Angelo Vacca

Università degli Studi di Bari Aldo Moro, Bari, Apulia, Italy

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Publications (413)1454.43 Total impact

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    ABSTRACT: The role of endothelial progenitor cell (EPC)-mediated vasculogenesis in hematological malignancies is not well explored. Here we showed that EPCs are mobilized from the bone marrow (BM) to the peripheral blood at early stages of multiple myeloma (MM); and recruited to MM cell-colonized BM niches. Using EPC-defective ID1+/- ID3-/- mice, we found that MM tumor progression is dependent on EPC-trafficking. By performing RNA sequencing studies, we confirmed that endothelial cells can enhance proliferation and favor cell cycle progression only in MM clones that are smoldering-like and have dependency on endothelial cells for tumor growth. We further confirmed that angiogenic dependency occurs early and not late during tumor progression in MM. By using a VEGFR2 antibody with anti-vasculogenic activity, we demonstrated that early targeting of EPCs delays tumor progression, while using the same agent at late stages of tumor progression is ineffective. Thus, although there is significant angiogenesis in myeloma, the dependency of the tumor cells on EPCs and vasculogenesis may actually precede this step. Manipulating vasculogenesis at an early stage of disease may be examined in clinical trials in patients with smoldering MM, and other hematological malignancies with precursor conditions.Leukemia accepted article preview online, 03 February 2016. doi:10.1038/leu.2016.3.
    No preview · Article · Feb 2016 · Leukemia
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    Solimando AG · Ribatti D · Vacca A · Einsele H.
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    ABSTRACT: The management of B-cell malignancies continues to pose a clinical challenge. In the past years, rituximab (anti-CD20) emerged as the standard of care in the induction treatment of follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), and mantle cell lymphoma (MCL), as well as in other subsets. Since the benefits of immuno-chemotherapy have been clearly demonstrated in a whole range of lymphomas, several innovative approaches are being explored to achieve significant responses, particularly in refractory B-cell non-Hodgkin lymphoma (NHL) cases. Studies of the comparative effectiveness and structure/function relationship of therapeutic monoclonal antibodies, together with an increased understanding of the molecular features of NHLs, have led to the development of a range of novel therapies, many of which target the tumor in a tailored fashion. Although several molecules can help clinicians to dissect the pathological mechanisms acting in the natural history of the disease, the main purpose of this review emphasize the recent developments in targeting the B-cell NHLs surface. These novel approaches are illustrated, and the new intriguing opportunities offered by bispecific antibodies and antibody-associated immune modulation are addressed.
    Full-text · Article · Jan 2016 · Leukemia Research
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    ABSTRACT: Bortezomib (bort) has improved overall survival in patients with multiple myeloma (MM), but the majority of them develop drug-resistance. In this study, we demonstrate that bone marrow (BM) fibroblasts (cancer associated fibroblasts, CAFs) from bort-resistant patients are insensitive to bort and protect the RPMI8226 and patients' plasma cells against bort-induced apoptosis. Bort triggers CAFs to produce high levels of IL-6, IL-8, IGF-1, and TGFβ. Proteomic studies on CAFs demonstrate that bort-resistance parallels activation of oxidative stress and pro-survival autophagy. Indeed, bort induces reactive oxygen species in bort-resistant CAFs and activates autophagy by increasing LC3-II and inhibiting p62 and p-mTOR. The siRNA knock-down of Atg7, and treatment with 3-methyladenine, restored bort sensitivity in bort-resistant CAFs and produced cytotoxicity in plasma cells co-cultured with CAFs. In the syngeneic 5T33 MM model, bort-treatment induced the expansion of LC3-II(+) CAFs. TGFβ mediated bort-induced autophagy, and its blockade by LY2109761, a selective TβRI/II inhibitor, reduced the expression of p-Smad2/3 and LC3-II and induced apoptosis in bort-resistant CAFs. A combination of bort and LY2109761 synergistically induced apoptosis of RPMI8226 co-cultured with bort-resistant CAFs. These data define a key role for CAFs in bort-resistance of plasma cells and provide the basis for a novel targeted therapeutic approach.Leukemia accepted article preview online, 21 October 2015. doi:10.1038/leu.2015.289.
    No preview · Article · Oct 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    ABSTRACT: Objective: Obstructive sleep apnea (OSA) and obesity are increasingly prevalent worldwide. Both promote endothelial dysfunction contributing to systemic and pulmonary hypertension over time. Endothelin-1 (ET-1) plays a pivotal role in the development of pulmonary hypertension (PH). The aim of the present study was to assess the association between plasma ET-1 and echocardiographic findings in obese individuals with and without OSA, as well as in non-obese patients with OSA. Methods: Ninety-seven subjects (56 males) were enrolled in the study. All subjects underwent the following tests: venous endothelin-1 levels, pulmonary function testing, and arterial blood gas analysis. All patients except controls underwent transthoracic echocardiography and portable testing for sleep-disordered breathing. Results: Plasma ET-1 levels were significantly higher in obese patients, both with and without OSA (respectively, n = 30 (mean value, 268.06 ± 49.56 pg/ml) and n = 32 (mean value, 263.12 ± 65.26 pg/ml)), compared with non-obese patients with OSA or to healthy controls (respectively, n = 20 (mean value, 149.8 ± 23.09 pg/ml) and n = 15 (mean value, 152.3 ± 27.64 pg/ml); p < 0.0001). Pulmonary artery pressure (PAPs) in obese patients with OSA were significantly higher than in obese patients without OSA (p < 0.0001), while there was no statistical difference between PAPs of obese patients without OSA, compared with the group of non-obese OSA patients. Plasma ET-1 levels significantly correlated with systolic PAPs in obese patients both with and without OSA (respectively, n = 30, r = 0.385, p = 0.03567; n = 32, r = 0.3497, p = 0.0497). Conclusions: Our study suggests that endothelin levels are more strongly associated with weight than the presence of sleep-disordered breathing, but pulmonary artery hypertension is associated with both weight and OSA.
    Full-text · Article · Sep 2015 · Sleep And Breathing

