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Biomedical subjects

Denis English

Publications and source records attributed to Denis English.

16 recordsLinked to original sources
PubMed2003

Angiogenesis and anti-angiogenesis in hematological malignancies.

Although it is well established that the growth of solid tumors requires vigorous neovascularization, it has been assumed that leukemias and other hematological malignancies do not depend on angiogenesis. However, the role of angiogenesis in growth and survival of neoplastic cells of the hematopoietic system has recently been recognized, and provides a rationale for novel therapeutic approaches to hematological malignancy. This review summarizes the literature concerning the relationship between angiogenesis and disease progression of several hematological malignancies. It is becoming increasingly evident that agents that interfere with blood vessel formation also block tumor progression, and, accordingly, antiangiogenic therapy has gained much interest as a potential adjunct to conventional therapy of many hematological malignancies. Recent successful applications of antiangiogenic agents that interfere or block the progression of hematological malignancies are evaluated in light of recent demonstrations of potent angiogenic activity of several hematopoietic growth factors. A novel finding regarding the role of angiogenesis in hematological malignancies, which accounts for many clinical observations as well as the apparent independence of these tumors on marrow vascularity, is presented. The information presented in this review will facilitate the design of future clinical trials using antiangiogenic agents for the treatment of hematological malignancies and will provide a basis for the design of experiments undertaken to define the mechanisms involved, mechanisms that may shed new light on the pathology of hematological malignancies.

Angiogenesis Inhibitors↗
PubMed2002

Lipid phosphate phosphatases regulate signal transduction through glycerolipids and sphingolipids.

Lipid phosphate esters including lysophosphatidate (LPA), phosphatidate (PA), sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) are bioactive in mammalian cells and serve as mediators of signal transduction. LPA and S1P are present in biological fluids and activate cells through stimulation of their respective G-protein-coupled receptors, LPA(1-3) and S1P(1-5). LPA stimulates fibroblast division and is important in wound repair. It is also active in maintaining the growth of ovarian cancers. S1P stimulates chemotaxis, proliferation and differentiation of vascular endothelial and smooth muscle cells and is an important participant in the angiogenic response and neovessel maturation. PA and C1P are believed to act primarily inside the cell where they facilitate vesicle transport. The lipid phosphates are substrates for a family of lipid phosphate phosphatases (LPPs) that dramatically alter the signaling balance between the phosphate esters and their dephosphorylated products. In the case of PA, S1P and C1P, the products are diacylglycerol (DAG), sphingosine and ceramide, respectively. These latter lipids are also bioactive and, thus, the LPPs change signals that the cell receives. The LPPs are integral membrane proteins that act both inside and outside the cell. The "ecto-activity" of the LPPs regulates the circulating and locally effective concentrations of LPA and S1P. Conversely, the internal activity controls the relative accumulation of PA or C1P in response to stimulation by various agonists thereby affecting cell signaling downstream of EDG and other receptors. This article will review the various LPPs and discuss how these enzymes could regulate signal transduction by lipid mediators.

Amino Acid Sequence↗
PubMed2002

Lipid mediators of angiogenesis and the signalling pathways they initiate.

Investigations carried out over the past 3 years have implicated a key role for sphingosine 1-phosphate (SPP) in angiogenesis and blood vessel maturation. SPP is capable of inducing almost every aspect of angiogenesis and vessel maturation in vitro, including endothelial cell chemotaxis, survival, proliferation, capillary morphogenesis and adherence antigen deployment, as well as stabilizing developing endothelial cell monolayers and recruitment of smooth muscle cells to maturing vessels. Acting in conjunction with protein angiogenic factors, SPP induces prolific vascular development in many established models of angiogenesis in vivo. Thus, SPP is a unique, potent and multifaceted angiogenic agent. While SPP induces angiogenic effects by ligating members of the endothelial differentiation gene (EDG) G-protein-coupled family of receptors, recent studies suggest that endogenously produced SPP may also account for the ability of tyrosine kinase receptors to induce cell migration. Thus, SPP provides a clear link between tyrosine kinase and G-protein-coupled receptor agonists involved in the angiogenic response. However, the mechanisms by which SPP exerts its effects on vascular cells remain unclear, conflicting and controversial. Precise definition of the signalling pathways by which SPP induces specific aspects of the angiogenic response promises to lead to new and effective therapeutic approaches to regulate angiogenesis at sites of tissue damage, neoplastic transformation and inflammation. This review will trace the discovery of SPP as a novel angiogenic factor as it outlines present information on the signalling pathways by which SPP induces its effects on cells of the developing vascular bed.

