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1.
Ned Tijdschr Geneeskd ; 147(35): 1675-80, 2003 Aug 30.
Article in Dutch | MEDLINE | ID: mdl-14513538

ABSTRACT

An important development in the treatment of cancer is the recognition that the tumour's microenvironment, notably its vasculature, may be an attractive target for therapy. In the eighties of the last century, the concept of angiogenesis (the formation of new blood vessels from existing vasculature) was developed. Angiogenesis is the driving force behind tumour growth and metastasis. Recent angiogenesis research has elucidated the role of growth factors (vascular endothelial growth factor (VEGF), epidermal growth factor), metalloproteinases and endogenous proteins such as angiostatin and endostatin. This new knowledge has led to the rapid development of several angiogenesis inhibiting strategies. Although these new strategies showed very promising results in preclinical animal studies, early clinical studies with individual angiogenesis inhibitors have shown no antitumour effect so far. However, in recent studies blocking VEGF in addition to conventional chemotherapy has led to an increase in disease-free survival time and in response rate to chemotherapy. Angiogenesis research has contributed to the knowledge of the biology of cancer, the design of modified clinical studies and the development of surrogate markers that can be used as pharmacodynamic end points in future studies.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Neoplasms/blood supply , Neoplasms/drug therapy , Neovascularization, Pathologic/prevention & control , Angiogenesis Inducing Agents/antagonists & inhibitors , Angiogenesis Inducing Agents/physiology , Angiostatins , Animals , Clinical Trials as Topic , Collagen/therapeutic use , Disease Models, Animal , Endostatins , Humans , Neoplasm Metastasis/prevention & control , Peptide Fragments/therapeutic use , Plasminogen/therapeutic use
2.
Am J Pharmacogenomics ; 3(4): 261-77, 2003.
Article in English | MEDLINE | ID: mdl-12930159

ABSTRACT

Retinopathy of prematurity (ROP) is an ischemia-induced proliferative retinopathy, which affects premature infants with low birth weight. It is a leading cause of visual impairment and blindness in children, and shares pathophysiological characteristics with other common ocular diseases such as diabetic retinopathy, central vein occlusion, and age-related macular degeneration. Pathologically similar inherited diseases such as Norrie disease suggest a possible genetic component in the susceptibility to ROP. The process of retinal neovascularization in ROP and in animal models of oxygen-induced retinopathy is complex, and involves angiogenic factors, such as vascular endothelial growth factor, and basement membrane components. Potential medical therapies for ROP, including modulators of angiogenic factors, inhibitors of basement membrane changes, endogenous inhibitors such as pigment epithelium derived factor, and anti-inflammatory drugs, have shown efficacy against neovascularization in several animal models. Some of these therapies are in clinical trials now for diabetic retinopathy and age-related macular degeneration, and in the future may prove efficacious for the treatment of ROP.


Subject(s)
Retinopathy of Prematurity/genetics , Retinopathy of Prematurity/pathology , Angiogenesis Inducing Agents/physiology , Angiogenesis Inhibitors/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Basement Membrane/physiology , Disease Models, Animal , Humans , Infant, Newborn , Retinopathy of Prematurity/therapy , Risk Factors
3.
Biochem Biophys Res Commun ; 308(1): 101-5, 2003 Aug 15.
Article in English | MEDLINE | ID: mdl-12890486

ABSTRACT

Angiopoietin-1 (Ang1) and its receptor, Tie2, play critical roles in blood vessel formation. Ang1 triggers a variety of signaling events in endothelial cells leading to vasculogenic and angiogenic processes. However, the underlying mechanism for Ang1/Tie2 signaling is not fully understood. Here, we show that Tie2 and phospholipase D (PLD) are localized in the caveolae, specialized subdomains of the endothelial cell plasma membrane enriched with signaling molecules. Interestingly, Ang1 increased PLD activities in a dose- and time-dependent manner. Ang1-induced MEK/ERK activation was abrogated when PLD was inhibited, suggesting that PLD mediates Ang1-induced MEK/ERK activation. Moreover, PLD inhibitor, 1-butanol, inhibited Ang1-induced endothelial cell migration. Our results indicate that: (1) caveolae may be the platform for Tie2/PLD association in endothelial cells; (2) PLD is a new mediator of Ang1/Tie2-induced signaling pathway, and it participates in MAPK activation and endothelial cell migration.


