Biomedical subjects

Teresa Padró

Publications and source records attributed to Teresa Padró.

8 recordsLinked to original sources

PubMed2006

Aggregated low density lipoproteins decrease metalloproteinase-9 expression and activity in human coronary smooth muscle cells.

Plaque stability largely depends on vascular smooth muscle cell (VSMC) function. VSMC secrete metalloproteinases (MMPs), matrix degrading endopeptidases, that regulate VSMC migration and function. Among them, gelatinase B or MMP-9 seems to have a protective effect by promoting a stable plaque phenotype. In macrophage foam cells oxidized LDL (oxLDL) uptake regulates MMP-9 expression. However, it is unknown whether VSMC-lipid loading by aggregated LDL (agLDL) internalization produces any effect on MMP-9 production by human resident vascular cells. In the present study, we analyzed the effect of lipid-internalization in MMP-9 and MMP-2 expression and activity and its consequences in VSMC migration. Our results show that agLDL-internalization down-regulates MMP-9 activity in a time-dependent manner up to 42% at 48h and in a dose-dependent manner up to 87% at 300 microg/mL. nLDL induced similar but not sustained decrease on MMP-9 activity. However, neither agLDL nor nLDL exerted any significant effect on MMP-2 and TIMP-1. VSMC regrowth after a scratch injury was significantly reduced by exposure to agLDL. We conclude that agLDL-lipid loading reduces MMP-9 activity and this effect is associated to inhibition of VSMC migration. Thus, agLDL internalization may have consequences on vascular remodeling after injury, and the stability of lipid-rich atherosclerotic plaques.

Cell Movement↗

PubMed2005

Inhibition of tumor growth by RGD peptide-directed delivery of truncated tissue factor to the tumor vasculature.

Selective activation of blood coagulation in tumor vessels with subsequent tumor infarction is a promising anticancer strategy. To this end, a fusion protein consisting of the extracellular domain of tissue factor [truncated tissue factor (tTF)] was fused to the peptide GRGDSP selectively targeting alpha(v)-integrins on tumor endothelial cells. tTF-RGD retained its thrombogenic and integrin-binding activity in vitro. In vivo studies in mice bearing human adenocarcinomas (CCL185), melanoma (M21), and fibrosarcoma (HT1080) revealed that i.v. administration of tTF-RGD induced thrombotic occlusion of tumor vessels resulting in tumor growth retardation or regression in all three types of solid tumors. No apparent side effects, such as thrombosis, in other organs or other treatment-related toxicities were observed. Reduced tumor blood flow in tTF-RGD-treated animals as determined by contrast-enhanced magnetic resonance imaging underlines the proposed mechanism. In conclusion, we consider RGD peptide-directed delivery of tTF as alternative to previously used antibody fusion proteins. Small peptide-directed delivery of coaguligands does not cause immunologic side effects and those caused by accumulation in the reticuloendothelial system. This is the first report to describe the induction of selective thrombosis in tumor vessels by RGD peptide-directed delivery of tTF, which may be a promising strategy for the treatment of cancer.

Animals↗

PubMed2004

Overexpression of urokinase receptor and cell surface urokinase-type plasminogen activator in the human vessel wall with different types of atherosclerotic lesions.