  • No preview · Conference Paper · Sep 2015

  • No preview · Article · Sep 2015

  • No preview · Article · Sep 2015 · European Respiratory Journal

  • No preview · Article · Sep 2015
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    ABSTRACT: Phospholipases A2 (PLA2) are enzymes which specifically hydrolyze the sn-2 acyl ester bond of phospholipids producing free fatty acids and lysophospholipids. The secreted PLA2 (sPLA2) are the most common types of PLA2 purified from the snake venom, mammalian pancreatic juice and other sources. They display a variety of toxic actions and biological activities, including antitumoral and antiangiogenic effects. In this study, we report the isolation, characterization and the antiangiogenic activity of Hemilipin, a novel sPLA2 extracted from Hemiscorpius lepturus venom, the most dangerous scorpion in Iran. Hemilipin was purified by HPLC and analyzed by MALDI TOF/MS. The primary structure was determined by EDMAN degradation method and the PLA2 activity by titration of fatty acids released from the egg yolk phospholipids. Its antiangiogenic activity was studied in vitro by evaluating effects on apoptosis, Matrigel angiogenesis, migration and adhesion of human umbilical vein endothelial cells (HUVECs) and human pulmonary artery endothelial cells (HPAECs) and in vivo by the chorioallontoic membrane (CAM) assay. Mass spectrometry profile showed that Hemilipin is heterodimeric and the PLA2 test demonstrated its strong hydrolytic activity. N-terminal amino acid sequence highlighted a significant homology of Hemilipin's small and large subunits with other sPLA2 group III. Hemilipin had no effect on apoptosis, but strongly impacted angiogenesis both in vitro and in vivo. Our results demonstrate that this novel non toxic sPLA2 could be a new tool to disrupt at different steps human angiogenesis. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Aug 2015 · Toxicon
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    ABSTRACT: 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.
    Preview · Article · Aug 2015 · International Journal of Stem Cells
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    ABSTRACT: Many researchers have speculated that the clinical progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is driven by defects in dendritic cell (DC) function. Evidence supporting this assumption is, however, controversial and no mechanism for the putative DC dysfunction has so far been demonstrated. We studied DC subsets from the bone marrow of MM patients, in comparison to those of MGUS patients and control subjects. We found that myeloid DC (mDC) and plasmacytoid DC (pDC) accumulate in the bone marrow during the MGUS-to-MM progression. After engulfment of apoptotic tumor plasma cells via CD91, bone marrow mDC and pDC mature and are able to activate tumor-specific CD8(+) T cells. However, by interacting directly with CD28 on live (non-apoptotic) tumor plasma cells, bone marrow mDC downregulate the expression of proteasome subunits in these cells, thus enabling their evasion from HLA class I-restricted CD8(+) T cell killing. These results suggest that DC play a dual, but opposing role in MM: on one hand DC activate CD8(+) T cells against tumor plasma cells and, on the other hand, DC protect tumor plasma cells from CD8(+) T cell killing. This information should be taken into account in designing immunotherapy approaches to enhance immune surveillance in MGUS and to break down immune tolerance in MM. Copyright © 2015 American Society of Hematology.
    No preview · Article · Jul 2015 · Blood
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    ABSTRACT: AIM: To evaluate vascular endothelial growth factor (VEGF) and tryptase in hepatocellular cancer (HCC) before and after trans-arterial chemoembolization (TACE). METHODS: VEGF and tryptase serum concentrations were assessed from 71 unresectable HCC patients before and after hepatic TACE performed by binding ® DC-Beads to doxorubicin. VEGF levels were examined for each serum sample using the Quantikine Human VEGF-enzyme-linked immuno-absorbent assay (ELISA), whereas tryptase serum concentrations were assessed for each serum sample by means of fluoro-enzyme immunoassay (FEIA) using the Uni-CAP100 tool. Differences between serum VEGF and tryptase values before and after TACE were evaluated using Student t test. Person's correlation