Subject(s)
Angiogenesis Inducing Agents/physiology , Caveolae/metabolism , Cell Movement/physiology , Endothelium, Vascular/metabolism , Membrane Glycoproteins/physiology , Mitogen-Activated Protein Kinases/metabolism , Neoplasm Proteins/metabolism , Phospholipase D/metabolism , Proto-Oncogene Proteins , Receptor Protein-Tyrosine Kinases/metabolism , Angiopoietin-1 , Caveolae/enzymology , Cells, Cultured , Endothelium, Vascular/enzymology , Enzyme Activation , Humans , Phosphorylation , Receptor, TIE-2
4.
EMBO J ; 22(16): 4091-102, 2003 Aug 15.
Article in English | MEDLINE | ID: mdl-12912908

ABSTRACT

Previous gene targeting studies have implicated an indispensable role of vascular endothelial growth factor (VEGF) in tumor angiogenesis, particularly in tumors of embryonal or endocrine origin. In contrast, we report here that transformation of VEGF-deficient adult fibroblasts (MDF528) with ras or neu oncogenes gives rise to highly tumorigenic and angiogenic fibrosarcomas. These aggressive VEGF-null tumors (528ras, 528neu) originated from VEGF(-/-) embryonic stem cells, which themselves were tumorigenically deficient. We also report that VEGF production by tumor stroma has a modest role in oncogene-driven tumor angiogenesis. Both ras and neu oncogenes down-regulated at least two endogenous inhibitors of angiogenesis [pigment epithelium derived factor (PEDF) and thrombospondin 1 (TSP-1)]. This is functionally important as administration of an antiangiogenic TSP-1 peptide (ABT-526) markedly inhibited growth of VEGF(-/-) tumors, with some ingress of pericytes. These results provide the first definitive genetic demonstration of the dispensability of tumor cell-derived VEGF in certain cases of 'adult' tumor angiogenesis, and thus highlight the importance of considering VEGF-independent as well as VEGF-dependent pathways when attempting to block this process pharmacologically.


Subject(s)
Angiogenesis Inducing Agents/genetics , Cell Transformation, Neoplastic/genetics , Eye Proteins , Genes, erbB-2 , Genes, ras , Nerve Growth Factors , Stem Cells/physiology , Vascular Endothelial Growth Factor A , Angiogenesis Inducing Agents/metabolism , Angiogenesis Inducing Agents/physiology , Animals , Cell Line , Cell Transformation, Viral/genetics , Cells, Cultured , Chimera , Fibroblasts/cytology , Fibroblasts/metabolism , Fibrosarcoma/genetics , Fibrosarcoma/pathology , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Gene Targeting , Mice , Mice, Knockout , Mice, SCID , Models, Biological , Mutation , Neovascularization, Pathologic/genetics , Peptide Fragments/metabolism , Peptide Fragments/pharmacology , Proteins/metabolism , Serpins/metabolism , Teratoma/blood supply , Teratoma/pathology , Thrombospondin 1/metabolism , Thrombospondin 1/pharmacology
5.
J Immunol ; 171(2): 1085-93, 2003 Jul 15.
Article in English | MEDLINE | ID: mdl-12847283

ABSTRACT

The cytokine/extracellular matrix protein osteopontin (OPN/Eta-1) is an important component of cellular immunity and inflammation. It also acts as a survival, cell-adhesive, and chemotactic factor for endothelial cells. Here, subtractive suppression hybridization showed that serum-deprived murine aortic endothelial (MAE) cells transfected with the angiogenic fibroblast growth factor-2 (FGF2) overexpress OPN compared with parental cells. This was confirmed by Northern blotting and Western blot analysis of the conditioned media in different clones of endothelial cells overexpressing FGF2 and in endothelial cells treated with the recombinant growth factor. In vivo, FGF2 caused OPN expression in newly formed endothelium of the chick embryo chorioallantoic membrane (CAM) and of murine s.c. Matrigel plug implants. Recombinant OPN (rOPN), the fusion protein GST-OPN, and the deletion mutant GST-DeltaRGD-OPN were angiogenic in the CAM assay. Angiogenesis was also triggered by OPN-transfected MAE cells grafted onto the CAM. OPN-driven neovascularization was independent from endothelial alpha(v)beta(3) integrin engagement and was always paralleled by the appearance of a massive mononuclear cell infiltrate. Accordingly, rOPN, GST-OPN, GST-DeltaRGD-OPN, and the conditioned medium of OPN-overexpressing MAE cells were chemotactic for isolated human monocytes. Also, rOPN triggered a proangiogenic phenotype in human monocytes by inducing the expression of the angiogenic cytokines TNF-alpha and IL-8. OPN-mediated recruitment of proangiogenic monocytes may represent a mechanism of amplification of FGF2-induced neovascularization during inflammation, wound healing, and tumor growth.


