Hypoxia-inducible factor (HIF)-1 alpha as a therapeutical target in myeloma induced angiogenesis and bone destruction in vitro and in vivo

Abstract

Hypoxia-inducible transcription factor-1 (HIF-1α) is overexpressed in multiple myeloma (MM) cells within the hypoxic microenvironment. Herein we explored the effect of persistent HIF-1α inhibition by a lentivirus shRNA pool on proliferation, survival and transcriptional and pro-angiogenic profiles of MM cells either in vitro or in vivo in mouse models. Among the significantly modulated genes (326 and 361 genes in hypoxic and normoxic condition, respectively), we found that HIF-1α inhibition in MM cells down-regulates the pro-angiogenic molecules VEGF, IL8, IL10, CCL2, CCL5 and MMP9. Interestingly, pro-osteoclastogenic cytokines were also inhibited, such as IL-7 and CCL3/MIP-1α. The effect of HIF-1α inhibition on a human myeloma cell line was assessed in vivo in NOD/SCID mice both in a subcutaneous and an intratibial model. HIF-1α inhibition caused a dramatic reduction in the weight and volume of the tumor burden in both mouse models. Moreover, a significant reduction of the number of vessels and VEGF immunostaining was observed. Finally, in the intra-tibial experiments HIF-1α inhibition significantly blocked JJN3-induced bone destruction. Overall our data indicate that HIF-1α suppression in MM cells significantly blocks MM-induced angiogenesis and reduces MM tumor burden and bone destruction in vivo, supporting HIF-1α as a potential therapeutic target in MM.