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:

Scavenging of CXCL12 by CXCR7 promotes tumor growth and metastasis of CXCR4-positive breast cancer cells

Oncogene volume 31, pages 4750–4758 (2012)Cite this article

Subjects

Abstract

Chemokine CXCL12 and receptor CXCR4 control multiple steps in primary tumor growth and metastasis in breast cancer and more than 20 other human malignancies. Mechanisms that regulate availability of CXCL12 in tumor microenvironments will substantially impact cancer progression and ongoing efforts to target the CXCL12-CXCR4 pathway for cancer chemotherapy. We used dual luciferase imaging to investigate CXCR7-dependent scavenging of CXCL12 in breast tumors in vivo and quantify effects of CXCR7 on tumor growth and metastasis of a separate population of CXCR4+ breast cancer cells. In a mouse xenograft model of human breast cancer, in vivo imaging showed that malignant cells expressing CXCR7 reduced bioluminescent CXCL12 secreted in the primary tumor microenvironment. Capitalizing on sensitive detection of bioluminescent CXCL12, we also demonstrated that CXCR7+ cells reduced amounts of chemokine released from orthotopic tumors into the circulation. Immunofluorescence staining of human primary breast cancers showed expression of CXCR4 and CXCR7 on malignant cells in ≈30% of cases. In most cases, CXCR4 and CXCR7 predominantly were expressed on separate populations of malignant cells in a tumor. We modeled these cases of human breast cancer by co-implanting tumor xenografts with CXCR4+ breast cancer cells, human mammary fibroblasts secreting CXCL12, and CXCR7+ or control breast cancer cells. Bioluminescence imaging showed that CXCR7+ breast cancer cells enhanced proliferation of CXCR4+ breast cancer cells in orthotopic tumors and spontaneous metastases. Treatment with a small-molecule inhibitor of CXCR7 chemokine limited the growth of CXCR4+ breast cancer cells in tumors that also contained malignant CXCR7+ cells. These studies establish a new in vivo imaging method to quantify chemokine scavenging by CXCR7 in the tumor microenvironment and identify that CXCR7+ cells promote growth and metastasis of CXCR4+ breast cancer cells.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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. Smith M, Luker K, Garbow J, Prior J, Jackson E, Piwnica-Worms D et al. CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Res 2004; 64: 8604–8612.

    Article  CAS  Google Scholar 

  2. Orimo A, Gupta P, Sgroi D, Arenzana-Seisdedos F, Delaunay T, Naeem R et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005; 121: 335–348.

    Article  CAS  Google Scholar 

  3. Zou W, Machelon V, Coulomb-L’Hermin A, Borvak J, Nome F, Isaeva T et al. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat Med 2001; 7: 1339–1346.

    Article  CAS  Google Scholar 

  4. Lee B, Lee T, Avraham S, Avraham H . Involvement of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha in breast cancer cell migration through human brain microvascular endothelial cells. Mol Cancer Res 2004; 2: 327–338.

    CAS  Google Scholar 

  5. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanon M et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410: 50–56.

    Article  CAS  Google Scholar 

  6. Jiang Y, Wu X, Shi B, Wu W, Yin G . Expression of chemokine CXCL12 and its receptor CXCR4 in human epithelial ovarian cancer: an independent prognostic factor for tumor progression. Gynecol Oncol 2006; 103: 226–233.

    Article  CAS  Google Scholar 

  7. Chu Q, Panu L, Holm N, Li B, Johnson L, Zhang S . High chemokine receptor CXCR4 level in triple negative breast cancer specimens predicts poor clinical outcome. J Surg Res 2010; 159: 689–695.

    Article  CAS  Google Scholar 

  8. Akashi T, Koizumi K, Tsuneyama K, Saiki I, Takano Y, Fuse H . Chemokine receptor CXCR4 expression and prognosis in patients with metastatic prostate cancer. Cancer Sci 2008; 99: 539–542.

