Ilaria Saltarella
University of Bari
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Ilaria Saltarella.
Stem Cells International | 2016
Antonia Reale; Assunta Melaccio; Aurelia Lamanuzzi; Ilaria Saltarella; Franco Dammacco; Angelo Vacca; Roberto Ria
It was believed that vasculogenesis occurred only during embryo life and that postnatal formation of vessels arose from angiogenesis. Recent findings demonstrate the existence of Endothelial Precursor Cells (EPCs), which take partin postnatal vasculogenesis. EPCs are recruited from the bone marrow under the stimulation of growth factors and cytokines and reach the sites of neovascularization in both physiological and pathological conditions such as malignancies where they contribute to the “angiogenic switch” and tumor progression. An implementation of circulating EPCs in the bloodstream of patients with haematological malignancies has been demonstrated. This increase is strictly related to the bone marrow microvessel density and correlated with a poor prognosis. The EPCs characterization is a very complex process and still under investigation. This literature review aims to provide an overview of the functional and biological role of EPCs in haematological malignancies and to investigate their potential as a new cancer therapeutic target.
World Journal of Stem Cells | 2015
Ilaria Saltarella; Aurelia Lamanuzzi; Antonia Reale; Angelo Vacca; Roberto Ria
Multiple myeloma (MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells (CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activates stemness signaling (Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs.
Oncotarget | 2016
Aurelia Lamanuzzi; Ilaria Saltarella; Arianna Ferrucci; Roberto Ria; Simona Ruggieri; Vito Racanelli; Luigia Rao; Tiziana Annese; Beatrice Nico; Angelo Vacca; Domenico Ribatti
Increasing evidences suggest several biological roles for erythropoietin and its receptor (Epo and EpoR), unrelated to erythropoiesis, including angiogenesis. Here, we detected the expression of EpoR in bone marrow-derived endothelial cells from monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) patients (MGECs and MMECs, respectively) and assessed whether Epo plays a role in MGECs- and MMECs-mediated angiogenesis. We show that EpoR is expressed by both MGECs and MMECs even though at a higher level in the first ones. Both EC types respond to rHuEpo in terms of cell proliferation, whereas other responses, including activation of JAK2/STAT5 and PI3K/Akt pathways, cell migration and capillarogenesis are enhanced by Epo in MGECs, but not in MMECs. In addition, the conditioned media of both Epo-treated cells induce a strong angiogenic response in vivo in the chorioallantoic membrane assay, comparable to that of vascular endothelial growth factor (VEGF). Overall, these data highlight the effect of Epo on MGECs- and MMECs-mediated angiogenesis: MGECs are more responsive to Epo treatment than MMECs, probably because over-angiogenic phenotype of MMECs is already activated by their autocrine/paracrine loops occurring in the “angiogenic switch” from MGUS.
Oncotarget | 2016
Roberto Ria; Vittorio Simeon; Assunta Melaccio; Giovanna Di Meo; Stefania Trino; Carmela Mazzoccoli; Ilaria Saltarella; Aurelia Lamanuzzi; Annalisa Morano; Angela Gurrado; Alessandro Pasculli; Gaetano Lastilla; Pellegrino Musto; Antonia Reale; Franco Dammacco; Angelo Vacca; Mario Testini
Gene expression profiling (GEP) of normal thyroid tissue from 43 patients with thyroid carcinoma, 6 with thyroid adenoma, 42 with multinodular goiter, and 6 with Graves-Basedow disease was carried out with the aim of achieving a better understanding of the genetic mechanisms underlying the role of normal cells surrounding the tumor in the thyroid cancer progression. Unsupervised and supervised analyses were performed to compare samples from neoplastic and non-neoplastic diseases. GEP and subsequent RT-PCR analysis identified 28 differentially expressed genes. Functional assessment revealed that they are involved in tumorigenesis and cancer progression. The distinct GEP is likely to reflect the onset and/or progression of thyroid cancer, its molecular classification, and the identification of new potential prognostic factors, thus allowing to pinpoint selective gene targets with the aim of realizing more precise preoperative diagnostic procedures and novel therapeutic approaches. STATEMENT OF SIGNIFICANCE This study is focused on the gene expression profiling analysis followed by RT-PCR of normal thyroid tissues from patients with neoplastic and non-neoplastic thyroid diseases. Twenty-eight genes were found to be differentially expressed in normal cells surrounding the tumor in the thyroid cancer. The genes dysregulated in normal tissue samples from patients with thyroid tumors may represent new molecular markers, useful for their diagnostic, prognostic and possibly therapeutic implications.
