Search PubMed⌕ Search

Biomedical subjects

Angelo Vacca

Publications and source records attributed to Angelo Vacca.

53 records · Page 3Linked to original sources
PubMed2002

In vivo angiogenic activity of neuroblastoma correlates with MYCN oncogene overexpression.

Neuroblastoma (NB) is the most common malignant solid tumor in early childhood. Amplification of the MYCN oncogene is associated with a more malignant course of disease and poor outcome. The role that MYCN plays in the regulation of angiogenesis in NB remains unclear. To better elucidate this matter, fresh biopsy samples from 21 patients, 10 with MYCN-amplified tumors (defined as having >10 copies of the oncogene) and 11 with nonamplified tumors, were tested for their angiogenic capacity using the chick embryo chorioallantoic membrane assay, a useful model for such investigation. Moreover, using the same experimental model, conditioned media obtained from 5 different human NB cell lines MYCN-amplified (HTLA-230, LAN-5 and GI-LI-N) or nonamplified (ACN and SH-SY5Y) and biopsy fragments obtained from xenografts derived from 4 NB cell lines (HTLA-230, GI-LI-N, ACN and SH-SY5Y) injected in nude mice were assayed for angiogenic potential. Our results clearly demonstrated that MYCN amplification parallels angiogenesis in NB. When fresh biopsy samples from patients, CM derived from NB cell lines and biopsy fragments derived from xenografts of the same cell lines injected in nude mice were tested, the response was univocal: the angiogenic response, evaluated both macroscopically and microscopically, was significantly higher in the MYCN-amplified specimens compared to the nonamplified ones.

Adolescent↗
PubMed2002

Prognostic value of enhanced bone marrow angiogenesis in early B-cell chronic lymphocytic leukemia.

Because tumor progression is angiogenesis-dependent, angiogenesis density was investigated by immunohistochemistry and computed image analysis in bone marrow (BM) biopsies of 45 newly diagnosed patients with Binet stage A B-cell chronic lymphocytic leukemia (BCLL) and correlated to upstaging and progression-free survival during a 40-month follow-up period. Their microvessel areas and counts were significantly higher than those of patients with anemia due to iron or vitamin B(12) deficiencies. A cutoff value of 0.90 mm(2) x 10(-2) or greater of the microvessel area identified patients with earlier upstaging and shorter progression-free survival. When the cutoff was applied to the Rai subclassification, both Rai 0 and Rai I-II patients who upstaged and shortened the progression-free survival were classified correctly. Information of this type was not given by the microvessel counts. The cutoff did not correlate with other predictors representative of tumor mass or disease progression. The microvessel area correlated with the expression of angiogenic vascular endothelial growth factor (VEGF) by tumor tissue, and serum levels of VEGF were found to be of prognostic value. A causal relationship between risk of progression and BM angiogenesis in BCLL is suggested. A risk stratification inside Rai is proposed. The prognostic usefulness of BM angiogenesis in patients with BCLL is envisaged.

Adult↗
PubMed2002

Vascular endothelial growth factor and vascular endothelial growth factor receptor-2 expression in mdx mouse brain.

Recent data have demonstrated that vascular endothelial growth factor (VEGF) is expressed by subsets of neurons, coincident with angiogenesis within its developing cerebral cortex. In this study, with the aim of elucidating the mechanisms of vascular involvement during brain impairment in Duchenne muscular distrophy (DMD), we have correlated the vascular density with VEGF and VEGF receptor-2 (VEGFR-2) expression in the brain cortex of normal and mdx mouse, an animal model with a genetic defect in a region homologous with the human DMD gene. Results showed that in mdx mouse, tissue area occupied by microvessels positive to factor VIII related antigen and VEGFR-2 increased in parallel to the tissue area occupied by neurons positive to VEGF. Our data suggest that increased vascularity in the brain of mdx mouse may be due, at least in part, to proliferation of endothelial cells in response to VEGF secreted by neuronal cells.

Animals↗
PubMed2002

In situ hybridization and immunogold localization of vascular endothelial growth factor receptor-2 on the pericytes of the chick chorioallantoic membrane.

This paper describes the expression of VEGF and of VEGFR-2 in the vasculature of the chorioallantoic membrane (CAM) as revealed by in situ hybridization and immunoelectron microscopy. Results showed that VEGFR-2 is expressed in both the endothelial cells and the pericytes, while VEGF in the chorionic epithelial cells. VEGF may therefore be released to promote both angiogenesis, by initiating an angiogenic response by endothelial cells expressing VEGFR-2, and the recruitment of pericytes along the capillary wall, playing also a crucial role in maturation and stabilization of the CAM blood vessels.

