HIF-1α of Bone Marrow Endothelial Cells Implies Relapse and Drug Resistance in Patients with Multiple Myeloma and May Act as a Therapeutic Target

Abstract

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/refractory multiple myeloma. It may also have prognostic significance. Clin Cancer Res; 20(4); 847-58. Ó2013 AACR.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Assessment of Antiangiogenic Treatment Effects in Multiple Myeloma

“…Therefore, DCE-MRI before the start of therapy might have predictive and prognostic implications. This assumption is supported by a recent study, which demonstrated that proangiogenic factors lead to drug resistance and relapse in patients with multiple myeloma (28).…”

A HGF/cMET Autocrine Loop Is Operative in Multiple Myeloma Bone Marrow Endothelial Cells and May Represent a Novel Therapeutic Target

“…Gels were silver stained and analyzed on PDQuest software (Bio-Rad; ref. 21). Spots of interest were excised, destained, dehydrated in acetonitrile, and digested with trypsin.…”

Different Adaptive Responses to Hypoxia in Normal and Multiple Myeloma Endothelial Cells

“…Indeed, MM endothelial cells (MMEC) play a crucial role in MM progression and HIF-1α protein is reported to be expressed constitutively and activated in MMEC in a well-defined proportion of patients experiencing relapse or refractory to treatment. More importantly, patients with MMEC expressing the HIF-1α protein have shorter overall survival [15]. …”

“…Although the pro-angiogenic role of HIF-1α has already been established in MM [15, 16], to our knowledge no studies have documented MMEC adaptive response to hypoxia in terms of survival, apoptosis and/or autophagy. We therefore decided to investigate and compare the effects of hypoxia on bone marrow EC of active multiple myeloma patients and on healthy quiescent EC, namely human umbilical vein EC (HUVEC).…”