was used to assess the degree of association between the two variables. RESULTS: VEGF levels and serum tryptase in HCC patients before TACE had a mean value and standard deviation (SD) of 114.31 ± 79.58 pg/mL and 8.13 ± 3.61 μg/L, respectively. The mean levels and SD of VEGF levels and serum tryptase in HCC patients after TACE were 238.14 ± 109.41 pg/mL and 4.02 ± 3.03 μg/L. The changes between the mean values of concentration of VEGF and tryptase before treatment and after treatment was statistically significant (P < 0.000231 and P < 0.00124, by Wilcoxon-Mann-Whitney respectively). A significant correlation between VEGF levels before and after TACE and between tryptase levels before and after TACE was demonstrated (r = 0.68, P = 0.003; r = 0.84, P = 0.000 respectively). CONCLUSION: Our pilot results suggest that the higher serum VEGF levels and the lower tryptase levels following TACE may be potential biomarkers changing in response to therapy.
    Full-text · Article · May 2015 · World Journal of Gastroenterology
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    ABSTRACT: While multiple myeloma (MM) is almost invariably preceded by asymptomatic monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM), the alterations of the bone marrow (BM) microenvironment that establish progression to symptomatic disease are circumstantial. Here we show that in Vk*MYC mice harboring oncogene-driven plasma cell proliferative disorder, disease appearance associated with substantial modifications of the BM microenvironment, including a progressive accumulation of both CD8+ and CD4+ T cells with a dominant T helper type 1 (Th1) response. Progression from asymptomatic to symptomatic MM was characterized by further BM accrual of T cells with reduced Th1 and persistently increased Th2 cytokine production, which associated with accumulation of CD206+Tie2+ macrophages, and increased pro-angiogenic cytokines and microvessel density (MVD). Notably, MVD was also increased at diagnosis in the BM of MGUS and SMM patients that subsequently progressed to MM when compared with MGUS and SMM that remained quiescent. These findings suggest a multistep pathogenic process in MM, in which the immune system may contribute to angiogenesis and disease progression. They also suggest initiating a large multicenter study to investigate MVD in asymptomatic patients as prognostic factor for the progression and outcome of this disease.
    Full-text · Article · May 2015 · OncoImmunology
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    ABSTRACT: Allergic reactions to mannitol have been reported rarely, despite its widespread use as a drug and as a food excipient. This is the first case report in which oral mannitol induces an immediate type hypersensitivity as a drug excipient, in a 42 year old man affected by rhinitis to olive tree pollen. Unusual and undervalued risk factors for mannitol hypersensitivity are examined.
    Full-text · Article · May 2015 · European annals of allergy and clinical immunology
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    Full-text · Article · Feb 2015 · Journal of Allergy and Clinical Immunology
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    Domenico Ribatti · Beatrice Nico · Angelo Vacca
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    ABSTRACT: Bone marrow (BM) contains hematopoietic stem cells (HSCs) and nonhematopoietic cells. HSCs give rise to all types of mature blood cells, while the nonhematopoietic component includes osteoblasts/osteoclasts, endothelial cells (ECs), endothelial progenitor cells (EPCs), and mesenchymal stem cells (MSCs). These cells form specialized "niches" which are close to the vasculature ("vascular niche") or to the endosteum ("osteoblast niche"). The "vascular niche", rich in blood vessels where ECs and mural cells (pericytes and smooth muscle cells), create a microenvironment affecting the behavior of several stem and progenitor cells. The vessel wall acts as an independent niche for the recruitment of EPCs and MSCs. This chapter will focus on the description of the role of BM niches in the control of angiogenesis occurring during multiple myeloma progression. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Jan 2015 · International review of cell and molecular biology
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    ABSTRACT: 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.
