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

Nature Medicine volume 21, pages 572–580 (2015)Cite this article

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Abstract

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.

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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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Di Zhu, Zhongqiu Wang, Jian-Jun Zhao, Jiang Meng, Teru Hideshima, Mariateresa Fulciniti, Yue Kang, Yu-Tzu Tai, Zachary Hunter, Douglas McMilin, Constantine S Mitsiades, Catherine J Wu, Steven P Treon, Nikhil C Munshi, Kenneth C Anderson & Ruben D Carrasco

  2. Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangdong, China

    Zhongqiu Wang

  3. Department of Experimental and Clinical Medicine, Magna Graecia University and Cancer Center, Catanzaro, Italy

    Teresa Calimeri & Pierfrancesco Tassone

  4. Fourth Affiliated Hospital of Harbin Medical University, Heilongjiang, China

    Jiang Meng

  5. Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Teru Hideshima, Mariateresa Fulciniti, Yu-Tzu Tai, Douglas McMilin, Nikhil C Munshi & Kenneth C Anderson

  6. Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Yue Kang

  7. Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Scott B Ficarro, Haoxuan Tong & Jarrod A Marto

  8. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

    Scott B Ficarro & Jarrod A Marto

  9. Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts, USA

    David M Dorfman, Geraldine Pinkus & Ruben D Carrasco

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Contributions

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.

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Correspondence to Ruben D Carrasco.

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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). https://doi.org/10.1038/nm.3867

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