TY - JOUR
T1 - HIF-1a of bone marrow endothelial cells implies relapse and drug resistance in patients with multiple myeloma and may act as a therapeutic target
AU - Ria, Roberto
AU - Catacchio, Ivana
AU - Berardi, Simona
AU - De Luisi, Annunziata
AU - Caivano, Antonella
AU - Piccoli, Claudia
AU - Ruggieri, Vitalba
AU - Frassanito, Maria Antonia
AU - Ribatti, Domenico
AU - Nico, Beatrice
AU - Annese, Tiziana
AU - Ruggieri, Simona
AU - Guarini, Attilio
AU - Minoia, Carla
AU - Ditonno, Paolo
AU - Angelucci, Emanuele
AU - Derudas, Daniele
AU - Moschetta, Michele
AU - Dammacco, Franco
AU - Vacca, Angelo
PY - 2014
Y1 - 2014
N2 - Purpose: To investigate the role of hypoxia-inducible factor-1a (HIF-1a) in angiogenesis and drug resistance of bone marrow endothelial cells of patients with multiple myeloma. Experimental Design: HIF-1a mRNA and protein were evaluated in patients with multiple myeloma endothelial cells (MMEC) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies or on refractory phase to these drugs, at remission; in endothelial cells of patients with monoclonal gammapathies of undetermined significance (MGUS; MGECs), and of those with benign anemia (controls). The effects of HIF-1a inhibition by siRNA or panobinostat (an indirect HIF-1a inhibitor) on the expression of HIF-1a proangiogenic targets, on MMEC angiogenic activities in vitro and in vivo, and on overcoming MMEC resistance to bortezomib and lenalidomide were studied. The overall survival of the patients was also observed. Results: Compared with the other endothelial cell types, only MMECs from 45% of relapsed/refractory patients showed a normoxic HIF-1a protein stabilization and activation that were induced by reactive oxygen species (ROS). The HIF-1a protein correlated with the expression of its proangiogenic targets. The HIF-1a inhibition by either siRNA or panobinostat impaired the MMECs angiogenesis-related functions both in vitro and in vivo and restored MMEC sensitivity to bortezomib and lenalidomide. Patients with MMECs expressing the HIF-1a protein had shorter overall survival. Conclusions: The HIF-1a protein in MMECs may induce angiogenesis and resistance to bortezomib and lenalidomide and may be a plausible target for the antiangiogenic management of patients with well-defined relapsed/ refractorymultiplemyeloma. Itmay also have prognostic significance.
AB - Purpose: To investigate the role of hypoxia-inducible factor-1a (HIF-1a) in angiogenesis and drug resistance of bone marrow endothelial cells of patients with multiple myeloma. Experimental Design: HIF-1a mRNA and protein were evaluated in patients with multiple myeloma endothelial cells (MMEC) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies or on refractory phase to these drugs, at remission; in endothelial cells of patients with monoclonal gammapathies of undetermined significance (MGUS; MGECs), and of those with benign anemia (controls). The effects of HIF-1a inhibition by siRNA or panobinostat (an indirect HIF-1a inhibitor) on the expression of HIF-1a proangiogenic targets, on MMEC angiogenic activities in vitro and in vivo, and on overcoming MMEC resistance to bortezomib and lenalidomide were studied. The overall survival of the patients was also observed. Results: Compared with the other endothelial cell types, only MMECs from 45% of relapsed/refractory patients showed a normoxic HIF-1a protein stabilization and activation that were induced by reactive oxygen species (ROS). The HIF-1a protein correlated with the expression of its proangiogenic targets. The HIF-1a inhibition by either siRNA or panobinostat impaired the MMECs angiogenesis-related functions both in vitro and in vivo and restored MMEC sensitivity to bortezomib and lenalidomide. Patients with MMECs expressing the HIF-1a protein had shorter overall survival. Conclusions: The HIF-1a protein in MMECs may induce angiogenesis and resistance to bortezomib and lenalidomide and may be a plausible target for the antiangiogenic management of patients with well-defined relapsed/ refractorymultiplemyeloma. Itmay also have prognostic significance.
UR - http://www.scopus.com/inward/record.url?scp=84896734974&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84896734974&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-13-1950
DO - 10.1158/1078-0432.CCR-13-1950
M3 - Article
C2 - 24297864
AN - SCOPUS:84896734974
VL - 20
SP - 847
EP - 858
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 4
ER -