HIF-2α-ILK Is Involved in Mesenchymal Stromal Cell Angiogenesis in Multiple Myeloma Under Hypoxic Conditions

Abstract

Mesenchymal stromal cells are proven to be likely induce the angiogenic response in multiple myeloma and thus represent an enticing target for antiangiogenesis therapies for multiple myeloma. Substantial evidence indicates that angiogenesis in multiple myeloma is complex and involves direct production of angiogenic cytokines by abnormal plasma cells and these B-cell neoplasia generated pathophysiology change within the microenvironment. In this study, we demonstrated that mesenchymal stromal cells cultured with U266/Lp-1 under hypoxic conditions resulted in an increased α-smooth muscle actin expression and high productive levels of both hypoxia-inducible factor-2α and integrin-linked kinase proteins. Moreover, inhibition of hypoxia-inducible factor-2α by Small interfering RNA (siRNA) in mesenchymal stromal cells decreased the protein levels of both α-smooth muscle actin and integrin-linked kinase after mesenchymal stromal cells cultured with U266 under hypoxic conditions. We further demonstrated that transfection of integrin-linked kinase-siRNA reduced the protein level of α-smooth muscle actin and attenuated angiogenesis in vitro by decreasing the attachment of Q-dot labeled cells and secretion of angiogenic factors. In conclusion, our research showed that mesenchymal stromal cells cultured with myeloma cells under hypoxia participated in the angiogenesis of multiple myeloma, which is regulated by the hypoxia-inducible factor-2α-integrin-linked kinase pathway. Thus, targeting integrin-linked kinase may represent an effective strategy to block hypoxia-inducible factor-2α-induced angiogenesis in the treatment of multiple myeloma.

Next-Generation Biomarkers in Multiple Myeloma: Understanding the Molecular Basis for Potential Use in Diagnosis and Prognosis

“…Mesenchymal stromal cells are non-hematopoietic multipotent cells that play an important role in MM development and progression via coordinating cellular migration and enhancing angiogenesis [ 42 ]. The stromal cells cultured with MM cell lines (U266/Lp-1) under hypoxic conditions were associated with a rise in α-smooth muscle actin, hypoxia-inducible factor (HIF)-2α and integrin-linked kinase proteins, indicating their role as potential angiogenic markers [ 43 ]. Interestingly, the inhibition of HIF-2α reduced both α-smooth muscle actin and integrin-linked kinase, resulting in attenuating angiogenesis in vitro.…”

“…Interestingly, the inhibition of HIF-2α reduced both α-smooth muscle actin and integrin-linked kinase, resulting in attenuating angiogenesis in vitro. Mechanistically, the HIF-2α released by stromal cells promotes angiogenesis via increasing the attachment of Q-dot labeled cells and the excretion of angiogenic factors [ 43 ]. Along with the role of these angiogenic markers in the diagnosis/prognosis of MM, they represent possible drug targets.…”