Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients

Colla, Simona; Morandi, Francesca; Lazzaretti, Mirca; Rizzato, Rita; Lunghi, Paolo; Bonomini, Sabrina; Mancini, Cristina; Pedrazzoni, M.; Crugnola, Monica; Rizzoli, Vittorio; Giuliani, Nicola

doi:10.1038/sj.leu.2403976

Cited by 63 publications

(69 citation statements)

References 38 publications

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“…In an in vitro model of angiogenesis, OPN-immunodepleted CM from myeloma cells failed to induce a proangiogenic effect and an anti-OPN Ab blocked myelomainduced angiogenesis [74]. These observations support the potential role of OPN as a direct pro-angiogenic factor in MM.…”

Section: Matrix Metalloproteinasessupporting

confidence: 62%

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Angiogenesis and Multiple Myeloma

Giuliani

Storti

Bolzoni

et al. 2011

Cancer Microenvironment

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The bone marrow microenvironment in multiple myeloma is characterized by an increased microvessel density. The production of pro-angiogenic molecules is increased and the production of angiogenic inhibitors is suppressed, leading to an "angiogenic switch". Here we present an overview of the role of angiogenesis in multiple myeloma, the pro-angiogenic factors produced by myeloma cells and the microenvironment, and the mechanisms involved in the myeloma-induced angiogenic switch. Current data suggest that the increased bone marrow angiogenesis in multiple myeloma is due to the aberrant expression of angiogenic factors by myeloma cells, the subsequent increase in pro-angiogenic activity of normal plasma cells as a result of myeloma cell angiogenic activity, and the increased number of plasma cells overall. Hypoxia also contributes to the angiogenic properties of the myeloma marrow microenvironment. The transcription factor hypoxia-inducible factor-1α is overexpressed by myeloma cells and affects their transcriptional and angiogenic profiles. In addition, potential roles of the tumor suppressor gene inhibitor of growth family member 4 and homeobox B7 have also been recently highlighted as repressors of angiogenesis and pro-angiogenic related genes, respectively. This complex pathogenetic model of myeloma-induced angiogenesis suggests that several proangiogenic molecules and related genes in myeloma cells and the microenvironment are potential therapeutic targets.

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Section: Matrix Metalloproteinasessupporting

confidence: 62%

“…OPN expression by myeloma cells was also correlated with increased BM angiogenesis in MM patients. In particular, it has been demonstrated that OPN positive MM patients have a significantly higher MVD and number of microvessels per field as compared to OPN negative patients [74].…”

Section: Relationship Between Angiogenic Factors and Bm Angiogenesis mentioning

confidence: 99%

Angiogenesis and Multiple Myeloma

Giuliani

Storti

Bolzoni

et al. 2011

Cancer Microenvironment

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“…[2][3][4][5][6][7][8] The angiogenic switch in MM is mainly sustained by the overproduction of vascular endothelial growth factors (VEGFs) by MM cells and the BM microenvironment. 2,9,10 Other proangiogenic molecules, such as basic fibroblast growth factor, 11,12 interleukin-8 (IL-8), 13 angiopoietin-1 14 and osteopontin 15 are involved in the pro-angiogenic process. Hypoxia is a common feature of solid tumors and is associated with angiogenesis and malignant phenotype.…”

Section: Introductionmentioning

confidence: 99%

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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“…Runt-related transcription factor-2 regulation and transcriptional activity are linked with increased growth, invasion, and metastasis in breast cancer (Barnes et al, 2003), prostate cancer (Brubaker et al, 2003;Pratap et al, 2005), colorectal cancer (Wai et al, 2006), lymphoma, leukaemia and myeloma (Wotton et al, 2002;Castilla et al, 2004;Colla et al, 2005;Blyth et al, 2006).…”

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confidence: 99%

Regulation and functional role of the Runt-related transcription factor-2 in pancreatic cancer

et al. 2007

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Recent evidence suggests that Runt-related transcription factors play a role in different human tumours. In the present study, the localisation of the Runt-related transcription factor-2 (Runx2), its transcriptional activity, as well as its regulation of expression was analysed in human pancreatic ductal adenocarcinoma (PDAC). Quantitative real-time PCR and immunohistochemistry were used for Runx2 expression and localisation analysis. Runt-related transcription factor-2 expression was silenced using specific siRNA oligonucleotides in pancreatic cancer cells (Panc-1) and immortalised pancreatic stellate cells (IPSCs). Overexpression of Runx2 was achieved using a full-length expression vector. TGF-b1, BMP2, and other cytokines were assessed for their potential to regulate Runx2 expression. There was a 6.1-fold increase in median Runx2 mRNA levels in PDAC tissues compared to normal pancreatic tissues (Po0.0001). Runt-related transcription factor-2 was localised in pancreatic cancer cells, tubular complexes, and PanIN lesions of PDAC tissues as well as in tumour-associated fibroblasts/stellate cells. Coculture of IPSCs and Panc-1 cells, as well as treatment with TGF-b1 and BMP2, led to increased Runx2 expression in Panc-1 cells. Runt-related transcription factor-2 overexpression was associated with decreased MMP1 release as well as decreased growth and invasion of Panc-1 cells. These effects were reversed by Runx2 silencing. In conclusion, Runx2 is overexpressed in PDAC, where it is regulated by certain cytokines such as TGF-b1 and BMP2 in an auto-and paracrine manner. In addition, Runx2 has the potential to regulate the transcription of extracellular matrix modulators such as SPARC and MMP1, thereby influencing the tumour microenvironment.

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Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients

Cited by 63 publications

References 38 publications

Angiogenesis and Multiple Myeloma

Angiogenesis and Multiple Myeloma

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

Regulation and functional role of the Runt-related transcription factor-2 in pancreatic cancer

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