Angiopoietin-2 in Bone Marrow milieu promotes Multiple Myeloma-associated angiogenesis

Belloni, Daniela; Marcatti, Magda; Ponzoni, Maurilio; Ciceri, Fabio; Veschini, Lorenzo; Corti, Angelo; Cappio, F. Caligaris; Ferrarini, Marina; Ferrero, Elisabetta

doi:10.1016/j.yexcr.2014.10.017

Cited by 20 publications

(19 citation statements)

References 47 publications

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“…Increased levels of Ang-2 are known to correlate with progression in MM [8–10]. The tyrosine kinase receptor TIE2 is located on vascular endothelial cells and activated TIE2 is able to support their survival and adhesion, resulting in the stabilization of blood vessels [11].…”

Section: Introductionmentioning

confidence: 99%

High levels of FLT3-ligand in bone marrow and peripheral blood of patients with advanced multiple myeloma

et al. 2017

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IntroductionMultiple myeloma (MM) is still incurable due to resistance against various therapies. Thus, the identification of biomarkers predicting progression is urgently needed. Here, we evaluated four biomarkers in bone marrow and peripheral blood of MM patients for their prognostic significance.Materials & methodsBone marrow- and peripheral blood plasma levels of FLT3-L, soluble TIE2, endostatin, and osteoactivin were determined in patients with monoclonal gammopathy of undetermined significance (MGUS, n = 14/n = 4), patients with newly diagnosed MM (NDMM, n = 42/n = 31) and patients with relapsed/refractory MM (RRMM, n = 27/n = 16) by sandwich ELISA.ResultsMedian FLT3-L expression increased from MGUS (58.77 pg/ml in bone marrow; 80.40 pg/ml in peripheral blood) to NDMM (63.15 pg/ml in bone marrow; 85.05 pg/ml in peripheral blood) and was maximal in RRMM (122 pg/ml in bone marrow; 160.47 pg/ml in peripheral blood; NDMM vs. RRMM p<0.001). A cut-off value of FLT3-L >92 pg/ml in bone marrow and >121 pg/ml in peripheral blood was associated with relapse or refractoriness in MM patients. FLT3-L was found to be a high predictive marker for discrimination between NDMM and RRMM as well in bone marrow as in peripheral blood (AUC 0.75 in bone marrow; vs 0.84 in peripheral blood).ConclusionHigh levels of FLT3-L in bone marrow and peripheral blood of MM patients identify patients with progressive disease and are associated with relapse or refractoriness in MM patients. FLT3-L could be useful as a marker to identify RRMM patients and should be evaluated as target for future therapies.

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Section: Introductionmentioning

confidence: 99%

High levels of FLT3-ligand in bone marrow and peripheral blood of patients with advanced multiple myeloma

et al. 2017

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“…We have previously shown the ability of nAb and A83-01 to neutralize Activin A signaling in this model system [34, 48]. Treatment with nAb increased cell invasion in dysplastic empty vector control cells, yet could not overcome the inhibition of cell invasion in the context of Fibro-ActA cultures (Fig.…”

Section: Resultsmentioning

confidence: 77%

Esophageal squamous cell carcinoma invasion is inhibited by Activin A in ACVRIB-positive cells

et al. 2016

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BackgroundEsophageal squamous cell carcinoma (ESCC) is a global public health issue, as it is the eighth most common cancer worldwide. The mechanisms behind ESCC invasion and progression are still poorly understood, and warrant further investigation into these processes and their drivers. In recent years, the ligand Activin A has been implicated as a player in the progression of a number of cancers. The objective of this study was to investigate the role of Activin A signaling in ESCC.MethodsTo investigate the role Activin A plays in ESCC biology, tissue microarrays containing 200 cores from 120 ESCC patients were analyzed upon immunofluorescence staining. We utilized three-dimensional organotypic reconstruct cultures of dysplastic and esophageal squamous tumor cells lines, in the context of fibroblast-secreted Activin A, to identify the effects of Activin A on cell invasion and determine protein expression and localization in epithelial and stromal compartments by immunofluorescence. To identify the functional consequences of stromal-derived Activin A on angiogenesis, we performed endothelial tube formation assays.ResultsAnalysis of ESCC patient samples indicated that patients with high stromal Activin A expression had low epithelial ACVRIB, the Activin type I receptor. We found that overexpression of stromal-derived Activin A inhibited invasion of esophageal dysplastic squamous cells, ECdnT, and TE-2 ESCC cells, both positive for ACVRIB. This inhibition was accompanied by a decrease in expression of the extracellular matrix (ECM) protein fibronectin and podoplanin, which is often expressed at the leading edge during invasion. Endothelial tube formation was disrupted in the presence of conditioned media from fibroblasts overexpressing Activin A. Interestingly, ACVRIB-negative TE-11 cells did not show the prior observed effects in the context of Activin A overexpression, indicating a dependence on the presence of ACVRIB.ConclusionsWe describe the first observation of an inhibitory role for Activin A in ESCC progression that is dependent on the expression of ACVRIB.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2920-y) contains supplementary material, which is available to authorized users.

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“…The identification and specific contribution of proangiogenic molecules to be used as therapeutic targets and/or reliable angiogenesis biomarkers in MM is still unresolved [17]. In this article, we show that IL-37 correlates significantly with important angiogenetic factors, suggesting that IL-37 may be a biomarker for MM disease stage and angiogenesis processes.…”

Section: Discussionmentioning

confidence: 75%

The Low Expression of IL-37 Involved in Multiple Myeloma – Associated Angiogenesis

Sun

Zheng

et al. 2016

Med Sci Monit

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BackgroundAngiogenesis plays a significant role in complex inflammatory and angiogenic processes and is also involved in multiple myeloma (MM) pathogenesis. IL-37 is a proinflammatory cytokine in antitumor activity. Our purpose was to evaluate the IL-37 clinical significance on MM.Material/MethodsWe measured serum levels of IL-37 in 45 patients with different stages of MM and 30 healthy control subjects and correlated IL-37 with numerous cytokines, such as angiogenesis factors including vascular endothelial growth factor (VEGF) and angiotensin-2 (Ang-2). We also measured the tube formation of human umbilical vein endothelial cells (HUVECs) after pretreatment with recombinant human IL-37 (rhIL-37).ResultsSerum IL-37 level was lower in the patients with MM than in the healthy control subjects, whereas VEGF and Ang-2 levels were higher, depending on International Staging System stage. Serum IL-37 level had a negative correlation to VEGF and Ang-2 levels, and VEGF had a positive correlation to Ang-2 level. The tube formation of HUVECs was suppressed by the rhIL-37 pretreatment.ConclusionsOur results indicate that serum level of IL-37 plays a part in the pathophysiology of MM progression. Therefore, IL-37 serum level may be a biomarker for disease stage and angiogenesis processes.

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Angiopoietin-2 in Bone Marrow milieu promotes Multiple Myeloma-associated angiogenesis

Cited by 20 publications

References 47 publications

High levels of FLT3-ligand in bone marrow and peripheral blood of patients with advanced multiple myeloma

High levels of FLT3-ligand in bone marrow and peripheral blood of patients with advanced multiple myeloma

Esophageal squamous cell carcinoma invasion is inhibited by Activin A in ACVRIB-positive cells

The Low Expression of IL-37 Involved in Multiple Myeloma – Associated Angiogenesis

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