Animals↗
PubMed2002

The human melanoma associated protein melanotransferrin promotes endothelial cell migration and angiogenesis in vivo.

Melanotransferrin is a member of the transferrin family, which is comprised of serum transferrin, lactoferrin and ovotransferrin, and is highly expressed on melanoma cells compared to normal melanocytes. Since melanoma is an highly vascularized tumour that expresses melanotransferrin at high levels, we tested purified recombinant melanotransferrin for its capability to induce angiogenesis in the chick chorioallantoic membrane. Macroscopic and microscopic evaluation of the vascular density demonstrated that melanotransferrin exerts an angiogenic response quantitatively similar to that elicited by fibroblast growth factor-2. Overexpression of vascular endothelial growth factor-receptor-2 was observed in newly formed vessels, suggesting that the angiogenic activity of melanotransferrin may depend on activation of endogenous vascular endothelial growth factor. In addition, when antibodies against vascular endothelial growth factor were included in the assay, the angiogenic response was inhibited by 50%. In a Boyden chamber assay purified recombinant melanotransferrin induced chemotactic migration of vascular cells, which was decreased in the the presence of anti-vascular endothelial growth factor antibodies suggesting an involvement of vascular endothelial growth factor present in endothelial cells also in this assay. However, melanotransferrin was found not to directly bind to integrin alphavbeta3 or the vascular endothelial growth factor-receptor-2 as assessed in a BlAcore assay. A possible correlation between vascularization occurring during melanoma progression and the expression of melanotransferrin and vascular endothelial growth factor was established by immunolocalization of the two factors in sections of melanoma at different clinical steps of melanoma progression. These latter data strongly imply that melanotransferrin may participate in the vascularization of solid tumours and that inhibition of melanotransferrin could form the basis for intervention in tumours which use this pathway.

Adult↗
PubMed2002

Mast cell heterogeneity in B-cell non-Hodgkin's lymphomas: an ultrastructural study.

Mast cells (MC) are critical for a number of pathological conditions, including acute and chronic inflammation and tumor angiogenesis. We have previously demonstrated that in B-cell non-Hodgkin's lymphoma (B-NHL) angiogenesis is correlated with total methachromatic and tryptase-positive MC and that both counts increase in step with the increase in malignancy, whereas the role of MC in malignant lymph nodes is not fully clear. An extensive ultrastructural study has been made of representative samples of 30 B-NHL and 10 benign lymphadenopathies. A heterogeneous population of MC characterized by the presence of granules with a semilunar aspect and containing scrolls was observed. The former are the expression of a slow but progressive release of angiogenic factors due to chronic, progressive stimulation of MC degranulation, while the latter contain tryptase, an angiogenic factor. These two ultrastructural data confirm the important role played by MC in the angiogenesis associated with progression in B-NHL.

Cell Degranulation↗
PubMed2002

Endothelial cell heterogeneity and organ specificity.

Endothelial cells consist of a heterogeneous population covering the entire inner surface of blood vessels. This review will focus on the factors influencing this heterogeneity including: (1) morphological and functional differences between large and small vessels and between cells derived from various microvascular endothelial beds; (2) the microenvironment and extracellular matrix modulating the phenotype; (3) different response to growth factors; (4) organ specificity reflecting the cumulative expression of post-translation modifications and also the expression of unique genes under the control of organ-specific regulatory elements; and (5) pathological conditions, such as tumor growth, which is accompanied by the development of a characteristic tumor vasculature and tumors formed by endothelial cells.

Animals↗
PubMed2002

Docetaxel versus paclitaxel for antiangiogenesis.

