The emerging role of hypoxia, HIF-1 and HIF-2 in multiple myeloma

Abstract

Hypoxia is an imbalance between oxygen supply and demand, which deprives cells or tissues of sufficient oxygen. It is wellestablished that hypoxia triggers adaptive responses, which contribute to short-and long-term pathologies such as inflammation, cardiovascular disease and cancer. Induced by both microenvironmental hypoxia and genetic mutations, the elevated expression of the hypoxia-inducible transcription factor-1 (HIF-1) and HIF-2 is a key feature of many human cancers and has been shown to promote cellular processes, which facilitate tumor progression. In this review, we discuss the emerging role of hypoxia and the HIFs in the pathogenesis of multiple myeloma (MM), an incurable hematological malignancy of BM PCs, which reside within the hypoxic BM microenvironment. The need for current and future therapeutic interventions to target HIF-1 and HIF-2 in myeloma will also be discussed.

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

“…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.…”

“…[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.…”

“…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.…”

ARNT/HIF‐1β links high‐risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

“…HIF is a heterodimeric complex composed of one α (eg, HIF‐1α or HIF‐2α) and one β‐subunit (HIF‐1β) 11. MM microenvironment is featured by hypoxia naturally existing in bone marrow niches where MM cells reside, which plays a critical role in MM cell survival, growth, metabolism, drug resistance, and angiogenesis, etc 13, 14, 15. To date, the studies of hypoxia in cancer (including MM) have focused almost exclusively on HIF‐1α, while the role of HIF‐1β remains a little known.…”

HIF-1α and rapamycin act as gerosuppressant in multiple myeloma cells upon genotoxic stress

“…25 Under hypoxic conditions, cells express the transcription factor HIF-1a, which has been shown to sensitize cells to genotoxic stress. 26 We tested if HIF-1a expression could overcome genotoxic stress resistance in 8226 cells.…”