Targeting Angiogenesis via a c-Myc/Hypoxia-Inducible Factor-1α–Dependent Pathway in Multiple Myeloma

Abstract

Bone marrow angiogenesis is associated with multiple myeloma (MM) progression. Here, we report high constitutive hypoxia-inducible factor-1α (Hif-1α) expression in MM cells, which is associated with oncogenic c-Myc. A drug screen for anti-MM agents that decrease Hif-1α and c-Myc levels identified a variety of compounds, including bortezomib, lenalidomide, enzastaurin, and adaphostin. Functionally, based on transient knockdowns and overexpression, our data delineate a c-Myc/Hif-1α-dependent pathway mediating vascular endothelial growth factor production and secretion. The antiangiogenic activity of our tool compound, adaphostin, was subsequently shown in a zebrafish model and translated into a preclinical in vitro and in vivo model of MM in the bone marrow milieu. Our data, therefore, identify Hif-1α as a novel molecular target in MM and add another facet to anti-MM drug activity. [Cancer Res 2009;69(12):5082-90]

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

“…[16][17][18]22 HIF-1a is overexpressed in many tumors 22,23 including some hematological malignancies such as MM. [27][28][29]35 We and others 27,35 have recently shown that BM microenvironment is hypoxic both in MM patients 27 and in mice. 35 In addition HIF-1a also may be overexpressed by MM cells under normoxic conditions 27,28 dependent at least in part on c-myc upregulation.…”

“…[27][28][29]35 We and others 27,35 have recently shown that BM microenvironment is hypoxic both in MM patients 27 and in mice. 35 In addition HIF-1a also may be overexpressed by MM cells under normoxic conditions 27,28 dependent at least in part on c-myc upregulation. 27 Finally, it has been reported that hypoxia modulates the expression of proangiogenic genes such as VEGF and IL-8 27 by MM cells, and that HIF-1a is involved in MM-induced angiogenesis in vitro.…”

“…In this context, it has been recently reported that adaphostin inhibits HIF-1a expression and induces a significant antiangiogenic and anti-MM activity in a MM xenograft mouse model. 28 Furthermore, a growing number of novel anticancer agents have been demonstrated to inhibit HIF-1a with different molecular mechanisms including histone deacetylases, molecules acting on RAS-RAK-MEK-ERK pathways and PI3K-AKT, and mTOR inhibitors, that are also currently in phase I-II clinical trials in MM. 1,29 Overall, our study provides the rationale for clinical trial with selective inhibitors of HIF-1a mRNA, such as EZN-2968 50 in MM patients.…”

“…26 Recently it has been demonstrated that the BM microenvironment is hypoxic in MM patients 27 and that HIF-1a is overexpressed by MM cells, and modulates their transcriptional and pro-angiogenic profiles. [27][28][29] Moreover, the role of hypoxia in tumor progression and dissemination has been demonstrated in MM mouse models. 30,31 These findings suggest that hypoxia could be a target in MM.…”

Angiogenesis and Multiple Myeloma

“…Interestingly, the presence of HIF-1α protein was also observed in CD138 + purified cells of about 28% of MM patients analyzed under normoxic conditions [112], suggesting that hypoxiaindependent stabilization of HIF-1α may occur in myeloma cells together with HIF-1α over-expression induced by the hypoxic microenvironment. Others also reported that myeloma cells express HIF-1α in normoxia, showing that constitutive expression of HIF-1α by myeloma cells is associated with oncogenic c-Myc, delineating a common signaling pathway in myeloma cells [115].…”