Osteopontin overproduced by tumor cells acts as a potent angiogenic factor contributing to tumor growth

Hirama, Michihiro; Takahashi, Fumiyuki; Takahashi, Kazuhisa; Akutagawa, Shigeru; Shimizu, Kazuharu; Soma, Sanae; Shimanuki, Yuri; Nishio, Kazuto; Fukuchi, Yoshinosuke

doi:10.1016/s0304-3835(03)00286-6

Cited by 84 publications

(65 citation statements)

References 28 publications

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“…[16][17][18][19] OPN enhances tumoral cell proliferation increasing the malignant phenotype 16,17,25,26 and its downregulation in cancer cells reduces their growth and tumorigenicity in mice. 27 In line with these observations we found that OPN enhances HMCLs proliferation and increases IL-6 proproliferative effect on myeloma cells.…”

Section: Discussionmentioning

confidence: 99%

“…14 OPN has been associated with tumoral angiogenesis in mouse model 13,14 and in human solid tumors. [17][18][19] In lung adenocarcinoma, it has been demonstrated that double OPN and VEGFpositive tumors have higher MVD as compared to those negative. 19 In our study, we demonstrate for the first time the involvement of OPN in the angiogenic process that occurs in MM patients.…”

Section: Discussionmentioning

confidence: 99%

“…7,13 Recent data indicate that OPN also stimulates endothelial cell survival and migration [13][14][15] and acts as a potent proangiogenic factor in vivo. 16,17 In several solid tumors it has been shown that OPN is overexpressed and promotes tumoral growth, angiogenesis and progression. 18,19 Recently, high OPN levels have been demonstrated in MM patients; therefore, OPN production by BM mononuclear cells or by myeloma cells has been hypothesized.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2005

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Osteopontin (OPN) is a multifunctional bone matrix glycoprotein that is involved in angiogenesis, cell survival and tumor progression. In this study we show that human myeloma cells directly produce OPN and express its major regulating gene Runx2/Cbfa1. The activity of Runx2/Cbfa1 protein in human myeloma cells has also been demonstrated. Moreover, using small interfering RNA (siRNA) to silent Runx2 in myeloma cells, we suppressed OPN mRNA and protein expression. OPN production in myeloma cells was stimulated by growth factors as IL-6 and IFG-1 and in turn OPN stimulated myeloma cell proliferation. In an 'in vitro' angiogenesis system we showed that OPN production by myeloma cells is critical for the proangiogenic effect of myeloma cells. The expression of OPN by purified bone marrow (BM) CD138 þ cells has also been investigated in 60 newly diagnosed multiple myeloma (MM) patients, finding that 40% of MM patients tested expressed OPN. Higher OPN levels have been detected in the BM plasma of MM patients positive for OPN as compared to controls. Moreover, significantly higher BM angiogenesis has been observed in MM patients positive for OPN as compared to those negative. Our data highlight that human myeloma cells with active Runx2/Cbfa1 protein directly produce OPN that is involved in the pathophysiology of MM-induced angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 2005

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“…It is well described that Opn enhances non-haemopoietic tumour cell proliferation increasing the malignant phenotype (Takahashi et al, 2002;Hirama et al, 2003;Angelucci et al, 2004). Furthermore, downregulation of Opn in cancer cells reduces growth and tumorigenicity in mice (Behrend et al, 1994).…”

Section: Osteopontin and Aberrant Haemopoiesismentioning

confidence: 97%

Osteopontin: a bridge between bone and blood

2006

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SummaryThe production of mature blood cells within the bone marrow (BM) is attributed to a pool of haemopoietic stem cells (HSC). It is now evident that HSC reside preferentially at the endosteal region within the BM where bone-lining osteoblasts are a key cellular component of the HSC niche that directly regulates HSC fate. Osteoblasts synthesise proteins that stimulate and inhibit HSC proliferation. In addition to angiopoietin 1 (Ang-1), osteoblasts synthesise and express the highly acidic glycoprotein, osteopontin (Opn), which, like Ang-1, acts as a potent constraining factor on HSC proliferation. Overexpression of Opn is a feature of haemopoietic malignancies, such as multiple myeloma and chronic myeloid leukaemia, although its exact role in the aetiology and progression of these diseases remains unclear. Through osteoblasts and their cell surface and expressed proteins including Opn, bone is able to regulate the tissue that resides within it. In doing so, Opn can be considered a bridge between bone and blood.

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“…Osteopontin Osteopontin (OPN) is a pro-angiogenic factor that promotes endothelial cell migration and survival [60][61][62][63][64][65][66][67][68][69][70], adhesion of both endothelial and smooth muscle cells [71], and has been associated with tumoral angiogenesis in mouse models [72,73]. OPN is produced directly by myeloma cells and is critical for the stimulation of endothelial cells.…”

Section: Matrix Metalloproteinasesmentioning

confidence: 99%

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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Osteopontin overproduced by tumor cells acts as a potent angiogenic factor contributing to tumor growth

Cited by 84 publications

References 28 publications

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

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

Osteopontin: a bridge between bone and blood

Angiogenesis and Multiple Myeloma

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