    Article  CAS  Google Scholar 

  9. Konoplev S, Jorgensen J, Thomas D, Lin E, Burger J, Kantarjian H et al. Phosphorylated CXCR4 is associated with poor survival in adults with B-acute lymphoblastic leukemia. Cancer 2011 (e-pub ahead of print; doi:10.1002/cncr.26113).

    Article  CAS  Google Scholar 

  10. Busillo J, Benovic J . Regulation of CXCR4 signaling. Biochim Biophys Acta 2007; 1768: 952–963.

    Article  CAS  Google Scholar 

  11. Torisawa Y, Mosadegh B, Bersano-Begey T, Steele J, Luker K, Luker G et al. Microfluidic platform for chemotaxis in gradients formed by CXCL12 source-sink cells. Integr Biol 2010; 2: 680–686.

    Article  CAS  Google Scholar 

  12. Allinen M, R B, Cai L, Brennan C, Lahti-Domerci J, Huang H et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 2004; 6: 17–32.

    Article  CAS  Google Scholar 

  13. Boldajipour B, Mahabaleshwar S, Kardash E, Reichman-Fried M, Blaser H, Minina S et al. Control of chemokine-guided cell migration by ligand sequestration. Cell 2008; 132: 463–473.

    Article  CAS  Google Scholar 

  14. Naumann U, Cameroni E, Pruenster M, Mahabaleshwar S, Raz E, Zerwes H et al. CXCR7 functions as a scavenger for CXCL12 and CXCL11. PLoS One 2010; 5: e9175.

    Article  Google Scholar 

  15. Luker K, Steele J, Mihalko L, Luker G . Constitutive and chemokine-dependent internalization and recycling of CXCR7 in breast cancer cells to degrade chemokine ligands. Oncogene 2010; 29: 4599–4610.

    Article  CAS  Google Scholar 

  16. Luker K, Gupta M, Luker G . Bioluminescent CXCL12 fusion protein for cellular studies of CXCR4 and CXCR7. Biotechniques 2009; 47: 625–632.

    Article  CAS  Google Scholar 

  17. Albright C, Graciani N, Han W, Yue E, Stein R, Lai Z et al. Matrix metalloproteinase–activated doxorubicin prodrugs inhibit HT1080 xenograft growth better than doxorubicin with less toxicity. Mol Cancer Ther 2005; 4: 751–760.

    Article  CAS  Google Scholar 

  18. Tannous B, Kim D, Fernandez J, Weissleder R, Breakefield X . Codon-optimized Gaussia luciferase cDNA for mammalian gene expression in culture and in vivo. Mol Ther 2005; 11: 435–443.

    Article  CAS  Google Scholar 

  19. Miao Z, Luker K, Summers B, Berahovich R, Bhojani M, 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 USA 2007; 104: 15735–15740.

    Article  CAS  Google Scholar 

  20. Takano S, Yamashita T, Ohneda O . Molecular therapeutic targets for glioma angiogenesis. J Oncol 2010; 2010: 351908.

    Article  Google Scholar 

  21. Darash-Yahana M, Pikarsky E, Abramovitch R, Zeira E, Pal B, Karplus R et al. Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis. FASEB J 2004; 18: 1240–1242.

    Article  CAS  Google Scholar 

  22. Sanchez-Alcaniz J, Haege S, Mueller W, Pla R, Mackay F, Schulz S et al. Cxcr7 controls neuronal migration by regulating chemokine responsiveness. Neuron 2011; 69: 77–90.

    Article  CAS  Google Scholar 

  23. Wang Y, Li G, Stanco A, Long J, Crawford D, Potter G et al. CXCR4 and CXCR7 have distinct functions in regulating interneuron migration. Neuron 2011; 69: 61–76.

    Article  CAS  Google Scholar 

  24. Song J, Cavnar S, Walker A, Luker K, Gupta M, Tung Y et al. Microfluidic endothelium for studying the intravascular adhesion of metastatic breast cancer cells. PLoS One 2009; 4: e5756.

    Article  Google Scholar 

  25. Salcedo R, Wasserman K, Young H, Grimm M, Howard O, Avnver M et al. Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: in vivo neovascularization induced by stromal-derived factor-1alpha. Am J Pathol 1999; 154: 1125–1134.