Subject(s)
Fibroblast Growth Factor 2/physiology , Neovascularization, Physiologic , Sialoglycoproteins/physiology , Angiogenesis Inducing Agents/metabolism , Angiogenesis Inducing Agents/physiology , Animals , Cell Line , Cell Line, Transformed , Cell Movement/immunology , Chick Embryo , Chorion/cytology , Chorion/immunology , Chorion/metabolism , Endothelium, Vascular/metabolism , Fibroblast Growth Factor 2/genetics , Fibroblast Growth Factor 2/metabolism , Humans , Immunophenotyping , Integrin alphaVbeta3/metabolism , Integrin alphaVbeta3/physiology , Interleukin-6/biosynthesis , Interleukin-8/biosynthesis , Mice , Mice, Inbred BALB C , Monocytes/cytology , Monocytes/immunology , Monocytes/metabolism , Neovascularization, Physiologic/genetics , Osteopontin , Recombinant Proteins/pharmacology , Sialoglycoproteins/biosynthesis , Sialoglycoproteins/genetics , Sialoglycoproteins/metabolism , Tumor Necrosis Factor-alpha/biosynthesis , Up-Regulation/genetics
6.
Proc Natl Acad Sci U S A ; 100(15): 8904-9, 2003 Jul 22.
Article in English | MEDLINE | ID: mdl-12861074

ABSTRACT

A hallmark of highly malignant human gliomas is their infiltration of the brain. We analyzed a large number of primary human glioma biopsies and found high levels of expression of an angiogenic regulator, angiopoietin-2 (Ang2), in the invasive areas, but not in the central regions, of those tumors. In the invasive regions where Ang2 was overexpressed, increased levels of matrix metalloprotease-2 (MMP-2) were also apparent. Consonant with these features, intracranial xenografts of glioma cells engineered to express Ang2 were highly invasive into adjacent brain parenchyma compared with isogenic control tumors. In regions of the Ang2-expressing tumors that were actively invading the brain, high levels of expression of MMP-2 and increased angiogenesis were also evident. A link between these two features was apparent, because stable expression of Ang2 by U87MG cells or treatment of several glioma cell lines with recombinant Ang2 in vitro caused activation of MMP-2 and acquisition of increased invasiveness. Conversely, MMP inhibitors suppressed Ang2-stimulated activation of MMP-2 and Ang2-induced cell invasion. These results suggest that Ang2 plays a critical role in inducing tumor cell infiltration, and that this invasive phenotype is caused by activation of MMP-2.


Subject(s)
Angiogenesis Inducing Agents/physiology , Brain Neoplasms/enzymology , Glioma/enzymology , Matrix Metalloproteinase 2/metabolism , Angiopoietin-2 , Animals , Brain Neoplasms/blood supply , Brain Neoplasms/pathology , Brain Neoplasms/physiopathology , Enzyme Activation , Glioma/blood supply , Glioma/pathology , Glioma/physiopathology , Humans , In Vitro Techniques , Mice , Mice, Nude , Neoplasm Invasiveness , Neovascularization, Pathologic , Transplantation, Heterologous , Tumor Cells, Cultured
7.
Cancer Res ; 63(12): 3370-7, 2003 Jun 15.
Article in English | MEDLINE | ID: mdl-12810673