Cytoskeleton-toxic chemotherapeuticals, such as vinblastine and paclitaxel, display antiangiogenic activity. This study was designed to compare paclitaxel to its analog docetaxel and assess their doses still antiangiogenic in vitro and in vivo. Human endothelial cell functions involved in angiogenesis, namely proliferation, chemotaxis, morphogenesis, and secretion of matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-type plasminogen activator (uPA) were studied in vitro upon exposure to docetaxel and paclitaxel, whereas their effect on angiogenesis was studied in vivo by using the chick embryo chorioallantoic membrane (CAM) model. Proliferation of mouse embryo fibroblasts and human Kaposi's sarcoma, breast and endometrial carcinoma, and lymphoid tumor cells was also studied. In vitro, 0.5, 0.75, and 1 nM docetaxel and 2, 3, and 4 nM paclitaxel, i.e., non-cytotoxic doses, impacted all endothelial cell functions, but not protease secretion, in a dose-dependent fashion, whereas they did not affect the proliferation of other cells, except those of Kaposi's sarcoma. No apoptosis was induced by 0.5 nM docetaxel and 2 nM paclitaxel, and moderate apoptosis was induced by 1 nM docetaxel and 4 nM paclitaxel. The antiangiogenic effect rapidly disappeared on drug suspension and was accompanied ultrastructurally by thin lesions of cytoskeleton in the form of slight and equally reversible depolymerization and accumulation of microfilaments. Massive endothelial cell apoptosis with evident cytotoxicity and irreversibility were associated with 2 nM docetaxel and 5 nM paclitaxel, although these higher doses were ineffective on other cells except Kaposi's sarcoma cells. In vivo, 1, 2, and 3 nM docetaxel and 4, 8, and 12 nM paclitaxel displayed a dose-dependent antiangiogenic activity. We suggest that very low docetaxel and paclitaxel doses selectively cause organic and functional damage of endothelial cells and that docetaxel is four times stronger. Their antiangiogenic activity could be applied to treat Kaposi's sarcoma and cancers.

Angiogenesis Inhibitors↗
PubMed2002

Human chorionic gonadotropin inhibits Kaposi's sarcoma associated angiogenesis, matrix metalloprotease activity, and tumor growth.

Kaposi's sarcoma is a highly angiogenic, AIDS-associated neoplasm that is more frequent in male than in female patients. Cases of spontaneous regression during pregnancy have been reported and the pregnancy hormone human chorionic gonadotropin (hCG) has shown anti-Kaposi's sarcoma activity in several, but not all, clinical trials. Antiproliferative and proapoptotic activities specific for Kaposi's sarcoma (KS) cells have been shown. We report here further analyses of the anti-KS activity of the hormone and show that urinary hCG, the hCG beta-subunit, the hCG beta-core, and to a lesser extent a recombinant hCG, directly inhibit the activity of matrix metalloproteases of different origin. The hCG hormone also inhibited angiogenesis in vivo in the matrigel sponge assay as well as growth of KS cell xenografts in nude mice. The effect of the pure recombinant hormone dimer on xenograft growth was transient, indicating that the activity of intact hCG alone is not sufficient to overcome the growth potential of this tumor and suggesting that active hCG fragments or other anti-KS activities contribute to the activity of urinary hCG.

Animals↗
PubMed2002

Cross-talk between hematopoiesis and angiogenesis signaling pathways.

The relationship between hematopoietic cells and endothelial cells has been seen as an indication that a common progenitor, the hemangioblast, gives rise to both cell types in the yolk sac, the initial site of hematopoiesis and blood vessel formation during mammalian development. The existence of angioblast-like circulating endothelial precursor cells in adults humans has recently been suggested. In this review, we have summarized the principle mechanisms involved in the cross-talk signaling pathway between hematopoiesis and angiogenesis in order to further understand how the hematopoietic and vascular systems are established during the development.

Animals↗
PubMed2002

Salvage therapy with thalidomide in patients with advanced relapsed/refractory multiple myeloma.