    Article  CAS  Google Scholar 

  26. Teicher B, Fricker S . CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res 2010; 16: 2927–2931.

    Article  CAS  Google Scholar 

  27. Duda D, Kozin S, Kirkpatrick N, Xu L, Fukumura D, Jain R . CXCL12 (SDF1α) - CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anti-cancer therapies? Clin Cancer Res 2011; 17: 2074–2080.

    Article  CAS  Google Scholar 

  28. Pablos J, Amara A, Bouloc A, Santiago B, Caruz A, Galindo M et al. Stromal-cell derived factor is expressed by dendritic cells and endothelium in human skin. Am J Pathol 1999; 155: 1577–1586.

    Article  CAS  Google Scholar 

  29. Karnoub A, Dash A, Vo A, Sullivan A, Brooks M, Bell G et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449: 557–563.

    Article  CAS  Google Scholar 

  30. Zhang X, Wang Q, Gerald W, Hudis C, Norton L, Smid M et al. Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 2009; 16: 67–78.

    Article  CAS  Google Scholar 

  31. Wang J, Shiozawa Y, Wang J, Wang Y, Jung Y, Pienta K et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem 2008; 283: 4283–4294.

    Article  CAS  Google Scholar 

  32. Zabel B, Wang Y, Lewen S, Berahovich R, Penfold M, Zhang P et al. Elucidation of CXCR7-mediated signaling events and inhibition of CXCR4-mediated tumor cell transendothelial migration by CXCR7 ligands. J Immunol 2009; 183: 3204–3211.

    Article  CAS  Google Scholar 

  33. Hattermann K, Held-Feindt J, Lucius R, Muerkoster S, Penfold M, Schall T et al. The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects. Cancer Res 2010; 70: 3299–3308.

    Article  CAS  Google Scholar 

  34. Lois C, Hong E, Pease S, Brown E, Baltimore D . Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science 2002; 295: 868–872.

    Article  CAS  Google Scholar 

  35. Luker K, Gupta M, Luker G . Imaging chemokine receptor dimerization with firefly luciferase complementation. FASEB J 2009; 23: 823–834.

    Article  CAS  Google Scholar 

  36. Wurdinger T, Badr C, Pike L, de Kleine R, Weissleder R, Breakefield X et al. A secreted luciferase for ex vivo monitoring of in vivo processes. Nat Methods 2008; 5: 171–173.

    Article  CAS  Google Scholar 

  37. Luker G, Pica C, Song J, Luker K, Piwnica-Worms D . Imaging 26S proteasome activity and inhibition in living mice. Nat Med 2003; 9: 969–973.

    Article  CAS  Google Scholar 

  38. Meng H, Chen G, Zhang X, Wang Z, Thomas D, Giordano T et al. Stromal LRP1 in lung adenocarcinoma predicts clinical outcome. Clin Cancer Res 2011; 17: 2426–2433.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Research was supported by NIH grantsR01CA136553, R01CA136829, P50CA093990 and R24CA083099. Support also was provided by Fashion Footwear Association of New York (FFANY)/QVC presents Shoes on Sale. We thank ChemoCentryx for small-molecule inhibitors of CXCR7 and antibody 11G8.

Author information

Authors and Affiliations

  1. Department of Radiology, Center for Molecular Imaging, University of Michigan Medical School, Ann Arbor, MI, USA

    K E Luker, S A Lewin, L A Mihalko, B T Schmidt, J S Winkler, N L Coggins & G D Luker

  2. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

    D G Thomas

  3. Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA

    G D Luker

Authors
  1. K E Luker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S A Lewin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L A Mihalko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B T Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J S Winkler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N L Coggins
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D G Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G D Luker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G D Luker.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Luker, K., Lewin, S., Mihalko, L. et al. Scavenging of CXCL12 by CXCR7 promotes tumor growth and metastasis of CXCR4-positive breast cancer cells. Oncogene 31, 4750–4758 (2012). https://doi.org/10.1038/onc.2011.633

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.633

Keywords

This article is cited by

Search

Advanced search

Quick links