ABSTRACT

Angiopoietin (Ang)-1 and -2 are critical regulators of embryonic and postnatal neovascularization. Ang-1 activates the endothelial cell-specific tyrosine kinase receptor Tie-2, which in turn leads to enhanced endothelial cell survival and stabilization. The effects of Ang-1 on tumor angiogenesis remain controversial; although we have previously demonstrated that Ang-1 overexpression in colon cancer cells leads to a decrease in s.c. tumor growth, others have shown that Ang-1 may be proangiogenic. Few studies have addressed the role of the Angs in tumors growing in the organ of metastatic growth. We hypothesized that overexpression of Ang-1 may inhibit the growth of colon cancers growing in the liver by inhibition of angiogenesis. We also wanted to investigate the mechanisms by which Ang-1 affects angiogenesis in vivo. Human colon cancer cells (HT29) were stably transfected with an Ang-1 construct or an empty vector (pcDNA) and injected directly into the livers of nude mice. After 37 days, livers were harvested and weighed, and tumor sizes were measured. In an additional experiment, to validate the paracrine effect of Ang-1, various mixtures of control cells and Ang-1-transfected cells were injected into livers, and tumor growth was assessed. Direct effects of recombinant Ang-1 on angiogenesis were studied with an in vivo Gelfoam angiogenesis assay. The impact of Ang-1 on vascular permeability was investigated using an intradermal Miles assay with conditioned media from transfected cells. Liver weights (P < 0.05), tumor volumes (P < 0.05), vessel counts (P < 0.01), and tumor cell proliferation (P < 0.01) in the Ang-1 group were significantly lower than those in the control (pcDNA) group. Tumor vessels in the Ang-1 group developed a significantly higher degree of pericyte coverage (P < 0.02) than vessels in pcDNA tumors. In the cell mixture experiment, even as few as a 1:10 mixture of Ang-1-transfected cells/control cells resulted in a significant reduction of hepatic tumor volumes (P < 0.04). In the angiogenesis assay, vessel counts in Gelfoam implants were significantly decreased by the addition of Ang-1 (P < 0.01). Finally, conditioned medium from Ang-1-transfected cells decreased vascular permeability more than that from control cells (P < 0.05). Our results suggest that Ang-1 is an important regulator of angiogenesis and vascular permeability and that this effect may be secondary to increasing periendothelial support and vessel stabilization. Thus, Ang-1 could potentially serve as an antineoplastic or anti-permeability agent for patients with metastatic colorectal cancer.


Subject(s)
Angiogenesis Inducing Agents/physiology , Capillary Permeability/physiology , Colonic Neoplasms/pathology , Genetic Therapy , Liver Neoplasms, Experimental/secondary , Membrane Glycoproteins/physiology , Neovascularization, Pathologic/therapy , Angiogenesis Inducing Agents/genetics , Angiogenesis Inducing Agents/therapeutic use , Angiopoietin-1 , Animals , Coculture Techniques , Culture Media, Conditioned/pharmacology , Humans , Liver Neoplasms, Experimental/blood supply , Liver Neoplasms, Experimental/drug therapy , Male , Membrane Glycoproteins/genetics , Membrane Glycoproteins/therapeutic use , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Proteins/metabolism , Paracrine Communication , Pericytes/pathology , Phosphorylation , Protein Processing, Post-Translational , Receptor Protein-Tyrosine Kinases/metabolism , Receptor, TIE-2 , Recombinant Fusion Proteins/physiology , Transfection , Tumor Cells, Cultured/metabolism , Tumor Cells, Cultured/transplantation , Xenograft Model Antitumor Assays
8.
Endocr Relat Cancer ; 10(2): 141-52, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12790776

