Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction.
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.
Hematology, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
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P
Storti
M
M
Bolzoni
G
G
Donofrio
I
I
Airoldi
D
D
Guasco
D
D
Toscani
E
E
Martella
M
M
Lazzaretti
C
C
Mancini
L
L
Agnelli
K
K
Patrene
S
S
Maïga
V
V
Franceschi
S
S
Colla
J
J
Anderson
A
A
Neri
M
M
Amiot
F
F
Aversa
G David
GD
Roodman
N
N
Giuliani
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D010014:Osteolysis / Q000235:genetics* / Q000473:pathology*; D047368:Tumor Burden / Q000235:genetics
D051795:Hypoxia-Inducible Factor 1, alpha Subunit