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Multiple Myeloma, Gammopathies

Targeting vasculogenesis to prevent progression in multiple myeloma

Leukemia volume 30, pages 1103–1115 (2016)Cite this article

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Abstract

The role of endothelial progenitor cell (EPC)-mediated vasculogenesis in hematological malignancies is not well explored. Here, we showed that EPCs are mobilized from the bone marrow (BM) to the peripheral blood at early stages of multiple myeloma (MM); and recruited to MM cell-colonized BM niches. Using EPC-defective ID1+/− ID3−/− mice, we found that MM tumor progression is dependent on EPC trafficking. By performing RNA-sequencing studies, we confirmed that endothelial cells can enhance proliferation and favor cell-cycle progression only in MM clones that are smoldering-like and have dependency on endothelial cells for tumor growth. We further confirmed that angiogenic dependency occurs early and not late during tumor progression in MM. By using a VEGFR2 antibody with anti-vasculogenic activity, we demonstrated that early targeting of EPCs delays tumor progression, while using the same agent at late stages of tumor progression is ineffective. Thus, although there is significant angiogenesis in myeloma, the dependency of the tumor cells on EPCs and vasculogenesis may actually precede this step. Manipulating vasculogenesis at an early stage of disease may be examined in clinical trials in patients with smoldering MM, and other hematological malignancies with precursor conditions.

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Acknowledgements

We wish to thank the Animal Research Facility (ARF) team of the Dana Farber Cancer Institute for the valuable technical support. We thank Dr Benezra R (Memorial Sloan–Kettering Institute, NY, USA) for providing us the ID1/ID3 transgenic mice. We thank Sonal Jhaveri (PGSAO, Dana Farber Cancer Institute) for editing the manuscript. We thank Eli Lilly & Co. for providing the DC101 antibody. This work was supported by NIH R01 CA181683-01A1 and the Leukemia and Lymphoma Society. This work was supported by Associazione Italiana per la Ricerca sul Cancro, AIRC 5 × 1000 Molecular Clinical Oncology Special Program, Milan, IT (grant no. 9965 to M Bellone and A Vacca). Arianna Calcinotto was awarded a fellowship from AIRC/FIRC and conducted this study in partial fulfillment of her PhD at San Raffaele University.

Author contributions

MM and IMG contributed to conception and design. YM, YK, BP, LP, YA, AC, CU, IS, AS, SG, JS, MRR and SM contributed to acquisition of data. MM, YM, YK, AMR and IMG contributed to analysis and interpretation of data. MM, MB, MC, FP, PLB, AMR and IMG contributed to writing, review and/or revision of the manuscript.

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Authors and Affiliations

  1. Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA

    M Moschetta, Y Mishima, Y Kawano, S Manier, Y Aljawai, I Sahin, A Sacco, S Glavey, M R Reagan, A M Roccaro & I M Ghobrial

  2. University of Bari Medical School, Bari, Italy

    M Moschetta & A Vacca

  3. Clinica Universidad de Navarra, Centro de Investigaciones Medicas Aplicadas (CIMA), Pamplona, Spain

    B Paiva & F Prosper

  4. Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain

    L Palomera

  5. Cellular Immunology Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy

    A Calcinotto & M Bellone

  6. Dana Farber/Harvard Cancer Center, Boston, MA, USA

    C Unitt

  7. Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA

    J Shi

  8. Maine Medical Center Research Institute, Scarborough, ME, USA

    M R Reagan

  9. Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ, USA

    M Chesi & L P Bergsagel

  10. Department of Hematology, Spedali Civili di Brescia, Centro Ricerca Emato-oncologica AIL (CREA), Brescia, Italy

    A M Roccaro

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  1. M Moschetta
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Correspondence to A M Roccaro or I M Ghobrial.

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Moschetta, M., Mishima, Y., Kawano, Y. et al. Targeting vasculogenesis to prevent progression in multiple myeloma. Leukemia 30, 1103–1115 (2016). https://doi.org/10.1038/leu.2016.3

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