Targeting vasculogenesis to prevent progression in multiple myeloma
Moschetta M (1,2), Mishima Y (1), Kawano Y (1), Manier S (1), Paiva B (3), Palomera L (4), Aljawai Y (1), Calcinotto A (5), Unitt C (6), Sahin I (1), Sacco A (1), Glavey S (1), Shi J (7, Reagan MR (1), Prosper F (3), Bellone M (5), Chesi M (8), Bergsagel LP (8), Vacca A (2), Roccaro AM (1), Ghobrial IM (1).
(1) Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
(2) University of Bari Medical School, Bari, Italy.
(3) Clinica Universidad de Navarra; Centro de Investigaciones Medicas Aplicadas (CIMA), Pamplona, Spain.
(4) Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain.
(5) Cellular Immunology Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy.
(6) Dana Farber/Harvard Cancer Center.
(7) Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.
(8) Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ, USA.
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.
CITA DEL ARTÍCULO Leukemia. 2016 Feb 3. doi: 10.1038/leu.2016.3.