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Biomedical subjects

Domenico Ribatti

Publications and source records attributed to Domenico Ribatti.

At least 55 records · Page 3Linked to original sources
PubMed2005

Integrin alphavbeta3 as a target for blocking HIV-1 Tat-induced endothelial cell activation in vitro and angiogenesis in vivo.

OBJECTIVE: The transactivating factor (Tat) of HIV-1 binds to alphavbeta3 integrin present on endothelial cells contributing to neovascularization. Here, we investigated the biological consequences of Tat/alphavbeta3 interaction and the antagonist effect of an Arg-Gly-Asp (RGD)-based peptidomimetic. METHODS AND RESULTS: Binding of Tat to endothelial alphavbeta3 triggers focal adhesion kinase and nuclear factor-kappaB activation, leading to endothelial cell proliferation, membrane ruffling, and motility in vitro and neovascularization in vivo. The RGD-peptidomimetic SCH221153 inhibits Tat/alphavbeta3 interaction in a solid phase binding assay and endothelial cell adhesion to immobilized Tat with a potency higher than that of RGD-containing peptides. Accordingly, SCH221153 inhibits Tat/alphavbeta3-dependent focal adhesion kinase and nuclear factor-kappaB activation, proliferation, membrane ruffling, and motility in endothelial cells. Finally, SCH221153 inhibits the angiogenic response triggered by Tat in the chick-embryo chorioallantoic membrane without affecting physiological vascularization. SCH221153 exerts these inhibitory effects without affecting the interaction of Tat with endothelial heparan sulfate proteoglycans or with the vascular endothelial growth factor receptor-2/kinase domain-containing receptor. In all the assays the negative control SCH216687 was ineffective. CONCLUSIONS: These data provide new insights on the mechanism of endothelial cell activation by Tat and point to RGD peptidomimetics as prototypes for the development of novel Tat antagonists.

Animals↗
PubMed2005

Thalidomide downregulates angiogenic genes in bone marrow endothelial cells of patients with active multiple myeloma.

PURPOSE: To study the antiangiogenic effect of thalidomide. PATIENTS AND METHODS: The expression of key angiogenic genes was studied in bone marrow endothelial cells (ECs) of patients with active and nonactive multiple myeloma (MM), monoclonal gammopathies unattributed/unassociated (MG[u]), diffuse large B-cell non-Hodgkin's lymphoma, in a Kaposi's sarcoma (KS) cell line, and in healthy human umbilical vein ECs (HUVECs) following exposure to therapeutic doses of thalidomide. RESULTS: Thalidomide markedly downregulates the genes in a dose-dependent fashion in active MMECs and KS cell line, but upregulates them or is ineffective in nonactive MMECs, MG(u)ECs, NHL-ECs, and in HUVECs. Secretion of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and hepatocyte growth factor also diminishes according to the dose in culture conditioned media (CM) of active MMECs and KS, whereas it does not change in the other CM. CONCLUSION: Inhibition by thalidomide is probably confined to the genes of active MMECs and KS. This would account for its higher efficacy in these diseases.

Adult↗
PubMed2005

Microvascular growth, development, and remodeling in the embryonic avian kidney: the interplay between sprouting and intussusceptive angiogenic mechanisms.

Embryonic development is associated with extensive vascular growth and remodeling. We used immunohistochemical, light and electron microscopical techniques, as well as vascular casting methods to study the developing chick embryo kidney with special attention to the interplay between sprouting and intussusceptive vascular growth modes. During inauguration at embryonic day 5 (E5), the early mesonephros was characterised by extensive microvascular sprouting. By E7, the vascular growth mode switched to intussusception, which contributed to rapid kidney vasculature growth up to E11, when the first obvious signs of vascular degeneration were evident. The metanephros underwent similar phases of vascular development inaugurating at E8 with numerous capillary sprouts and changing at E13 to intussusceptive growth, which was responsible for vascular amplification and remodeling. A phenomenal finding was that future renal lobules arose as large glomerular tufts, supplied by large vessels, which were split into smaller intralobular feeding and draining vessels with subsequent formation of solitary glomeruli. This glomerular duplication was achieved by intussusception, i.e., by formation of pillars in rows and their successive merging to delineate the vascular entities. Ultimately, the maturation of the vasculature was achieved by intussusceptive pruning and branching remodeling. An interesting finding was that strong VEGF expression was associated with the sprouting phase of angiogenesis while bFGF was upregulated during the phase of intussusceptive microvascular growth. We conclude that microvascular growth and remodeling in avian kidney follows an adroitly crafted pattern, which entails a precise spaciotemporal interplay between sprouting and intussusceptive angiogenic growth modes supported partly by VEGF and bFGF.

