alpha-induced gene expression, invasion and chemosensitivity of colon cancer. Clin Cancer Res. 2014;20(3):604–16.

    Article  CAS  PubMed  Google Scholar 

  32. Ierano C, Santagata S, Napolitano M, Guardia F, Grimaldi A, Antignani E, et al. CXCR4 and CXCR7 transduce through mTOR in human renal cancer cells. Cell Death Dis. 2014;5:e1310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgment

This study was supported by a grant from the National Natural Science Foundation of China (No.: 81371564).

Author information

Authors and Affiliations

  1. Department of Medical Ultrasonics, Hongqi Hospital of Mudanjiang Medical University, 5 Tongxiang Road, Mudanjiang, Heilongjiang, 157011, China

    Xin Tang, Yunshuang Liu, Lihong Yao, Shuang Song, Hongyan Yang & Caijuan Li

  2. Department of Medical Ultrasonics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, China

    Xiang Li

  3. Department of Orthopaedic Surgery, Mudanjiang Forestry Central Hospital, Mudanjiang, Heilongjiang, 157000, China

    Zitao Li

Authors
  1. Xin Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zitao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yunshuang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lihong Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shuang Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hongyan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Caijuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Caijuan Li.

Ethics declarations

All experimental procedures were approved by the Animal Care and Use Committee of Mudanjiang Medical University.

Funding

This study was supported by a grant from the National Natural Science Foundation of China (No.: 81,371,564).

Conflicts of interest

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tang, X., Li, X., Li, Z. et al. Downregulation of CXCR7 inhibits proliferative capacity and stem cell-like properties in breast cancer stem cells. Tumor Biol. 37, 13425–13433 (2016). https://doi.org/10.1007/s13277-016-5180-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5180-1

Keywords

Search

Navigation