BACKGROUND AND OBJECTIVES: Few therapeutic options are presently available for patients with multiple myeloma (MM) who relapse after autologous or allogeneic stem cell transplantation, or for patients who are refractory to conventional chemotherapy and not eligible for salvage high-dose therapy. Thalidomide, a glutamic acid derivative with anti-angiogenic properties, has been recently proposed as an effective therapy for patients with advanced refractory disease. The aim of this study was to evaluate the activity of thalidomide in a large series of MM patients. DESIGN AND METHODS: From October 1999 to January 2001, 65 patients (46 males/19 females) from 8 Italian institutions were treated with thalidomide. Twenty-six patients had relapsed after autologous stem cell transplantation, either single (n = 12) or double (n= 12); 38 patients had shown disease progression after >= 2 lines of conventional chemotherapy, 2 patients had relapsed after allotransplant, one single patient had not received previous treatment. Sixty-one (93.8%) patients were in stage III, median b2 microglobulin was 2.9 mg/L, and median bone marrow plasma cell infiltration was 50%. Thalidomide was initially administered at a dose of 100 mg/day; if well tolerated, the dose was to be increased serially by 200mg every other week to a maximum of 800 mg/day. RESULTS: The median administered dose of thalidomide was 400 mg/day. WHO grade > II toxic effects were constipation (52%), lethargy (34%), skin rash (11%), peripheral neuropathy (14%) and leukopenia (3%). Sixty patients are presently evaluable for response; of these, 17 (28.3%) showed > or = 50% reduction in serum or urinary M protein concentration and 11 (18.3%) showed > or = 25% tumor reduction, for a total response rate averaging 46.6%. After a median of 8 months' follow-up, 15/28 patients are alive and progression-free (at 2 to 16 months), 12 patients have relapsed, and 1 patient died of pulmonary edema while still in partial remission. Among pre-treatment variables that were analyzed for their potential relationship with tumor response, only the concentration of vascular endothelial growth factor (VEGF) in the conditioned media obtained upon culture of bone marrow plasma cells was statistically significant. Plasma cells from patients who responded favorably to thalidomide secreted a significantly lower amount of VEGF than plasma cells from resistant patients (126.45 165 pg/mL vs 227.11 70 pg/mL, p=0.04). INTERPRETATION AND CONCLUSIONS: These data confirm that thalidomide is active in patients with advanced relapsed/refractory MM and represent the basis for ongoing clinical trials aimed at testing the role of this drug as front line therapy for newly diagnosed disease.

Adult↗
PubMed2002

Angiogenic activity of rat mast cells in the chick embryo chorioallantoic membrane is down-regulated by treatment with recombinant human alpha-2a interferon and partly mediated by fibroblast growth factor-2.

BACKGROUND AND OBJECTIVES: Many data suggest that the density of mast cells (MC) is strongly correlated with the extent of both normal and pathologic angiogenesis, such as the vessel formation that occurs in chronic inflammatory diseases and tumors. We have previously demonstrated that isolated MC and their secretory granules, but not degranulated MC, induce an angiogenic response in the chick embryo chorioallantoic membrane (CAM) assay. DESIGN AND METHODS: The aim of this study was to investigate whether pre-treatment of MC with an anti-angiogenic molecule, namely recombinant human interferon-alpha2a (rhIFN-alpha2a), reduced the angiogenic activity of their conditioned media (CM) in the CAM assay. RESULTS: Our data indicate that rhIFN-alpha2a at 500-1000 IU is able to reduce the angiogenic activity of CM significantly. When MC were treated with rhIFN-alpha2a at 25-250 IU they retained their angiogenic activity. Addition of anti-fibroblast growth factor-2 (FGF-2) antibodies (but not anti-vascular endothelial growth factor) substantially reduced the angiogenic activity of CM treated with sub-optimal concentrations of rhIFN-alpha2a. INTERPRETATION AND CONCLUSIONS: FGF-2 may be the main angiogenic factor secreted by MC and higher concentrations of rhIFN-alpha2a possibly inhibit angiogenesis by blocking the actions of FGF-2 produced by MC. Finally, the morphologic features of MC treated with rhIFN-alpha2a, characterized by an atypical secretory pathway, are compatible with a slow release of the angiogenic cytokines stored in MC granules.

Allantois↗
PubMed2002

Alpha(v)beta(3) integrin engagement enhances cell invasiveness in human multiple myeloma.

BACKGROUND AND OBJECTIVES: In multiple myeloma (MM), the mechanisms used by plasma cells to invade locally and metastasize are thought to be similar to those developed by solid tumors and include cell proliferation and secretion of extracellular matrix (ECM) degrading enzymes following adhesion to ECM proteins. We studied these mechanisms in fresh bone marrow plasma cells of patients with MM after adhesion to the ECM proteins vitronectin (VN) and fibronectin (FN). DESIGN AND METHODS: The ability of bone marrow plasma cells to adhere to VN and FN and the consequent formation of focal adhesion plaques on the cell surface, their composition and phosphorylation of several signal transduction proteins, cell proliferation and secretion of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) and urokinase-type plasminogen activator (uPA) were studied. RESULTS: Plasma cells adhered to immobilized VN and FN. Adhesion was fully prevented by neutralizing anti-avb3 integrin antibody. Integrin engagement caused aggregation of the plaques, which contained the b3 integrin subunit, some cytoskeletal proteins, tyrosine kinases, the Grb-2 adapter protein, and mitogen-activated protein (MAP) kinase. Free and immobilized VN and FN stimulated cell proliferation and the production and the release of uPA, and increased the release of the activated forms of MMP-2 and MMP-9 in an avb3 integrin-dependent manner. INTERPRETATION AND CONCLUSIONS: This ability of myeloma plasma cells to interact with VN and FN via avb3 integrin engagement suggests a novel mechanism for their invasion and spreading, since this interaction allows them to adhere to the substratum and enhances their proliferation and protease secretion.

