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

来自 EBSCO

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作者：

P Storti，M Bolzoni，G Donofrio，I Airoldi，N Giuliani

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摘要：

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 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 anti-proliferative effect of lenalidomide. On the other hand we found that HIF-1α inhibition in MM cells down-regulates 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 NOD/SCID 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 VEGF immunostaining was observed. Finally, in the intra-tibial 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.Leukemia accepted article preview online, 24 January 2013; doi:10.1038/leu.2013.24.

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关键词：

MULTIPLE-MYELOMA MARROW ANGIOGENESIS ENDOTHELIAL-CELLS EXPRESSION CANCER INTERLEUKIN-6 PROGRESSION HIF-1-ALPHA DISEASE FACTOR-1-ALPHA