Low bone marrow oxygen tension and hypoxia-inducible factor-1α overexpression characterize patients with multiple myeloma: role on the transcriptional and proangiogenic profiles of CD138+ cells

Colla, Simona; Storti, Paola; Donofrío, Gaetano; Todoerti, Katia; Bolzoni, Marina; Lazzaretti, Mirca; Abeltino, Manuela; Ippolito, Luigi; Neri, Antonino; Ribatti, Doménico; Rizzoli, Vittorio; Martella, Eugenia; Giuliani, Nicola

doi:10.1038/leu.2010.193

Cited by 111 publications

(137 citation statements)

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“…Finally, other genes with pro-angiogenic properties, such as IL10 and CCL5, were inhibited by HIF-1a suppression in JJN3 under both normoxic and hypoxic conditions (Supplementary Table S1). Consistent with our previous observation on small interfering RNA-mediated HIF-1a inhibition, 27 stable HIF-1a suppression by shRNA significantly blunted vessels formation induced by the conditioned media of HMCLs as Targeting HIF-1a in multiple myeloma in vivo P Storti et al determined by AngioKit (TCS Biologies, London, UK) (data not shown).…”

Section: Resultssupporting

confidence: 91%

“…22,23 Interestingly a critical role of HIF-1a in osteoclast formation and regulation has been shown 24,25 as well as its role in the development of osteolytic metastasis in breast cancer model. 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.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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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.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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“…As shown in Figure 3, either exposure to the hypoxic mimetic lactic acid (3 mmol/L or 10 mmol/L) or hypoxia (1% O 2 ) induced a time‐dependent expression of HIF‐1α and HIF‐1β, accompanied by NF‐κB activation (reflected by upregulation of TRAF2, a key component of the NF‐κB pathway,37 and S536 phosphorylation of p65, catalyzed by activated IKK‐β 30) in H929 (Figure 3A,B), RPMI8226 (Figure 3C,D), and U266 cells (Figure S3A). However, treatment with CoCl 2 , a chemical approach widely used to mimic hypoxia, failed to induce either HIF‐1β expression or NF‐κB activation in MM cells, while resulted in HIF‐1α accumulation (Figure S3B), presumably due to blockade of its degradation 13, 38. These results indicate that hypoxia (eg, low O 2 concentration or the chemical mimetic lactic acid, but not CoCl 2 ) is able to induce ARNT /HIF‐1β expression and NF‐κB activation in MM cells, suggesting a potential role of HIF‐1β and its relationship with NF‐κB in hypoxic MM microenvironment.…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Yang

Liu

et al. 2018

Cancer Medicine

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Abstract1q21 gain is a common cytogenetic abnormality featuring high‐risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF‐1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival. In a cohort of 40 MM patients, qPCR further validated that ARNT expression was higher in MM patients than normal donors. MM cells carrying 1q21 gain or acquired drug resistance displayed a robust increase in HIF‐1β protein level. Hypoxia induced HIF‐1β expression via a NF‐κB‐dependent process. Notably, HIF‐1β overexpression impaired bortezomib sensitivity, whereas shRNA knockdown of ARNT reversed hypoxia‐mediated drug resistance. Together, these findings suggest that ARNT/HIF‐1β might represent a novel biomarker for risk stratification and prognosis of HRMM patients, as well as a potential therapeutic target for overcoming 1q21 gain‐ or microenvironment‐mediated and acquired drug resistance in MM.

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Understanding the Bone in Cancer Metastasis

Fornetti

Welm

Stewart

2018

Journal of Bone and Mineral Research

351

225

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The bone is the third most common site of metastasis for a wide range of solid tumors including lung, breast, prostate, colorectal, thyroid, gynecologic, and melanoma, with 70% of metastatic prostate and breast cancer patients harboring bone metastasis. (1) Unfortunately, once cancer spreads to the bone, it is rarely cured and is associated with a wide range of morbidities including pain, increased risk of fracture, and hypercalcemia. This fact has driven experts in the fields of bone and cancer biology to study the bone, and has revealed that there is a great deal that each can teach the other. The complexity of the bone was first described in 1889 when Stephen Paget proposed that tumor cells have a proclivity for certain organs, where they "seed" into a friendly "soil" and eventually grow into metastatic lesions. Dr. Paget went on to argue that although many study the "seed" it would be paramount to understand the "soil." Since this original work, significant advances have been made not only in understanding the cell-autonomous mechanisms that drive metastasis, but also alterations which drive changes to the "soil" that allow a tumor cell to thrive. Indeed, it is now clear that the "soil" in different metastatic sites is unique, and thus the mechanisms that allow tumor cells to remain in a dormant or growing state are specific to the organ in question. In the bone, our knowledge of the components that contribute to this fertile "soil" continues to expand, but our understanding of how they impact tumor growth in the bone remains in its infancy. Indeed, we now appreciate that the endosteal niche likely contributes to tumor cell dormancy, and that osteoclasts, osteocytes, and adipocytes can impact tumor cell growth. Here, we discuss the bone microenvironment and how it impacts cancer cell seeding, dormancy, and growth. Fig. 1. Tumor cells closely associate with cells of the bone microenvironment in a mouse model of bone metastasis. Scale bar ¼ 50 mm. Ad ¼ adipocyte; EC ¼ endothelial cell; Oc ¼ osteocyte; Ocl ¼ osteoclast; Tu ¼ tumor.

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Low bone marrow oxygen tension and hypoxia-inducible factor-1α overexpression characterize patients with multiple myeloma: role on the transcriptional and proangiogenic profiles of CD138+ cells

Cited by 111 publications

References 12 publications

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

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

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

Understanding the Bone in Cancer Metastasis

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