Animals↗
PubMed2002

Migration of vascular smooth muscle cells induced by sphingosine 1-phosphate and related lipids: potential role in the angiogenic response.

The bioactive lipids sphingosine 1-phosphate (SPP), sphingosylphosphorylcholine, and lysophosphatidic acid play an important role in angiogenesis as a result of their effects on both the migration of endothelial cells (ECs) and the integrity of EC monolayers. Here we show that extremely low concentrations of serum and nanomolar concentrations of these biologically active lipids stimulate migration of human aortic smooth muscle cells (SMCs). However, at dosages most effective in promoting EC migration and in enhancing EC monolayer integrity, serum and SPP potently inhibited SMC migration; SPP also blocked the migration induced by protein growth factors. Treatment of SMCs with SPP induced transient phosphorylation of a 175- to 185-kDa protein corresponding to the PDGF receptor, indicating transactivation of this receptor. SPP and related lipids may play a key role in angiogenesis by coordinating the migration of both endothelial cells and vascular smooth muscle cells in response to the changing gradients of these bioactive lipid messengers.

Blood Proteins↗
PubMed2002

Protein kinase C induces motility of breast cancers by upregulating secretion of urokinase-type plasminogen activator through activation of AP-1 and NF-kappaB.

Cell migration is a crucial process in cancer metastasis that does not require extracellular matrix degradation-a characteristic of cell invasion. The urokinase-type plasminogen activator (uPA) system is responsible for invasion through uPA enzymatic activity and for migration through the binding of uPA to the uPA receptor (uPAR). Constitutively high levels of uPA are characteristic of the highly metastatic breast cancer cells MDA-MB-231, but the mechanisms underlying constitutive uPA expression are not fully characterized. In this report we show that inhibition of protein kinase C (PKC) represses constitutive (nonstimulated) migration of MDA-MB-231 cells. Bisindolylmaleimide I (Bis I) inhibits cell migration and constitutive activation of transcription factors AP-1 and NF-kappaB, suggesting that PKC is responsible for increased migration of MDA-MB-231 cells. It is clear that the inhibition of PKC occurs at the transactivation levels of AP-1 and NF-kappaB because Bis I did not affect constitutive DNA binding of AP-1 and NF-kappaB. Furthermore, we show that Bis I did not affect the levels of IkappaBalpha, suggesting that PKC-mediated cell migration is IkappaBalpha independent. Finally, we demonstrate that constitutive secretion of uPA is repressed by Bis I, implying an important role for AP-1 and NF-kappaB in cell migration. Our data demonstrate a connection among PKC, constitutively active AP-1 and NF-kappaB, constitutive secretion of uPA, and cell migration of highly invasive breast cancer cells. Thus, PKC controls cell motility by regulating expression of uPA through the activation of AP-1 and NF-kappaB. The disruption of PKC, AP- 1, and NF-kappaB signaling in breast cancer may be used to develop therapies for breast cancer prevention and intervention by reducing the secretion of uPA.

Breast Neoplasms↗
PubMed2002

Comparative analysis of in vitro angiogenic activities of endothelial cells of heterogeneous origin.

Endothelial cells are dynamic participants in many aspects of host defense, innate immunity, inflammation, angiogenesis, and vasculogenesis, but the interpretation of studies of their responses is often clouded by the source of the cells under observation. Thus, it is not clear which endothelial cell type should be utilized in in vitro studies to clarify the basis and physiological relevance of essential processes, including chemotactic migration and morphogenic differentiation. In this study, we compared responses of endothelial cells of a variety of origins, as well as an immortalized cell line, using both protein growth factors and biologically active lipid mediators as agonists. While cells of divergent origin displayed marked differences in the extent of their responsiveness, with a few notable exceptions, their pattern of responsiveness to receptor-dependent stimuli was remarkably similar. Moreover, even the immortalized endothelial cell line Py-4-l migrated in a pattern consistent to that seen with primary cells in culture although the immortalized cells failed to form capillarylike structures under any of the conditions tested. We conclude that although the immortalized endothelial cell line Py-4-l is not appropriate for investigations of endothelial cell morphogenic responses, cultured cells from other sources, including arteries, veins, and capillaries, often provide qualitatively similar results to divergent metabolic stimuli.

Capillaries↗
PubMed2002

Sphingosine 1-phosphate signaling: providing cells with a sense of direction.

