Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets

Berardi, Simona; Caivano, Antonella; Ria, Roberto; Nico, Beatrice; Savino, Rocco; Terracciano, Rosa; Tullio, Giacoma De; Ferrucci, Arianna; Luisi, Annunziata De; Moschetta, Michele; Mangialardi, Giuseppe; Catacchio, Ivana; Basile, Antonio; Giacosa, Attilio; Zito, Alfredo; Ditonno, Paolo; Musto, Pellegrino; Dammacco, Franco; Vacca, Angelo

doi:10.1038/onc.2011.412

Cited by 33 publications

(34 citation statements)

References 50 publications

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“…In particular, it has been demonstrated that FLNA physically interacts with HIF-1a (Zhenga et al 2014), that regulates angiogenesis through upregulation of vascular endothelial growth factor (VEGF) (Uramoto et al 2010, Berardi et al 2011, Semenza 2012. Whereas VEGF-driven angiogenesis may play an important role in endocrine tumourigenesis and tumour progression (Hanahan et al 1996) and several in vitro studies suggested that SS analogues display potent antiangiogenic properties (Woltering et al 1991, Barrie et al 1993, Danesi & Del Tacca 1996, Kumar et al 2004, we showed that SST2 agonist reduced VEGF protein levels and release, but this inhibitory effect was totally abolished in the absence of FLNA.…”

Section: Discussionmentioning

confidence: 78%

Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours

Vitali

Cambiaghi

Zerbi

et al. 2016

Endocrine-Related Cancer

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Somatostatin receptor type 2 (SST2) is the main pharmacological target of somatostatin (SS) analogues widely used in patients with pancreatic neuroendocrine tumours (P-NETs), this treatment being ineffective in a subset of patients. Since it has been demonstrated that Filamin A (FLNA) is involved in mediating GPCR expression, membrane anchoring and signalling, we investigated the role of this cytoskeleton protein in SST2 expression and signalling, angiogenesis, cell adhesion and cell migration in human P-NETs and in QGP1 cell line. We demonstrated that FLNA silencing was not able to affect SST2 expression in P-NET cells in basal conditions. Conversely, a significant reduction in SST2 expression (K43G21%, P!0.05 vs untreated cells) was observed in FLNA silenced QGP1 cells after long term SST2 activation with BIM23120. Moreover, the inhibitory effect of BIM23120 on cyclin D1 expression (K46G18%, P!0.05 vs untreated cells), P-ERK1/2 levels (K42G14%; P!0.05 vs untreated cells), cAMP accumulation (K24G3%, P!0.05 vs untreated cells), VEGF expression (K31G5%, P!0.01 vs untreated cells) and in vitro release (K40G24%, P!0.05 vs untreated cells) was completely lost after FLNA silencing. Interestingly, BIM23120 promoted cell adhesion (C86G45%, P!0.05 vs untreated cells) and inhibited cell migration (K24G2%, P!0.00001 vs untreated cells) in P-NETs cells and these effects were abolished in FLNA silenced cells. In conclusion, we demonstrated that FLNA plays a crucial role in SST2 expression and signalling, angiogenesis, cell adhesion and cell migration in P-NETs and in QGP1 cell line, suggesting a possible role of FLNA in determining the different responsiveness to SS analogues observed in P-NET patients.

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Section: Discussionmentioning

confidence: 78%

Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours

Vitali

Cambiaghi

Zerbi

et al. 2016

Endocrine-Related Cancer

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“…The MGUS patients (23 male and 12 female), ages 42 to 79 (median 60.5) years, were IgG (n ¼ 22), IgA (n ¼ 8), and k or l (n ¼ 5). Normal (control) endothelial cells were derived from 12 subjects with anemia due to iron or vitamin B 12 deficiency (20). The study was approved by the Ethics Committee of the University of Bari Medical School (Bari, Italy), and all patients provided their informed consent in accordance with the Declaration of Helsinki.…”

Section: Patients and Endothelial Cellsmentioning

confidence: 99%

“…Chemotaxis. MMECs (5 Â 10 4 ) were tested in a Boyden microchamber assay toward DMEM with 1.5% fetal calf serum alone (negative control) or added with VEGF (10 ng/mL; Sigma Chemical Co.), and FGF-2 (10 ng/mL; Peprotech Inc.) as chemoattractants (20). After 8 hours at 37 C, the migrated cells were fixed, stained, and counted by the EVOS inverted microscope (EuroClone) at Â400.…”

Section: Functional Studiesmentioning

confidence: 99%

HIF-1α of Bone Marrow Endothelial Cells Implies Relapse and Drug Resistance in Patients with Multiple Myeloma and May Act as a Therapeutic Target