Animals↗
PubMed2005

The role of adrenomedullin in angiogenesis.

Adrenomedullin (AM) is a 52 amino acid peptide originally isolated from human pheochromocytoma. It was initially demonstrated to have profound effects in vascular cell biology, since AM protects endothelial cells from apoptosis, promotes angiogenesis and affects vascular tone and permeability. This review article summarizes the literature data concerning the relationship between AM and angiogenesis and describes the relationship between vascular endothelial growth factor, hypoxia and AM and tumor angiogenesis. Finally, the role of AM as a potential target of antiangiogenic therapy is discussed.

Adrenomedullin↗
PubMed2005

Antiangiogenic and vascular-targeting activity of the microtubule-destabilizing trans-resveratrol derivative 3,5,4'-trimethoxystilbene.

Neovascularization plays an important role in neoplasia and angioproliferative diseases. Two major modalities have been developed so far to affect neovascularization: its prevention by antiangiogenic compounds, and immature vessel disruption by vascular-targeting agents. trans-Resveratrol, found in grapes and wine, exerts antioxidant, antineoplastic, and antiangiogenic activities. Here, among various synthetic trans-resveratrol derivatives tested, 3,5,4'-trimethoxystilbene was an antiangiogenic agent 30 to 100 times more potent than parent compound in inhibiting endothelial cell proliferation, sprouting, collagen gel invasion, and morphogenesis (ID50 = 0.3-3.0 microM). In addition, 3,5,4'-trimethoxystilbene acts as a vascular-targeting agent by causing microtubule disassembling and tubulin depolymerization and by impairing the repositioning of the microtubule organization center and the formation of membrane ruffles in migrating endothelial cells. In keeping with a vascular-targeting ability, 3,5,4'-trimethoxystilbene induced apoptosis only in subconfluent endothelial cells and apoptotic regression of immature vessels in the ex vivo rat aorta ring assay. In vivo, 3,5,4'-trimethoxystilbene caused the rapid stasis of blood flow and regression of intersegmental vessels in the trunk of zebrafish embryos. In addition, it inhibited blood vessel growth and caused the disappearance of pre-existing blood vessels in the area vasculosa of the chick embryo. In conclusion, 3,5,4'-trimethoxystilbene associates an antiangiogenic profile to a significant vascular-targeting activity.

Angiogenesis Inhibitors↗
PubMed2005

Evaluation of the molecular mechanisms involved in the gain of function of a Li-Fraumeni TP53 mutation.