Urokinase-type plasminogen activator (UPA) has been implicated in a broad spectrum of pathogenic processes involved in the formation and disruption of atherosclerotic lesions. Up to now, there is no consensus on the contribution of membrane-bound UPA and its receptor CD87 (UPAR) to the development of atherosclerosis. In this study, we determined comparatively the levels of UPAR and UPAR-bound UPA in segments of human coronary and aortic vessels with different degrees of atherosclerotic lesions (macroscopically normal areas, early atherosclerotic lesions, fibrous and calcified plaques). The UPAR content increased progressively with the severity of atherosclerosis. In aortic segments, in which intima and media layers were analyzed separately, the content of UPAR in the intima significantly exceeded the levels measured in the media. Using a detergent-phase separation method with a Triton X-114-containing buffer, we could demonstrate that the levels of membrane (glycosylphosphatidylinositol)-anchored UPAR were significantly higher in the intima of early atherosclerotic lesions as well as in the cap areas of fibrous plaques compared with macroscopically normal areas. However, only 20-25% of the intimal and 30-50% of the medial glycosylphosphatidylinositol-UPAR was occupied by UPA as determined on a molar basis. These data confirm that the overexpression of UPAR in advanced atherosclerotic lesions contributes to lesion development. Whether UPAR's excess over cell surface UPA provides an additional role for this receptor in atherogenesis besides UPA-mediated proteolysis remains to be elucidated.

Aorta↗

PubMed2003

Overexpression of basic fibroblast growth factor and autocrine stimulation in acute myeloid leukemia.

Basic fibroblast growth factor (bFGF) is known to play a critical role in tumorigenesis of solid tumors. The importance of bFGF in hematological malignancies such as acute myeloid leukemia (AML) remains to be elucidated. Therefore, we determined bFGF protein expression by immunohistochemical analyses in bone marrow biopsies of patients with newly diagnosed, untreated AML. The expression of bFGF was significantly increased in AML patients [n = 81; median, 3.0 (interquartile range, 1.8-3.9) arbitrary units (AU)] as compared with controls [n = 18; 1.9 (1.5-2.3) AU]. The degree of bFGF expression did not correlate with microvessel density. bFGF/FGF receptor mRNA and bFGF protein were detected in different AML cell lines. To study autocrine growth stimulation of AML blasts, the AML cell lines HL-60, M-07e, and KG-1 were incubated with bFGF. A significant dose-dependent increase in proliferation and colony formation was observed. These effects were abrogated by the addition of a polyclonal anti-bFGF antibody. In conclusion, increased expression of bFGF in the bone marrow of AML patients seems to play an important role in the pathophysiology of AML by promoting autocrine growth stimulation of leukemic blasts.

Acute Disease↗

PubMed2002

Paracrine interactions of basic fibroblast growth factor and interleukin-6 in multiple myeloma.

Myeloma cells express basic fibroblast growth factor (bFGF), an angiogenic cytokine triggering marrow neovascularization in multiple myeloma (MM). In solid tumors and some lymphohematopoietic malignancies, angiogenic cytokines have also been shown to stimulate tumor growth via paracrine pathways. Since interleukin-6 (IL-6) is a potent growth and survival factor for myeloma cells, we have studied the effects of bFGF on IL-6 secretion by bone marrow stromal cells (BMSCs) and its potential reverse regulation in myeloma cells. Both myeloma-derived cell lines and myeloma cells isolated from the marrow of MM patients were shown to express and secrete bFGF. Cell-sorting studies identified myeloma cells as the predominant source of bFGF in MM marrow. BMSCs from MM patients and control subjects expressed high-affinity FGF receptors R1 through R4. Stimulation of BMSCs with bFGF induced a time- and dose-dependent increase in IL-6 secretion (median, 2-fold; P <.001), which was completely abrogated by anti-bFGF antibodies. Conversely, stimulation with IL-6 enhanced bFGF expression and secretion by myeloma cell lines (2-fold; P =.02) as well as MM patient cells (up to 3.6-fold; median, 1.5-fold; P =.002). This effect was inhibited by anti-IL-6 antibody. When myeloma cells were cocultured with BMSCs in a noncontact transwell system, both IL-6 and bFGF concentrations in coculture supernatants increased 2- to 3-fold over the sum of basal concentrations in the monoculture controls. The IL-6 increase was again partially, but significantly, inhibited by anti-bFGF. The data demonstrate a paracrine interaction between myeloma and marrow stromal cells triggered by mutual stimulation of bFGF and IL-6.