Ria

Catacchio

Berardi

et al. 2014

Clinical Cancer Research

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Purpose: To investigate the role of hypoxia-inducible factor-1a (HIF-1a) in angiogenesis and drug resistance of bone marrow endothelial cells of patients with multiple myeloma.Experimental Design: HIF-1a mRNA and protein were evaluated in patients with multiple myeloma endothelial cells (MMEC) at diagnosis, at relapse after bortezomib-or lenalidomide-based therapies or on refractory phase to these drugs, at remission; in endothelial cells of patients with monoclonal gammapathies of undetermined significance (MGUS; MGECs), and of those with benign anemia (controls). The effects of HIF-1a inhibition by siRNA or panobinostat (an indirect HIF-1a inhibitor) on the expression of HIF-1a proangiogenic targets, on MMEC angiogenic activities in vitro and in vivo, and on overcoming MMEC resistance to bortezomib and lenalidomide were studied. The overall survival of the patients was also observed.Results: Compared with the other endothelial cell types, only MMECs from 45% of relapsed/refractory patients showed a normoxic HIF-1a protein stabilization and activation that were induced by reactive oxygen species (ROS). The HIF-1a protein correlated with the expression of its proangiogenic targets. The HIF-1a inhibition by either siRNA or panobinostat impaired the MMECs angiogenesis-related functions both in vitro and in vivo and restored MMEC sensitivity to bortezomib and lenalidomide. Patients with MMECs expressing the HIF-1a protein had shorter overall survival.Conclusions: The HIF-1a protein in MMECs may induce angiogenesis and resistance to bortezomib and lenalidomide and may be a plausible target for the antiangiogenic management of patients with well-defined relapsed/refractory multiple myeloma. It may also have prognostic significance. Clin Cancer Res; 20(4); 847-58. Ó2013 AACR.

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“…After 18 hours, the skeletonization of the mesh was followed by measurement of mesh areas and vessel length in three randomly chosen Â200 fields on an EVOS digital inverted microscope (Euroclone; ref. 18). Three different doses of SU11274 (0.1, 0.5, and 1 mmol/L), bortezomib (7.5, 10, and 20 nmol/L), and lenalidomide (0.5, 0.25, and 1.75 mmol/L) were singularly tested in the Matrigel assay.…”

Section: Functional Studiesmentioning

confidence: 99%

“…Real-time RT-PCR was performed using primers (Invitrogen) shown in Supplementary Table S1, and the Applied Biosystems methodology (18). Relative quantification of the mRNA was performed using the comparative threshold cycle (C t ) method with GAPDH as the reference gene and with the 2 ÀDDCt formula (19).…”

Section: Elisa Immunoprecipitation Western Blot Analysis and Real-mentioning

confidence: 99%

A HGF/cMET Autocrine Loop Is Operative in Multiple Myeloma Bone Marrow Endothelial Cells and May Represent a Novel Therapeutic Target

Ferrucci

Moschetta

Frassanito

et al. 2014

Clinical Cancer Research

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Purpose: The aim of this study was to investigate the angiogenic role of the hepatocyte growth factor (HGF)/cMET pathway and its inhibition in bone marrow endothelial cells (EC) from patients with multiple myeloma versus from patients with monoclonal gammopathy of undetermined significance (MGUS) or benign anemia (control group). Experimental Design: The HGF/cMET pathway was evaluated in ECs from patients with multiple myeloma (multiple myeloma ECs) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies, or on refractory phase to these drugs; in ECs from patients with MGUS (MGECs); and in those patients from the control group. The effects of a selective cMET tyrosine kinase inhibitor (SU11274) on multiple myeloma ECs' angiogenic activities were studied in vitro and in vivo. Results: Multiple myeloma ECs express more HGF, cMET, and activated cMET (phospho (p)-cMET) at both RNA and protein levels versus MGECs and control ECs. Multiple myeloma ECs are able to maintain the HGF/cMET pathway activation in absence of external stimulation, whereas treatment with anti-HGF and anti-cMET neutralizing antibodies (Ab) is able to inhibit cMET activation. The cMET pathway regulates several multiple myeloma EC activities, including chemotaxis, motility, adhesion, spreading, and whole angiogenesis. Its inhibition by SU11274 impairs these activities in a statistically significant fashion when combined with bortezomib or lenalidomide, both in vitro and in vivo. Conclusions: An autocrine HGF/cMET loop sustains multiple myeloma angiogenesis and represents an appealing new target to potentiate the antiangiogenic management of patients with multiple myeloma. Clin Cancer Res; 20(22); 5796–807. ©2014 AACR.

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Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets

Cited by 33 publications

References 50 publications

Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours

Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours

HIF-1α of Bone Marrow Endothelial Cells Implies Relapse and Drug Resistance in Patients with Multiple Myeloma and May Act as a Therapeutic Target

A HGF/cMET Autocrine Loop Is Operative in Multiple Myeloma Bone Marrow Endothelial Cells and May Represent a Novel Therapeutic Target

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