The TP53 tumor suppressor gene is the most frequent target for genetic alterations in human cancer. TP53 gene alterations may result in the gain of oncogenic functions such as neoangiogenesis and resistance to therapy. The TP53 germ line mutation c.659A>C (p.Y220S) was identified in stored DNA from related patients with Li-Fraumeni syndrome (LFS) who died after developing clinically aggressive tumors. All of the patients were treated with protocols that included doxorubicin hydrochloride (DX) as a pivotal drug. To define the in vitro mutational phenotype of this germ line mutation, we used murine fibroblasts explanted from wild-type (wt) and p53 knockout (KO) mice from the same littermate. p53Y220S and p53R175H fibroblasts, obtained from p53KO fibroblasts transfected with expression vectors encoding the human Y220S and R175H p53 mutants, respectively, exhibited resistance to DX treatment. Moreover, p53Y220S fibroblasts exhibited angiogenetic properties, and after DX treatment, p53Y220S failed to translocate into the nucleus and showed an increase in its cytosolic levels. DX treatment does not influence p53 distribution within the nuclear and cytosolic compartments in p53R175H fibroblasts. Peroxiredoxin II (Prx II), a protein that is involved in eliminating reactive oxygen species (ROS), showed increased expression intensity in p53Y220S fibroblasts after DX treatment, as observed by two-dimensional electrophoresis analysis. Moreover, Thioredoxin (Trx), a protein that cooperates with Prx II, is overexpressed in p53Y220S mutants under basal conditions. These data suggest a relationship between the presence of the p53Y220S mutation and enhanced levels of Prx II and Trx in mutant fibroblasts. Since one of the mechanisms of the DX antitumor effect has been ascribed to production of ROS, future studies will evaluate the involvement of PrxII and Trx in the chemoresistance of p53Y220S fibroblasts to DX.

Adolescent↗
PubMed2005

Bcl-2 overexpression in melanoma cells increases tumor progression-associated properties and in vivo tumor growth.

In this study, we demonstrated that bcl-2 overexpression in human melanoma cells consistently enhanced the activity of multiple metastasis-related proteinases, in vitro cell invasion, and in vivo tumor growth. In particular, by using the M14 parental cell line, the MN8 control clone, and two bcl-2 overexpressing derivatives, we found that bcl-2 overexpressing cells exposed to hypoxia, when compared to parental cells, expressed higher level of several metalloproteases (MMPs) such as MMP-2, MMP-7, MT1-MMP, and tissue inhibitors of metalloproteases-1 and -2. Moreover, bcl-2 overexpression in melanoma cells enhanced in vitro invasion on matrigel and, in vivo tumor growth. The more aggressive behavior of bcl-2 transfectants tumors is significantly associated to an increase in MMP-2 expression as well as in a more elevated microvessel density as compared to the parental line. Taken together, our data suggest that bcl-2 plays a pivotal role in the regulation of molecules associated with the migratory and invasive phenotype, contributing, in cooperation to hypoxia, to tumor progression.

Animals↗
PubMed2005

Neovascularization and mast cells with tryptase activity increase simultaneously with pathologic progression in human endometrial cancer.

OBJECTIVE: In vitro and in vivo studies have linked mast cell (MC) degranulation and activation with angiogenesis and neovascularization. This assumption is partially supported by the close anatomic association between MC and the vasculature and the recruitment of these cells during tumor growth. The aim of this study was to correlate the extent of angiogenesis with the number of MC expressing tryptase in human endometrial adenocarcinoma. STUDY DESIGN: Tissues from human endometrial hyperplasia and endometrial adenocarcinoma were investigated immunohistochemically, using 2 murine monoclonal antibodies against the endothelial cell marker CD31 and the MC marker tryptase. RESULTS: Angiogenesis, measured as microvessel counts, was highly correlated with MC tryptase-positive cell counts and that these parameters increase in agreement with tumor progression. CONCLUSION: These results suggest that angiogenesis in endometrial cancer increases with tumor progression and that angiogenic tryptase secreted by host MC cooperate in its induction.

Adenocarcinoma↗
PubMed2005

Human peripheral blood eosinophils induce angiogenesis.