ABSTRACT

CYR61 (CNN1), a member of the cysteine rich 61/connective tissue growth factor/nephroblastoma overexpressed (CYR61/CTFG/NOV) family of growth regulators (CNN), is a pro-angiogenic factor that mediates diverse roles in development, cell proliferation, and tumorigenesis. We have recently shown that CYR61 is overexpressed in invasive and metastatic human breast cancer cells. Accordingly, elevated levels of CYR61 in breast cancer are associated with more advanced disease. Unfortunately, the exact mechanisms by which CYR61 promotes an aggressive breast cancer phenotype are still largely unknown. This review examines the functional role of CYR61 in breast cancer disease, presenting evidence that CYR61 signaling may play a major role in estrogen- as well as growth factor-dependent breast cancer progression. We also emphasize the functional significance of the molecular connection of CYR61 and its integrin receptor alpha(v)beta(3) enhancing breast cancer aggressiveness. Moreover, we describe experimental evidence that establishes a novel role for CYR61 determining the protection of human breast cancer cells against chemotherapy-induced apoptosis through its interactions with the integrin receptor alpha(v)beta(3). All these findings delineate a new noteworthy function of a CYR61/alpha(v)beta(3) autocrine-paracrine signaling pathway within both angiogenesis and breast cancer progression, which would allow a dual anti-angiogenic and anti-tumor benefit with a single drug.


Subject(s)
Adenocarcinoma/metabolism , Angiogenesis Inducing Agents/physiology , Breast Neoplasms/metabolism , Immediate-Early Proteins/physiology , Intercellular Signaling Peptides and Proteins/physiology , Adenocarcinoma/pathology , Breast Neoplasms/pathology , Cell Adhesion/physiology , Cell Division/physiology , Cell Movement/physiology , Cysteine-Rich Protein 61 , Disease Progression , Female , Gene Expression Regulation, Neoplastic , Humans , Neoplasm Invasiveness , Neoplasms, Hormone-Dependent/metabolism , Neoplasms, Hormone-Dependent/pathology
10.
Circ Res ; 92(9): 984-91, 2003 May 16.
Article in English | MEDLINE | ID: mdl-12690034

ABSTRACT

Angiopoietin-1 (Ang-1), a newly discovered ligand of the endothelial-specific tyrosine kinase receptor Tie-2, has been found to promote cell survival, vascular maturation, and stabilization. We hypothesized that Ang-1 gene transfer to the pulmonary microcirculation would improve pulmonary hemodynamics and vascular remodeling in experimental pulmonary hypertension. Rat pulmonary artery smooth muscle cells were transfected with Ang-1 cDNA or null (pFLAG-CMV-1) vector. Syngeneic Fisher 344 rats were treated with monocrotaline (MCT) (75 mg/kg IP) with or without delivery of 5x10(5) Ang-1-transfected cells into the right jugular vein. After 28 days, plasmid-derived Ang-1 mRNA was consistently and robustly detected by reverse transcriptase-polymerase chain reaction in lungs from all animals receiving Ang-1 gene therapy. Tie-2 receptor expression was markedly downregulated in rats treated with MCT, and this was partially restored by gene therapy with Ang-1. Animals receiving MCT exhibited 77% mortality by 28 days. In contrast, in pAng-1-treated animals, the 28-day mortality was only 14% (P<0.0001). In addition, right ventricular systolic pressure was reduced from 52+/-1.3 mm Hg in the MCT-treated group to 38+/-1.3 mm Hg by Ang-1 gene transfer (P<0.01), whereas the measurement of right to left ventricular plus septal weight ratio was also reduced from 0.41+/-0.03 to 0.31+/-0.01 (P<0.05). Moreover, MCT resulted in increased apoptosis, mainly in the microvasculature, and reduced endothelial NO synthase mRNA expression, both of which were prevented by Ang-1 gene transfer. Thus, cell-based gene transfer with Ang-1 improved survival and pulmonary hemodynamics in experimental pulmonary hypertension by a mechanism involving the inhibition of apoptosis and protection of the pulmonary microvasculature.


Subject(s)
Angiogenesis Inducing Agents/physiology , Hypertension, Pulmonary/therapy , Membrane Glycoproteins/physiology , Angiogenesis Inducing Agents/biosynthesis , Angiogenesis Inducing Agents/genetics , Angiopoietin-1 , Angiopoietin-2 , Animals , Apoptosis , Body Weight , Caspase 3 , Caspases/analysis , Caspases/metabolism , Cell Transplantation , Cells, Cultured , Cytoprotection , Genetic Therapy , Hypertension, Pulmonary/chemically induced , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/pathology , Lung/metabolism , Lung/pathology , Membrane Glycoproteins/genetics , Monocrotaline , Muscle, Smooth, Vascular/cytology , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type III , RNA, Messenger/biosynthesis , Rats , Rats, Inbred F344 , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Receptor, TIE-2 , Transfection , Transgenes , Ventricular Pressure
11.
Ophthalmologe ; 100(4): 284-91, 2003 Apr.
Article in German | MEDLINE | ID: mdl-12682760