    No preview · Article · Jan 2015
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    ABSTRACT: Metronomic chemotherapy (MC) refers to the close administration of a chemotherapeutic drug for a long time with no extended drug-free breaks. It was developed to overcome drug resistance, partly by shifting the therapeutic target from tumor cells to the tumor vasculature, with less toxicity. Because of this peculiar way of administration, MC can be viewed as a form of long-term ‘maintenance’ treatment, and can be integrated with standard and conventional chemotherapy in a “chemo-switching” strategy. Additional mechanisms are involved in its antitumor activity, such as activation of immunity, induction of tumor dormancy, chemotherapy-driven dependency of cancer cells, and the ‘4D effect’. In this paper we report the most important studies that have analysed these processes. In fact, a number of preclinical and clinical studies in solid tumors as well as in multiple myeloma, have been reported regarding several chemotherapy drugs which have been proposed with a metronomic schedule: vinorelbine, cyclophosphamide, capecitabine, methotrexate, bevacizumab, etoposide, gemcitabine, sorafenib, everolimus and temozolomide. The results of these studies have been sometimes conflicting, highlighting the need to develop reliable tools for patient selection and stratification. However, a more precise evaluation of MC strategies with the ongoing randomized phase II/III clinical is fundamental, because of the strict correlation of this approach with translational research and target therapy. Moreover, because of the low toxicity of MC, these studies will also help to better evaluate the clinical benefit of this treatment, with a special focus on elderly and low performance status patients.
    Full-text · Article · Jan 2015 · Critical Reviews in Oncology/Hematology
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    ABSTRACT: This current retrospective multicenter analysis represents, to our knowledge, the first Italian study evaluating the efficacy and toxicity profile of “lenalidomide plus dexamethasone” as salvage therapy in patients with recurrent-refractory MM in the real life contest. Our study included patients who are usually excluded from clinical trials because of unfavourable baseline characteristics. Median OS was significantly longer in patients receiving “lenalidomide plus dexamethasone” for more than 12 months compared with those who had received “lenalidomide plus dexamethasone” for a shorter interval (P < 0.0001). Median OS was not affected by best response achieved (P 0.4) and age (P 0.3). Quality of response did not correlate with number of previous lines of therapy (P 0.77) and age. Higher ORRs were recorded in the patients group with relapsed MM compared to those with refractory disease, but this difference was not statistically significant (P 0.38).
    No preview · Article · Dec 2014 · Leukemia Research
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    ABSTRACT: Tumor microenvironment plays an important role in cancer initiation and progression. In hematological malignancies, the bone marrow represents the paradigmatic anatomical site in which tumor microenvironment expresses its morphofunctional features. Among the cells participating in the composition of this microenvironment, cancer associated fibrobasts (CAFs) have received less attention in hematopoietic tumors compared to solid cancers. In this review article, we discuss the involvement of CAFs in progression of hematological malignancies and the potential targeting of CAFs in a therapeutic perspective.
    Full-text · Article · Nov 2014 · Oncotarget

Publication Stats

12k Citations
1,454.43 Total Impact Points

Institutions

  • 1984-2015
    • Università degli Studi di Bari Aldo Moro
      • • Dipartimento di Scienze Biomediche ed Oncologia Umana (DIMO)
      • • Department of Chemistry
      Bari, Apulia, Italy
  • 2003-2014
    • Policlinico di Bari
      • Department of Allergy and Clinical Immunology
      Bari, Apulia, Italy
  • 2002
    • Azienda Ospedaliera Pugliese Ciaccio
      • Department of Oncology and Hematology
      Catanzaro, Calabria, Italy
    • Università degli Studi di Trieste
      Trst, Friuli Venezia Giulia, Italy
  • 2000
    • Università degli Studi del Sannio
      Benevento, Campania, Italy