Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction

P. Storti, M. Bolzoni, G. Donofrio, I. Airoldi, D. Guasco, D. Toscani, E. Martella, M. Lazzaretti, C. Mancini, L. Agnelli, K. Patrene, S. Maïga, V. Franceschi, S. Colla, J. Anderson, A. Neri, M. Amiot, F. Aversa, G. David Roodman, N. Giuliani

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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 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-1α 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-1α 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-1α. The effect of HIF-1α inhibition was assessed in vivo in nonobese diabetic/severe combined immunodeficiency mice both in a subcutaneous and an intratibial MM 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 vascular endothelial growth factors (VEGFs) immunostaining was observed. Finally, in the intratibial experiments, HIF-1α inhibition significantly blocked 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.

Original languageEnglish (US)
Pages (from-to)1697-1706
Number of pages10
JournalLeukemia
Volume27
Issue number8
DOIs
StatePublished - Aug 1 2013

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Keywords

  • angiogenesis
  • bone disease
  • hypoxia
  • mice
  • myeloma

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Storti, P., Bolzoni, M., Donofrio, G., Airoldi, I., Guasco, D., Toscani, D., Martella, E., Lazzaretti, M., Mancini, C., Agnelli, L., Patrene, K., Maïga, S., Franceschi, V., Colla, S., Anderson, J., Neri, A., Amiot, M., Aversa, F., David Roodman, G., & Giuliani, N. (2013). Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction. Leukemia, 27(8), 1697-1706. https://doi.org/10.1038/leu.2013.24