Eosinophils play a crucial role in allergic reactions and asthma. They are also involved in responses against parasites, in autoimmune and neoplastic diseases, and in fibroses. There is increasing evidence that angiogenesis plays an important role in these processes. Since eosinophils are known to produce angiogenic mediators, we have hypothesized a direct contribution of these cells to angiogenesis. The effect of human peripheral blood eosinophil sonicates on rat aortic endothelial cell proliferation (in vitro), rat aorta sprouting (ex vivo) and angiogenesis in the chick embryo chorioallantoic membrane (in vivo) have been investigated. To determine whether eosinophil-derived vascular endothelial growth factor influences the eosinophil pro-angiogenic activity, eosinophil sonicates were incubated with anti-vascular endothelial growth factor antibodies and then added to the chorioallantoic membrane. Vascular endothelial growth factor mRNA expression and vascular endothelial growth factor receptor density on the endothelial cells were also evaluated. Eosinophils were found to enhance endothelial cell proliferation and to induce a strong angiogenic response both in the aorta rings and in the chorioallantoic membrane assays. Pre-incubation of eosinophil sonicates with anti-vascular endothelial growth factor antibodies partially reduced the angiogenic response of these cells in the chorioallantoic membrane. Eosinophils also increased vascular endothelial growth factor mRNA production on endothelial cells. Eosinophils are able to induce angiogenesis and this effect is partially mediated by their pre-formed vascular endothelial growth factor. This strongly suggests an important role of eosinophils in angiogenesis-associated diseases such as asthma.

Animals↗
PubMed2005

Osteocalcin is angiogenic in vivo.

The exact function of osteocalcin (OC), a protein synthesized by osteoblasts during the matrix mineralization phase, is still unknown. In this study we investigated the capacity of OC to promote vasoproliferation in chick embryo chorioallantoic membrane (CAM), a well established in vivo assay for angiogenesis and anti-angiogenesis. The results showed that OC stimulates angiogenesis and that the response is similar to that obtained with FGF-2, a well-known angiogenic cytokine. It has previously been demonstrated that OC is involved in bone repair, so the angiogenic activity reported here might also play a crucial role in bone formation.

Allantois↗
PubMed2005

Mast cells and eosinophils: a novel link between inflammation and angiogenesis in allergic diseases.

Mast cells and eosinophils are the key cells in the early and late stages of allergic inflammation. There is increasing evidence that angiogenesis plays an important role both in the development of inflammation and in the pathophysiology of tissue remodeling during allergic disorders. In this review we provide recent data showing a link between allergy and angiogenesis and some possible mechanisms through which vascular endothelial growth factor and the immune system can interact. We discuss the multifaceted roles of mast cells and eosinophils in tissue remodeling and angiogenesis during allergic diseases and whether these cells can be both source and target cells for pro-angiogenic mediators.

Animals↗
PubMed2005

Endothelial area and microvascular density in a canine non-Hodgkin's lymphoma: an interspecies model of tumor angiogenesis.

Experimental and clinical data indicate that tumor progression is associated with angiogenesis and that an increase in microvascular density (MVD) is associated with a poor prognosis, in both solid and hematological malignancies. No data have been published concerning the relationship between angiogenesis and malignancy grade in canine non-Hodgkin's lymphoma (NHL), which is a neoplasm that shares several biological and clinical characteristics with human NHL. In the present study, we evaluated this relationship in a series of 43 cases of canine NHL. The results demonstrate that both MVD and endothelial area (EA) were significantly higher in high-grade compared to low-grade lymphoma and a good statistical correlation was found between MVD and EA. These data indicate that increased angiogenesis paralleled with increased malignancy grade in canine NHL, which represents an interesting tumor model for studying the role of angiogenesis as an interspecies pathway of tumoral malignancy and biological aggressiveness.

Animals↗
PubMed2005

Piecemeal degranulation in human tumour pheochromocytes.

Piecemeal degranulation (PMD) has been recognized in two cases of human pheochromocytoma from the adrenal medulla, which were studied by transmission electron microscopy. Tumour pheochromocytes presented a highly characteristic cytoplasmic admixture of normal resting granules, swollen granules with eroded matrices and enlarged empty containers. Chromaffin granules that appeared to be normal and altered granules maintained their individual structure, and did not fuse with each other or with the plasma membrane. In accordance with the currently accepted model for granule discharge during PMD, electron-dense or clear vesicles 30-150 nm in diameter were seen either attached to the surface of chromaffin granules and the plasma membrane or free in the cytosol. This is the first description of PMD in human adrenal chromaffin cells and, in addition, is the first report of PMD in tumour secretory cells. These findings add further to the concept that PMD may have a broader spectrum of expression than hitherto recognized.