Adaptor Proteins, Signal Transducing↗
PubMed2002

[Chemokines and tumors].

Chemokines are cytokines which induce chemotaxis on many cell types, thus regulating cell migration within inflammatory and allergic sites, and leucocyte homing. Also, they play a crucial role in inflammatory and tumor-associated angiogenesis, as well as in tumor progression. Chemokines are grouped into: 1) alpha or CXC; 2) beta or CC; 3) gamma or C; 4) delta or CX3C molecules. Each of them recognizes one or more cell surface receptors, named CXCR, CCR, XCR, CX3CR respectively, according to the corresponding subfamily. Many chemokines have been identified within tumor tissues, as a secretory product of tumor cells and/or inflammatory cells. The CXC chemokines (such as IL-8, IP10, Mig, SDF-1 alpha) or CC chemokines (such as MCP-1, MIP-1 alpha, eotaxin, RANTES) have been frequently harvested from tumor tissues or the biological fluids of patients. Some chemokines inhibit tumor growth and progression by activating immunocompetent cytolytic cells or inhibiting tumor-associated angiogenesis. In contrast, other chemokines induce tumor progression by interacting with the specific receptor expressed on the tumor cells and hence by activating chemotaxis and secretion of proteolytic enzymes, or by inducing angiogenesis and metastatic spreading. Sometimes neoplastic cells express chemokine receptors which are not expressed on their normal counterpart. Data from this lab show the CXCR3 expression by cells from lymphoproliferative diseases, such as multiple myeloma and lymphoma, and the stimulation of an invasive phenotype following interaction with specific chemokines.

Chemokines↗
PubMed2001

In vivo activation of JAK2/STAT-3 pathway during angiogenesis induced by GM-CSF.

Besides the regulation of hematopoiesis, granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the expression of a functional program in cultured endothelial cells (ECs) related to angiogenesis and to the their survival in bone marrow microenvironment. ECs express the specific GM-CSF receptor that signals through the recruitment and the activation of Janus kinase (JAK)2 (Soldi et al., Blood 89, 863-872, 1987). We now report that GM-CSF in vivo induces angiogenesis and activates JAK-2 and signal transducers and activators of transcription (STAT)-3. This cytokine has an angiogenetic activity in chick chorioallantoic membrane (CAM) without recruitment of inflammatory cells and induces vessel sprouting from chicken aorta rings. When added to CAM, subnanomolar concentrations of GM-CSF cause a rapid phosphorylation in tyrosine residues of JAK-2 persisting at least for 10 min. Furthermore, we show that signal transducers and activators of transcription (STAT)-3, but not STAT-5, also are phosphorylated for 30 min after GM-CSF stimulation. AG-490, a JAK-2 inhibitor, reduced in a dose-dependent manner the angiogenic effect of GM-CSF in CAM. These findings provide the first evidence that the JAK-2/STAT-3 pathway is activated in vivo and participates in vessel formation triggered by GM-CSF.

Allantois↗
PubMedDate not supplied

Angiogenesis: basic and clinical aspects.

The cardiovascular system is the first functional organ system to develop in the vertebrate embryo. A widely accepted view is that blood vessels arise through two mechanisms during development, vasculogenesis and angiogenesis. New vessels in the adult arise mainly through angiogenesis, although vasculogenesis also may occur. The existence of a postnatal vasculogenesis is also supported by the evidence that both endothelial cells and endothelial precursor cells co-exist in the circulation. Angiogenesis is a biological process by which new capillaries are formed and it occurs in many physiological and pathological conditions. It is controlled by the net balance between molecules that have positive and negative regulatory activity and this concept had led to the notion of the "angiogenic switch", depending on an increased production of one or more of the positive regulators of angiogenesis. Considerable benefit can be derived in the clinical setting from manipulating angiogenesis, either positively or negatively. There is a variety of important clinical situations in which it would be desiderable to promote angiogenic processes, such as situations in which it would be desiderable to promote angiogenic processes, such as for the induction of collateral vascularization in an ischemic heart or limb. Conversely, there are pathologic conditions in which preventing angiogenic processes could be useful in the treatment of a growing tumor or a chronic inflammatory process.

Angiogenesis Inhibitors↗