Proangiogenic properties of human myeloma cells: production of angiopoietin-1 and its potential relationship to myeloma-induced angiogenesis

Giuliani, Nicola; Colla, Simona; Lazzaretti, Mirca; Sala, Roberto; Roti, Giovanni; Mancini, Cristina; Bonomini, Sabrina; Lunghi, Paolo; Hojden, Magda; Genestreti, Giovenzio; Svaldi, Mirija; Coser, P; Fattori, Pier Paolo; Sammarelli, Gabriella; Gazzola, Gian C.; Bataille, Régis; Almici, Camillo; Caramatti, Cecilia; Mangoni, L; Rizzoli, Vittorio

doi:10.1182/blood-2002-10-3257

Cited by 100 publications

(104 citation statements)

References 41 publications

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“…Ang-1 is expressed in about 47% of patients of newly diagnosed MM patients. However, Ang-2 is not present in any patients tested [56]. In addition, the potential role of Ang-1 in MMinduced angiogenesis has been confirmed in an experimental model of angiogenesis.…”

Section: Angiopoietinsmentioning

confidence: 82%

“…In addition, the potential role of Ang-1 in MMinduced angiogenesis has been confirmed in an experimental model of angiogenesis. In this system, the conditioned medium of myeloma cells increased vessel formation in comparison with either control or VEGF treatment [56]. The presence of an anti-Tie-2 blocking antibody completely blunted tubule formation induced by myeloma cells [56].…”

Section: Angiopoietinsmentioning

confidence: 84%

“…This process may lead either to vessel regression or promote angiogenesis [55]. Because Ang-1 has a critical role in the angiogenic switch its potential role in myelomainduced angiogenesis has been investigated [56]. First, it has been shown that myeloma cells express and secrete Ang-1 but not its antagonist Ang-2 [56].…”

Section: Angiopoietinsmentioning

confidence: 99%

“…Because Ang-1 has a critical role in the angiogenic switch its potential role in myelomainduced angiogenesis has been investigated [56]. First, it has been shown that myeloma cells express and secrete Ang-1 but not its antagonist Ang-2 [56]. Ang-1 is expressed in about 47% of patients of newly diagnosed MM patients.…”

Section: Angiopoietinsmentioning

confidence: 99%

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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: Angiopoietinsmentioning

confidence: 82%

Section: Angiopoietinsmentioning

confidence: 84%

Section: Angiopoietinsmentioning

confidence: 99%

Section: Angiopoietinsmentioning

confidence: 99%

See 2 more Smart Citations

Angiogenesis and Multiple Myeloma

Giuliani

Storti

Bolzoni

et al. 2011

Cancer Microenvironment

Self Cite

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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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Circulating angiopoietin‐1 to angiopoietin‐2 ratio is an independent prognostic factor for survival in newly diagnosed patients with multiple myeloma who received therapy with novel antimyeloma agents

Terpos

Anargyrou

Katodritou

et al. 2011

Intl Journal of Cancer

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The circulating levels of several angiogenic cytokines [angiopoietin‐1 (Ang‐1), angiopoietin‐2 (Ang‐2), vascular endothelial growth factor (VEGF), angiogenin and basic fibroblast growth factor (bFGF)] were evaluated in 174 consecutive patients with newly diagnosed, symptomatic, multiple myeloma (MM). Circulating levels of Ang‐1/Ang‐2 were reduced in myeloma patients compared to controls, whereas VEGF and angiogenin levels were increased. Reduced angiopoietin‐1/angiopoietin‐2 ratio correlated with advanced disease features including international staging system (ISS)‐3 stage, renal impairment and extensive bone disease. Based on immunohistochemical results in 20 patients (10 with the higher and 10 with the lower values of circulating angiopoietin‐2) we found that angiopoietin‐2 is expressed by myeloma cells and correlates with increased microvessel density in subsets of patients. Furthermore, Ang‐1/Ang‐2 ratio correlated with survival. Patients with circulating Ang‐1/Ang‐2 below or equal to the median value (6.03) had a median survival of 26.3 months compared to 53 months of all others (p = 0.002). Interestingly, this was mainly observed in patients who received first‐line therapy with novel agent‐based regimens (65% of our patients). Furthermore, a subset of ISS‐3 patients with serum Ang‐1/Ang‐2 above the median value had favourable prognosis (median survival: 45 months versus 17 months of all others; p = 0.0001). The multivariate analysis revealed that low Ang‐1/Ang‐2 ratio could independently predict for inferior survival in our cohort of patients (relative risk (RR) 2.07, 95% CI 1.50–2.42; p < 0.001). These results highlight the role of angiopoietins pathway in the biology of MM and reveal novel targets for the development of antimyeloma agents.

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Proangiogenic properties of human myeloma cells: production of angiopoietin-1 and its potential relationship to myeloma-induced angiogenesis

Cited by 100 publications

References 41 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

Circulating angiopoietin‐1 to angiopoietin‐2 ratio is an independent prognostic factor for survival in newly diagnosed patients with multiple myeloma who received therapy with novel antimyeloma agents

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