Skip to main content

Thank you for visiting 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.

The Cyclophilin A–CD147 complex promotes the proliferation and homing of multiple myeloma cells


B cell malignancies frequently colonize the bone marrow. The mechanisms responsible for this preferential homing are incompletely understood. Here we studied multiple myeloma (MM) as a model of a terminally differentiated B cell malignancy that selectively colonizes the bone marrow. We found that extracellular CyPA (eCyPA), secreted by bone marrow endothelial cells (BMECs), promoted the colonization and proliferation of MM cells in an in vivo scaffold system via binding to its receptor, CD147, on MM cells. The expression and secretion of eCyPA by BMECs was enhanced by BCL9, a Wnt–β-catenin transcriptional coactivator that is selectively expressed by these cells. eCyPA levels were higher in bone marrow serum than in peripheral blood in individuals with MM, and eCyPA-CD147 blockade suppressed MM colonization and tumor growth in the in vivo scaffold system. eCyPA also promoted the migration of chronic lymphocytic leukemia and lymphoplasmacytic lymphoma cells, two other B cell malignancies that colonize the bone marrow and express CD147. These findings suggest that eCyPA-CD147 signaling promotes the bone marrow homing of B cell malignancies and offer a compelling rationale for exploring this axis as a therapeutic target for these malignancies.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


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

Figure 1: Analysis of BCL9 expression and canonical Wnt activity in BMECs.
Figure 2: Effects of BMECs on MM cells.
Figure 3: In vitro and in vivo migration of MM cells.
Figure 4: Secretion of eCyPA by BMECs and eCyPA levels in bone marrow serum from MM subjects.
Figure 5: CD147 mediates the effects of eCyPA on MM cells.
Figure 6: Targeting of the eCyPA-CD147 complex is associated with anti-MM activity.

Accession codes


Gene Expression Omnibus


  1. Talmadge, J.E. & Fidler, I.J. AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res. 70, 5649–5669 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Valastyan, S. & Weinberg, R.A. Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275–292 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kuehl, W.M. & Bergsagel, P.L. Molecular pathogenesis of multiple myeloma and its premalignant precursor. J. Clin. Invest. 122, 3456–3463 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Muller-Hermelink, H.K. et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues 4th edn. (eds. Swerdlow, S.H. et al.) 180–182 (IARC Press, 2008).

  5. Anderson, K.C. Oncogenomics to target myeloma in the bone marrow microenvironment. Clin. Cancer Res. 17, 1225–1233 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Vande Broek, I., Vanderkerken, K., Van Camp, B. & Van Riet, I. Extravasation and homing mechanisms in multiple myeloma. Clin. Exp. Metastasis 25, 325–334 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Ghobrial, I.M. Myeloma as a model for the process of metastasis: implications for therapy. Blood 120, 20–30 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jakob, C. et al. Angiogenesis in multiple myeloma. Eur. J. Cancer 42, 1581–1590 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Ribatti, D. & Vacca, A. The role of microenvironment in tumor angiogenesis. Genes Nutr. 3, 29–34 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ribatti, D., Nico, B. & Vacca, A. Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma. Oncogene 25, 4257–4266 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Ria, R. et al. Gene expression profiling of bone marrow endothelial cells in patients with multiple myeloma. Clin. Cancer Res. 15, 5369–5378 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Alsayed, Y. et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood 109, 2708–2717 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mani, M. et al. BCL9 promotes tumor progression by conferring enhanced proliferative, metastatic, and angiogenic properties to cancer cells. Cancer Res. 69, 7577–7586 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Polakis, P. Drugging Wnt signalling in cancer. EMBO J. 31, 2737–2746 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Clevers, H. & Nusse, R. Wnt/β-catenin signaling and disease. Cell 149, 1192–1205 (2012).

    Article  CAS  Google Scholar 

  16. de la Roche, M. et al. An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid. Nat. Commun. 3, 680 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Takada, K. et al. Targeted disruption of the BCL9/β-catenin complex inhibits oncogenic Wnt signaling. Sci. Transl. Med. 4, 148ra117 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Giuliani, N., Colla, S. & Rizzoli, V. Angiogenic switch in multiple myeloma. Hematology 9, 377–381 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Rood, P.M., Calafat, J., von dem Borne, A.E., Gerritsen, W.R. & van der Schoot, C.E. Immortalisation of human bone marrow endothelial cells: characterisation of new cell lines. Eur. J. Clin. Invest. 30, 618–629 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Mitsiades, C.S., Mitsiades, N.S., Munshi, N.C., Richardson, P.G. & Anderson, K.C. The role of the bone microenvironment in the pathophysiology and therapeutic management of multiple myeloma: interplay of growth factors, their receptors and stromal interactions. Eur. J. Cancer 42, 1564–1573 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. De Bruyne, E. et al. Myeloma cells and their interactions with the bone marrow endothelial cells. Curr. Immunol. Rev. 3, 41–55 (2007).

    Article  CAS  Google Scholar 

  22. Hideshima, T. & Anderson, K.C. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat. Rev. Cancer 2, 927–937 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Chen, H. et al. Extracellular signal-regulated kinase signaling pathway regulates breast cancer cell migration by maintaining slug expression. Cancer Res. 69, 9228–9235 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Calimeri, T. et al. A unique three-dimensional SCID-polymeric scaffold (SCID-synth-hu) model for in vivo expansion of human primary multiple myeloma cells. Leukemia 25, 707–711 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Song, F. et al. Cyclophilin A (CyPA) induces chemotaxis independent of its peptidylprolyl cis-trans isomerase activity: direct binding between CyPA and the ectodomain of CD147. J. Biol. Chem. 286, 8197–8203 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nigro, P., Pompilio, G. & Capogrossi, M.C. Cyclophilin A: a key player for human disease. Cell Death Dis. 4, e888 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yurchenko, V., Constant, S., Eisenmesser, E. & Bukrinsky, M. Cyclophilin-CD147 interactions: a new target for anti-inflammatory therapeutics. Clin. Exp. Immunol. 160, 305–317 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Weidle, U.H., Scheuer, W., Eggle, D., Klostermann, S. & Stockinger, H. Cancer-related issues of CD147. Cancer Genomics Proteomics 7, 157–169 (2010).