Bone Marrow Cells↗

PubMed2002

The catalytic domain of endogenous urokinase-type plasminogen activator is required for the mitogenic activity of platelet-derived and basic fibroblast growth factors in human vascular smooth muscle cells.

Emerging data suggest that urokinase-type plasminogen activator (UPA), beyond its role in pericellular proteolysis, may also act as a mitogen. We investigated the function of endogenous UPA in mediating the mitogenic effects of platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) on human vascular smooth muscle cells (SMC). Growth-arrested SMC constitutively expressed UPA, but UPA expression and secretion increased several times upon stimulation with either PDGF or bFGF. Inhibition of endogenous UPA with a polyclonal antibody significantly reduced DNA synthesis and proliferation of PDGF or bFGF stimulated SMC, this effect already being evident when the cells entered S-phase. The proliferative activity of endogenous UPA was dependent on a functional catalytic domain as demonstrated by inhibition experiments with a specific monoclonal antibody (394OA) and p-aminobenzamidine, respectively. In contrast, neither plasmin generation nor binding of UPA to its receptor (CD87) were required for UPA-mediated mitogenic effects. The results demonstrate that endogenous UPA is not only overexpressed in SMC upon stimulation with PDGF/bFGF, but also mediates the mitogenic activity of the growth factors in a catalytic-domain-dependent manner. Specific inhibition of this UPA domain may represent an attractive target for pharmacological interventions in atherogenesis and restenosis after angioplasty.

Arteriosclerosis↗

PubMed2002

Efficacy and safety of thalidomide in patients with acute myeloid leukemia.

Emerging data suggest an involvement of angiogenesis in the pathophysiology of acute myeloid leukemia (AML). Thus, antiangiogenic therapy could constitute a novel strategy for the treatment of AML. To test this hypothesis, a phase I/II dose-escalating trial was performed to study the safety and efficacy of thalidomide, a putative inhibitor of angiogenesis, in 20 patients with AML. Thirteen patients were assessable for both toxicity and response, tolerating a maximum dose of 200 to 400 mg daily for at least 1 month. Seven patients had to be prematurely withdrawn from drug administration owing to progressive disease and death (3 patients), personal decision (2 patients), or inability to tolerate thalidomide (2 patients). Overall, adverse events were fatigue, constipation, rash, and neuropathy (grade 1 to 2 in most patients). In 4 patients, a partial response, defined as reduction of at least 50% in the blast cell infiltration of the bone marrow accompanied by increases in platelet counts and hemoglobin values, was observed. One additional patient showed a hematologic improvement without fulfilling the criteria of a partial response. The responses lasted a median of 3 months (range, 1-8 months). In parallel, microvessel densities significantly decreased in these 5 patients during treatment with thalidomide (P <.05). This decrease was accompanied by declining plasma levels of basic fibroblast growth factor, one of the most potent angiogenic growth factors. In conclusion, single-agent thalidomide has antiangiogenic and antileukemic activity in AML, although a causal relationship between both effects has still to be proven.

Acute Disease↗

PubMedDate not supplied

Interleukin 8 and Flt3 ligand as markers of advanced disease in primary gastrointestinal non-Hodgkin's lymphoma.

Tumor angiogenesis plays a significant role in cancer growth and metastasis. This complex process is influenced by a variety of angiogenic factors. Elevated serum levels or high expression of some of these factors have been shown to correlate with stage and prognosis in certain human malignancies. This has been demonstrated most consistently for vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). We tried to establish, whether pre-treatment serum levels of the angiogenic factors VEGF, bFGF, interleukin 8 (IL-8) and Flt3 ligand (Flt3L) correlate with prognostic variables in 30 patients with primary gastro-intestinal non-Hodgkin's lymphoma. Our results suggest that higher pretreatment serum levels of IL-8 and Flt3L are associated with higher stage (>or= II) and high grade, respectively. Elevated pretreatment serum levels of VEGF and bFGF were not associated with advanced disease characteristics and carried no prognostic information.

Adult↗