Hypoxia-inducible transcription factor-1 (HIF-1a) is overexpressed in multiple myeloma (MM) cells within the hypoxic microenvironment. Herein, we explored the effect of persistent HIF-1a 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-1a 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-1a 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-1a. The effect of HIF-1a inhibition was assessed in vivo in nonobese diabetic/severe combined immunodeficiency mice both in a subcutaneous and an intratibial MM model. HIF-1a 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-1a inhibition significantly blocked bone destruction. Overall, our data indicate that HIF-1a suppression in MM cells significantly blocks MM-induced angiogenesis and reduces MM tumor burden and bone destruction in vivo, supporting HIF-1a as a potential therapeutic target in MM.

Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction / Storti, Paola; Bolzoni, Marina; Donofrio, Gaetano; Airoldi, I; Guasco, D; Toscani, Denise; Martella, E; Lazzaretti, Mirca; Mancini, C; Agnelli, L; Patrene, K; Maïga, S; Franceschi, V; Colla, S; Anderson, J; Neri, A; Amiot, M; Aversa, Franco; David Roodman, G; Giuliani, Nicola. - In: LEUKEMIA. - ISSN 0887-6924. - 27:(2013), pp. 1697-1706. [10.1038/leu.2013.24]

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

STORTI, Paola;BOLZONI, Marina;DONOFRIO, Gaetano;TOSCANI, Denise;LAZZARETTI, Mirca;AVERSA, Franco;GIULIANI, Nicola
2013-01-01

Abstract

Hypoxia-inducible transcription factor-1 (HIF-1a) is overexpressed in multiple myeloma (MM) cells within the hypoxic microenvironment. Herein, we explored the effect of persistent HIF-1a 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-1a 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-1a 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-1a. The effect of HIF-1a inhibition was assessed in vivo in nonobese diabetic/severe combined immunodeficiency mice both in a subcutaneous and an intratibial MM model. HIF-1a 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-1a inhibition significantly blocked bone destruction. Overall, our data indicate that HIF-1a suppression in MM cells significantly blocks MM-induced angiogenesis and reduces MM tumor burden and bone destruction in vivo, supporting HIF-1a as a potential therapeutic target in MM.
2013
Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction / Storti, Paola; Bolzoni, Marina; Donofrio, Gaetano; Airoldi, I; Guasco, D; Toscani, Denise; Martella, E; Lazzaretti, Mirca; Mancini, C; Agnelli, L; Patrene, K; Maïga, S; Franceschi, V; Colla, S; Anderson, J; Neri, A; Amiot, M; Aversa, Franco; David Roodman, G; Giuliani, Nicola. - In: LEUKEMIA. - ISSN 0887-6924. - 27:(2013), pp. 1697-1706. [10.1038/leu.2013.24]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2579848
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