Oncotarget | 2018
Aurelia Lamanuzzi; Ilaria Saltarella; Vanessa Desantis; Maria Antonia Frassanito; Patrizia Leone; Vito Racanelli; Beatrice Nico; Domenico Ribatti; Paolo Ditonno; Marcella Prete; Antonio Giovanni Solimando; Francesco Dammacco; Angelo Vacca; Roberto Ria
The mammalian Target of Rapamycin (mTOR) is an intracellular serine/threonine kinase that mediates intracellular metabolism, cell survival and actin rearrangement. mTOR is made of two independent complexes, mTORC1 and mTORC2, activated by the scaffold proteins RAPTOR and RICTOR, respectively. The activation of mTORC1 triggers protein synthesis and autophagy inhibition, while mTORC2 activation promotes progression, survival, actin reorganization, and drug resistance through AKT hyper-phosphorylation on Ser473. Due to the mTOR pivotal role in the survival of tumor cells, we evaluated its activation in endothelial cells (ECs) from 20 patients with monoclonal gammopathy of undetermined significance (MGUS) and 47 patients with multiple myeloma (MM), and its involvement in angiogenesis. MM-ECs showed a significantly higher expression of mTOR and RICTOR than MGUS-ECs. These data were supported by the higher activation of mTORC2 downstream effectors, suggesting a major role of mTORC2 in the angiogenic switch to MM. Specific inhibition of mTOR activity through siRNA targeting RICTOR and dual mTOR inhibitor PP242 reduced the MM-ECs angiogenic functions, including cell migration, chemotaxis, adhesion, invasion, in vitro angiogenesis on Matrigel®, and cytoskeleton reorganization. In addition, PP242 treatment showed anti-angiogenic effects in vivo in the Chick Chorioallantoic Membrane (CAM) and Matrigel® plug assays. PP242 exhibited a synergistic effect with lenalidomide and bortezomib, suggesting that mTOR inhibition can enhance the anti-angiogenic effect of these drugs. Data to be shown indicate that mTORC2 is involved in MM angiogenesis, and suggest that the dual mTOR inhibitor PP242 may be useful for the anti-angiogenic management of MM patients.
Oncotarget | 2018
Luigia Rao; Kim De Veirman; Donato Giannico; Ilaria Saltarella; Vanessa Desantis; Maria Antonia Frassanito; Antonio Giovanni Solimando; Domenico Ribatti; Marcella Prete; Andreas Harstrick; Ulrike Fiedler; Hendrik De Raeve; Vito Racanelli; Karin Vanderkerken; Angelo Vacca
The investigational drug MP0250 is a multi-specific DARPin® molecule that simultaneously binds and neutralizes VEGF and HGF with high specificity and affinity. Here we studied the antiangiogenic effects of the MP0250 in multiple myeloma (MM). In endothelial cells (EC) isolated from bone marrow (BM) of MM patients (MMEC) MP0250 reduces VEGFR2 and cMet phosphorylation and affects their downstream signaling cascades. MP0250 influences the secretory profile of MMEC and inhibits their in vitro angiogenic activities (spontaneous and chemotactic migration, adhesion, spreading and capillarogenesis). Compared to anti-VEGF or anti-HGF neutralizing mAbs, MP0250 strongly reduces capillary network formation and vessel-sprouting in a Matrigel angiogenesis assay. MP0250 potentiates the effect of bortezomib in the same in vitro setting. It significantly reduces the number of newly formed vessels in the choriollantoic membrane assay (CAM) and the Matrigel plug assay. In the syngeneic 5T33MM tumor model, MP0250 decreases the microvessel density (MVD) and the combination MP0250/bortezomib lowers the percentage of idiotype positive cells and the serum levels of M-protein. Overall results define MP0250 as a strong antiangiogenic agent with potential as a novel combination drug for treatment of MM patients.
Translational Oncology | 2018
Vanessa Desantis; Ilaria Saltarella; Aurelia Lamanuzzi; Maria Addolorata Mariggiò; Vito Racanelli; Angelo Vacca; Maria Antonia Frassanito
Autophagy is an intracellular self-degradative process that balances cell energy source and regulates tissue homeostasis. In physiological condition, autophagy funnels cytoplasmic constituents to autophagolysosomes for degradation and is an alternative way for cell-death behavior. Here, we inspected autophagy as a prosurvival mechanism essential for drug resistance in multiple myeloma (MM). Accordingly, autophagy inhibitors used in association to conventional anti-MM drugs might enforce the effect against resistant MM plasma cells and render autophagy a new therapeutic target.
