Journal
LEUKEMIA
Volume 27, Issue 8, Pages 1697-1706Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2013.24
Keywords
myeloma; angiogenesis; bone disease; hypoxia; mice
Categories
Funding
- International Myeloma Foundation
- Associazione Italiana per la Ricerca sul Cancro A.I.R.C [8530, IG4569, IG2009, 13018]
- Special Program Molecular Clinical Oncology [9965, 9980]
- Multiple Myeloma Research Foundation
- Veterans Administration
- [R01 AR059679]
- [R21 CA141426]
- [R01AR057308]
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Hypoxia-inducible transcription factor-1 (HIF-1 alpha) is overexpressed in multiple myeloma (MM) cells within the hypoxic microenvironment. Herein, we explored the effect of persistent HIF-1 alpha inhibition by a lentivirus short hairpin RNA pool on MM cell growth either in vitro or in vivo and on the transcriptional and pro-angiogenic profiles of MM cells. HIF-1 alpha suppression did not have a significant impact on MM cell proliferation and survival in vitro although, increased the antiproliferative effect of lenalidomide. On the other hand, we found that HIF-1 alpha inhibition in MM cells downregulates the pro-angiogenic genes VEGF, IL8, IL10, CCL2, CCL5 and MMP9. Pro-osteoclastogenic cytokines were also inhibited, such as IL-7 and CCL3/MIP-1 alpha. The effect of HIF-1 alpha inhibition was assessed in vivo in nonobese diabetic/severe combined immunodeficiency mice both in a subcutaneous and an intratibial MM model. HIF-1 alpha 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 vascular endothelial growth factors (VEGFs) immunostaining was observed. Finally, in the intratibial experiments, HIF-1 alpha inhibition significantly blocked bone destruction. Overall, our data indicate that HIF-1 alpha suppression in MM cells significantly blocks MM-induced angiogenesis and reduces MM tumor burden and bone destruction in vivo, supporting HIF-1 alpha as a potential therapeutic target in MM.
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