    CAS  PubMed  Google Scholar 

  29. Damsker, J.M. et al. Targeting the chemotactic function of CD147 reduces collagen-induced arthritis. Immunology 126, 55–62 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sanderson, R.D. & Borset, M. Syndecan-1 in B lymphoid malignancies. Ann. Hematol. 81, 125–135 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Comerford, I., Kara, E.E., McKenzie, D.R. & McColl, S.R. Advances in understanding the pathogenesis of autoimmune disorders: focus on chemokines and lymphocyte trafficking. Br. J. Haematol. 164, 329–341 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Agrawal, S.M. & Yong, V.W. The many faces of EMMPRIN—roles in neuroinflammation. Biochim. Biophys. Acta 1812, 213–219 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Arendt, B.K. et al. Increased expression of extracellular matrix metalloproteinase inducer (CD147) in multiple myeloma: role in regulation of myeloma cell proliferation. Leukemia 26, 2286–2296 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Iacono, K.T., Brown, A.L., Greene, M.I. & Saouaf, S.J. CD147 immunoglobulin superfamily receptor function and role in pathology. Exp. Mol. Pathol. 83, 283–295 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Suzuki, J., Jin, Z.G., Meoli, D.F., Matoba, T. & Berk, B.C. Cyclophilin A is secreted by a vesicular pathway in vascular smooth muscle cells. Circ. Res. 98, 811–817 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Niu, H., Wang, R., Cheng, J., Gao, S. & Liu, B. Treatment of (131)I-labeled anti-CD147 monoclonal antibody in VX2 carcinoma-induced liver tumors. Oncol. Rep. 30, 246–252 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. McMillin, D.W. et al. Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity. Nat. Med. 16, 483–489 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sukhdeo, K. et al. Targeting the β-catenin/TCF transcriptional complex in the treatment of multiple myeloma. Proc. Natl. Acad. Sci. USA 104, 7516–7521 (2007).

    Article  PubMed  Google Scholar 

  39. Lanemo Myhrinder, A. et al. Molecular characterization of neoplastic and normal “sister” lymphoblastoid B-cell lines from chronic lymphocytic leukemia. Leuk. Lymphoma 54, 1769–1779 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Ditzel Santos, D. et al. Establishment of BCWM.1 cell line for Waldenstrom's macroglobulinemia with productive in vivo engraftment in SCID-hu mice. Exp. Hematol. 35, 1366–1375 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Zhao, J.J. et al. miR-30-5p functions as a tumor suppressor and novel therapeutic tool by targeting the oncogenic Wnt/β-catenin/BCL9 pathway. Cancer Res. 74, 1801–1813 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chng, W.J. et al. Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling. Cancer Res. 67, 2982–2989 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Peng, J. & Gygi, S.P. Proteomics: the move to mixtures. J. Mass Spectrom. 36, 1083–1091 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Levanon, K. et al. Primary ex vivo cultures of human fallopian tube epithelium as a model for serous ovarian carcinogenesis. Oncogene 29, 1103–1113 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Ficarro, S.B. et al. Improved electrospray ionization efficiency compensates for diminished chromatographic resolution and enables proteomics analysis of tyrosine signaling in embryonic stem cells. Anal. Chem. 81, 3440–3447 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references


R.D.C. is supported by a senior award from the Multiple Myeloma Research Foundation, by the Doctors Cancer Foundation, and by grants 1R01 CA151391-01 and 1P01 CA155258-01 from the National Institutes of Health. Human bone marrow–derived endothelial cell lines BMEC-60 and BMEC-1 were kindly provided by Dr. van der Schoot (University of Amsterdam, Amsterdam, the Netherlands) and Dr. Giuliani (University of Parma, Parma, Italy), respectively.

Author information

Authors and Affiliations



D.Z. performed most of the experiments, analyzed the data and prepared the manuscript; Z.W. performed ELISA studies and helped with immunoblots; J.M. planned and coordinated proteomic experiments; J.-J.Z. generated reagents; C.S.M. helped with scaffold experiments; S.B.F. performed total proteomic analysis; D.M. and C.S.M. helped with the design of cell-specific bioluminescence imaging experiments for myeloma–endothelial cell cocultures; D.M.D. selected subjects and analyzed CD147 expression by flow cytometry; T.H. performed the complement-dependent cytotoxicity assay; H.T. performed animal imaging; Y.K. performed proteomic analysis; G.P. performed immunohistochemistry studies; Y.-T.T., C.J.W., S.P.T., Z.H., M.F. and N.C.M. provided clinical samples and critically reviewed the manuscript; K.C.A. provided clinical samples and edited the manuscript; J.A.M. supervised the proteomic studies; P.T. and T.C. provided scaffolds, as well as technical and scientific assistance with scaffold experiments; and R.D.C. designed experiments, analyzed data and wrote the manuscript.

Corresponding author

Correspondence to Ruben D Carrasco.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 and Supplementary Tables 1–2 (PDF 2138 kb)

Source data

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, D., Wang, Z., Zhao, JJ. et al. The Cyclophilin A–CD147 complex promotes the proliferation and homing of multiple myeloma cells. Nat Med 21, 572–580 (2015).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research