Adrenal Gland Neoplasms↗
PubMed2005

The crucial role of vascular permeability factor/vascular endothelial growth factor in angiogenesis: a historical review.

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. Numerous inducers of angiogenesis have been identified and this review offers a historical account of the relevant literature concerning the discovery of one of the best characterized angiogenic factors, namely vascular endothelial growth factor (VEGF)/vascular permeability factor. Moreover, different strategies, designed to stimulate and to inhibit VEGF production in the context of several potential therapeutical implications, are discussed.

Angiogenesis Inducing Agents↗
PubMed2005

Bone marrow endothelial cells in multiple myeloma secrete CXC-chemokines that mediate interactions with plasma cells.

Bone marrow endothelial cells (EC) from patients with multiple myeloma (MM) were found to express and secrete higher amounts of the CXC-chemokines CXCL8/interleukin (IL)-8, CXCL11/interferon-inducible T-cell alpha chemoattractant (I-TAC), CXCL12/stromal cell-derived factor (SDF)-1alpha, and CCL2/monocyte chemotactic protein(MCP)-1 than EC from human umbilical vein (HUVEC), considered as a healthy counterpart. Paired plasma cells and several MM cell lines expressed cognate receptors of each chemokine to a variable extent. When cells were exposed to chemokines, CXCL8/IL-8 and CXCL12/SDF-1alpha stimulated their proliferation and all chemokines stimulated cell chemotaxis. It is suggested that angiogenesis also favours MM progression through the release of CXC-chemokines.

Adult↗
PubMed2005

Angiogenic response induced by acellular femoral matrix in vivo.

We investigated the angiogenic response induced by acellular femoral matrices implanted in vivo on to the chick embryo chorioallantoic membrane (CAM), a useful model for such investigation. The results showed that acellular matrices were able to induce a strong angiogenic response, comparable with that of fibroblast growth factor-2 (FGF-2), a well-known angiogenic cytokine. The angiogenic response was further increased when exogenous FGF-2 or transforming growth factor beta-1 (TGF-beta1) was added to the matrices and inhibited by the addition of anti-FGF-2 or anti-TGF-beta1 antibodies. The response may be considered to be dependent on a direct angiogenic effect exerted by the matrices, and also in part by the presence of FGF-2 and TGF-beta1 in the acellular matrices.

Angiogenesis Inducing Agents↗
PubMed2005

Circulating plasma vascular endothelial growth factor in mice bearing human ovarian carcinoma xenograft correlates with tumor progression and response to therapy.

Vascular endothelial growth factor (VEGF) performs as an angiogenic and permeability factor in ovarian cancer, and its overexpression has been associated with poor prognosis. However, models to study its role as a marker of tumor progression are lacking. We generated xenograft variants derived from the A2780 human ovarian carcinoma (1A9), stably transfected with VEGF(121) in sense (1A9-VS-1) and antisense orientation (1A9-VAS-3). 1A9, 1A9-VS-1, and 1A9-VAS-3 disseminated in the peritoneal cavity of nude mice, but only 1A9-VS-1, the VEGF(121)-overexpressing tumor variant, produced ascites. Tumor biopsies from 1A9-VS-1 showed alterations in the vascular pattern and caused an angiogenic response in the chorioallantoic membrane assay. A significant level of soluble VEGF was detectable in the plasma of mice bearing 1A9-VS-1 even at an early stage of tumor growth. Plasma VEGF correlated positively with tumor burden in the peritoneal cavity and ascites accumulation. Cisplatin reduced the tumor burden and ascites in mice bearing 1A9-VS-1; the response was associated with a significant decrease of VEGF in plasma. This 1A9-VS-1 xenograft model reproduces the behavior of human ovarian cancer by growing in the peritoneal cavity, being highly malignant, and producing ascites. Plasma VEGF as a marker of tumor progression offers a valuable means of detecting early tumor response and following up treatments in an animal model.

Animals↗