Sphingosine 1-phosphate (S1P) is a sphingolipid metabolite that regulates diverse biological functions. S1P has been identified as a high-affinity ligand for a family of five G-protein-coupled receptors, known as the S1P receptors. The physiological role of the S1P receptor S1P(1) in vascular maturation was recently revealed by gene disruption in mice. In addition to other cellular processes, the binding of S1P to its receptors regulates motility and directional migration of a variety of cell types, including endothelial cells and vascular smooth muscle cells. This review focuses on the important role of S1P and its receptors in cell migration and describes a new paradigm for receptor cross-communication in which transactivation of S1P(1) by a receptor tyrosine kinase (PDGFR) is crucial for cell motility.

Animals↗
PubMed2002

Serum factors involved in human microvascular endothelial cell morphogenesis.

Our previous studies have demonstrated that lipid and protein angiogenic factors operate in tandem to induce optimal angiogenic responses in vivo. This study was undertaken to clarify the nature of the substances in human serum that are responsible for its remarkable ability to promote capillary morphogenesis in vitro. The ability of dilute (2%) human serum to promote the morphogenic differentiation of human dermal microvascular endothelial cells on Matrigel supports was depleted by more than 50% by treatment of the serum with activated charcoal, a procedure that effectively removes biologically active lipid growth factors. The remainder of the activity within serum was lost on heating to 60 degrees C for 60 minutes, indicating the involvement of a protein in the response. The ability of charcoal-treated serum to promote capillary morphogenesis was completely restored by the addition of sphingosine 1-phosphate (SPP, 500 nmol/L), but other lipids thought to be released into serum during clotting were ineffective. In addition, basic fibroblast growth factor (bFGF) effectively restored the ability of heat-treated serum to promote endothelial cell morphogenesis, but other protein growth factors, including vascular endothelial growth factor and platelet-derived growth factor, were ineffective. Together, SPP and bFGF were as effective as whole serum in promoting capillary morphogenesis. Responses to purified SPP were entirely sensitive to the effects of preexposure of the cells to pertussis toxin, whereas responses to bFGF were entirely pertussis toxin-resistant. Consistent with our hypothesis that two distinct factors in serum play a role in promoting capillary morphogenesis, responses induced by serum were inhibited approximately 50% by preexposure of endothelial cells to pertussis toxin. We conclude that platelet-released SPP acts in conjunction with circulating bFGF to promote capillary formation by microvascular endothelial cells. Lipid and protein growth factors apparently exert complementary roles in the angiogenic response, as demonstrated by their ability to promote chemotaxis, angiogenic differentiation, and angiogenesis in vivo.

Angiogenesis Inducing Agents↗
PubMed2002

Hematotherapy for AIDS.

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Phosphatidylinositol 3-kinase and NF-kappaB regulate motility of invasive MDA-MB-231 human breast cancer cells by the secretion of urokinase-type plasminogen activator.

Cell migration is a fundamental aspect of the neoplastic cell metastasis. Here, we show that phosphatidylinositol (PI) 3-kinase is constitutively active and controls cell motility of highly invasive breast cancer cells by the activation of transcription factor, NF-kappaB. The urokinase-type plasminogen activator (uPA) promoter contains an NF-kappaB binding site, and uPA expression in MDA-MB-231 cells is induced by the constitutively active NF-kappaB. Thus, motility was inhibited by overexpression of a dominant negative p85alpha regulatory subunit of PI 3-kinase (p85DN), as well as by pretreatment of cells with specific inhibitors of the p110 catalytic subunit of PI 3-kinase, wortmannin and LY294002. The involvement of gene transcription in cell motility was suggested because treatment with actinomycin D and cycloheximide, which inhibit transcription and new protein synthesis, respectively, abolished endogenous migration of MDA-MB-231 cells. Although wortmannin, Ly294002, or overexpression of p85DN did not significantly reduce DNA binding activity of NF-kappaB in nuclear extracts, wortmannin, Ly294002, and the overexpression of p85DN or IkappaBalpha inhibited constitutive activation of NF-kappaB in a reporter gene assay. Highly invasive MDA-MB-231 cells constitutively secreted uPA in amounts significantly higher than poorly invasive MCF-7 cells. Furthermore, inhibition of NF-kappaB markedly attenuated endogenous migration, and inhibition of PI 3-kinase and NF-kappaB reduced secretion of uPA. Our data suggest a link between constitutively active PI 3-kinase, NF-kappaB, and secretion of uPA, which is responsible for the migration of highly invasive breast cancer cells. Thus, constitutively active PI 3-kinase controls cell motility by the regulation of expression of uPA through the activation of NF-kappaB.

Androstadienes↗