title: Targeting vasculogenesis to prevent progression in multiple myeloma.
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.
authors: Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.|University of Bari Medical School, Bari, Italy.
authors: M
authors: M
authors: Moschetta
authors: Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: Y
authors: Y
authors: Mishima
authors: Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: Y
authors: Y
authors: Kawano
authors: Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: S
authors: S
authors: Manier
authors: Clinica Universidad de Navarra, Centro de Investigaciones Medicas Aplicadas (CIMA), Pamplona, Spain.
authors: B
authors: B
authors: Paiva
authors: Hospital Clinico Universitario Lozano Blesa, Zaragoza. Spain.
authors: L
authors: L
authors: Palomera
authors: Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: Y
authors: Y
authors: Aljawai
authors: Cellular Immunology Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors: A
authors: A
authors: Calcinotto
authors: Dana Farber/Harvard Cancer Center, Boston, MA, USA.
authors: C
authors: C
authors: Unitt
authors: Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: I
authors: I
authors: Sahin
authors: Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: A
authors: A
authors: Sacco
authors: Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: S
authors: S
authors: Glavey
authors: Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.
authors: J
authors: J
authors: Shi
authors: Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.|Maine Medical Center Research Institute, Scarborough, ME, USA.
authors: M R
authors: MR
authors: Reagan
authors: Clinica Universidad de Navarra, Centro de Investigaciones Medicas Aplicadas (CIMA), Pamplona, Spain.
authors: F
authors: F
authors: Prosper
authors: Cellular Immunology Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy.
authors: M
authors: M
authors: Bellone
authors: Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ, USA.
authors: M
authors: M
authors: Chesi
authors: Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ, USA.
authors: L P
authors: LP
authors: Bergsagel
authors: University of Bari Medical School, Bari, Italy.
authors: A
authors: A
authors: Vacca
authors: Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.|Spedali Civili di Brescia, Centro Ricerca Emato-oncologica AIL (CREA), Department of Hematology, Brescia, Italy.
authors: A M
authors: AM
authors: Roccaro
authors: Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: I M
authors: IM
authors: Ghobrial
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D001853:Bone Marrow; D002465:Cell Movement; D002999:Clone Cells / Q000473:pathology; D018450:Disease Progression; D042783:Endothelial Cells / Q000473:pathology; D051379:Mice; D009101:Multiple Myeloma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000517:prevention & control; D055502:Secondary Prevention; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology
chemical_list: D000906:Antibodies; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2