Cellular Physiology and Biochemistry | 2018
Irene Filippi; Ilaria Saltarella; Carlo Aldinucci; Fabio Carraro; Roberto Ria; Angelo Vacca; Antonella Naldini
Background/Aims: Hypoxia is a powerful stimulator of angiogenesis under physiological as well as pathological conditions. Normal endothelial cells (EC), such as human umbilical vein EC (HUVEC), are relatively affected by hypoxic insult in terms of cell survival. In contrast, EC from tumors are particularly resistant to hypoxia-induced cell death. Previous reports have shown that EC in bone marrow from multiple myeloma (MM) patients had a hypoxic phenotype, even under normoxic conditions. The aim of this study was to evaluate whether HUVEC and MMEC adapt differently to hypoxia. Methods: Cell proliferation was assessed by the CyQUANT assay. Cdc25A, p21, Bax, Bcl-xl, BNIP3, glucose transporter (GLUT)-1, monocarboxylate transporter (MCT)-4 and carbonic anhydrase (CA)IX mRNA expression was determined by qRT-PCR. HIF-1α, BNIP3, Beclin-1, LC3B, livin, Bax, Bcl-xl, p21, p62 and β-actin protein expression was analyzed by western blot. Apoptosis was determined by TUNEL assay. Silencing of BNIP3 was achieved by stealth RNA system technology. Results: While HUVEC survival was reduced after prolonged hypoxic exposure, MMEC were completely unaffected. This difference was also significant in terms of livin, cdc25A and p21 expression. Hypoxia induced apoptosis and inhibited autophagy in HUVEC, but not in MMEC, where hypoxic treatment resulted in a more sustained adaptive response. In fact, MMEC showed a more significant increase in the expression of genes regulated transcriptionally by hypoxia-inducible factor (HIF)-1α. Interestingly, they showed higher expression of BNIP3 than did HUVEC, indicating a more pronounced autophagic (and pro-survival) phenotype. The potential role of BNIP3 in EC survival was confirmed by BNIP3 siRNA experiments in HUVEC, where BNIP3 inhibition resulted in reduced cell survival and increased apoptosis. Conclusion: These findings provide further information on how hypoxia may affect EC survival and could be important for a better understanding of EC physiology under normal and pathological conditions, such as in multiple myeloma.
Annals of Hematology | 2018
Vanessa Desantis; Maria Antonia Frassanito; Roberto Tamma; Ilaria Saltarella; Lucia Di Marzo; Aurelia Lamanuzzi; Antonio Giovanni Solimando; Simona Ruggieri; Tiziana Annese; Beatrice Nico; Angelo Vacca; Domenico Ribatti
We have previously demonstrated that recombinant human erythropoietin (rHuEpo) is involved in the regulation of the angiogenic response in multiple myeloma (MM) through a direct effect on macrophages and endothelial cells isolated from the bone marrow of patients with MM. The aim of the present study was designed to determine the effects of rHuEpo on cancer-associated fibroblasts (CAFs) from monoclonal gammopathy of undetermined significance (MGUS) and MM patients by means of in vitro and in vivo assays. rHuEpo treatment reduces the expression of mRNA levels of fibroblast activation markers, namely alpha smooth actin (αSMA) and fibroblast activation protein (FAP) in MGUS and MM CAFs, and of pro-inflammatory and pro-angiogenic cytokines, including interleukin (IL)-6 and IL-8, vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor-2 (FGF-2), and hepatocyte growth factor (HGF) in MM CAFs. Moreover, rHuEpo inhibits the proliferative activity of MM CAFs and increased the apoptosis of MGUS and MM CAFs. Overall, these data suggest that rHu-Epo down-regulates CAFs pro-tumorigenic activity. Moreover, these results are not suggestive for a pro-angiogenic activity of rHuEpo on CAFs. In fact, rHuEpo pre-treatment induces a low angiogenic response in vivo in the chorioallantoic membrane (CAM) assay of MGUS and MM CAFs conditioned medium, not comparable to that of a well-known angiogenic cytokine, VEGF-A, tested in the same assay.
The Journal of Pathology | 2018
Maria Antonia Frassanito; Vanessa Desantis; Lucia Di Marzo; Ilaria Craparotta; Luca Beltrame; Sergio Marchini; Tiziana Annese; Fabrizio Visino; Marcella Arciuli; Ilaria Saltarella; Aurelia Lamanuzzi; Antonio Giovanni Solimando; Beatrice Nico; Maria De Angelis; Vito Racanelli; Maria Addolorata Mariggiò; Rosistella Chiacchio; Michele Pizzuti; Anna Gallone; Ruggiero Fumarulo; Maurizio D'Incalci; Angelo Vacca