ABSTRACT

The basic mechanisms governing how endothelial cells, periendothelial cells, matrix molecules and blood constituents interact with each other are discussed. The many insights gained from this basic knowledge are being extended to further understand physiological and pathological features of vascular sprouting and maintenance. Understanding these basic principles that drive angiogenesis and vasculogenesis will lead to a more specific therapy of many disorders in ophthalmology and other fields, such as arteriosclerosis, tumor growth, myocardial ischemia and tissue repair.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Eye Diseases/physiopathology , Neovascularization, Pathologic , Neovascularization, Physiologic , Adult , Angiogenesis Inducing Agents/physiology , Angiogenesis Inhibitors/physiology , Animals , Arteriosclerosis/physiopathology , Blood Vessels/growth & development , Diabetic Retinopathy/physiopathology , Endothelial Growth Factors/physiology , Endothelium, Vascular/cytology , Extracellular Matrix/physiology , Eye Neoplasms/physiopathology , Growth Substances/physiology , Humans , Infant, Newborn , Intercellular Signaling Peptides and Proteins/physiology , Lymphokines/physiology , Melanoma/pathology , Melanoma/physiopathology , Mice , Morphogenesis , Neoplasms/blood supply , Neoplasms/physiopathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/physiopathology , Pericytes , Receptors, Vascular Endothelial Growth Factor/physiology , Retinal Neovascularization/physiopathology , Retinopathy of Prematurity/physiopathology , Stem Cells , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
13.
J Clin Invest ; 111(5): 707-16, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12618525

ABSTRACT

Kidney disease affects over 20 million people in the United States alone. Although the causes of renal failure are diverse, the glomerular filtration barrier is often the target of injury. Dysregulation of VEGF expression within the glomerulus has been demonstrated in a wide range of primary and acquired renal diseases, although the significance of these changes is unknown. In the glomerulus, VEGF-A is highly expressed in podocytes that make up a major portion of the barrier between the blood and urinary spaces. In this paper, we show that glomerular-selective deletion or overexpression of VEGF-A leads to glomerular disease in mice. Podocyte-specific heterozygosity for VEGF-A resulted in renal disease by 2.5 weeks of age, characterized by proteinuria and endotheliosis, the renal lesion seen in preeclampsia. Homozygous deletion of VEGF-A in glomeruli resulted in perinatal lethality. Mutant kidneys failed to develop a filtration barrier due to defects in endothelial cell migration, differentiation, and survival. In contrast, podocyte-specific overexpression of the VEGF-164 isoform led to a striking collapsing glomerulopathy, the lesion seen in HIV-associated nephropathy. Our data demonstrate that tight regulation of VEGF-A signaling is critical for establishment and maintenance of the glomerular filtration barrier and strongly supports a pivotal role for VEGF-A in renal disease.


Subject(s)
Angiogenesis Inducing Agents/physiology , Kidney Diseases/etiology , Kidney Glomerulus/metabolism , Vascular Endothelial Growth Factor A , Angiogenesis Inducing Agents/genetics , Animals , Gene Expression Regulation , Kidney/pathology , Kidney/ultrastructure , Kidney Diseases/congenital , Kidney Failure, Chronic/etiology , Mice , Nephrotic Syndrome/etiology
14.
Oncogene ; 22(10): 1501-10, 2003 Mar 13.
Article in English | MEDLINE | ID: mdl-12629513

ABSTRACT

Platelet-derived growth factors (PDGFs) are important for normal tissue growth and maintenance. Overexpression of the classical PDGFs, PDGF-A and PDGF-B, has been linked to several diseases, including cancer, fibrotic disease and atherosclerosis. Recently, two novel PDGFs, PDGF-C and PDGF-D, were discovered. It has not yet been established whether PDGF-C and PDGF-D are linked to disease phenotypes like the classical PDGFs. PDGF-B, the cellular homologue of the viral simian sarcoma oncogene v-sis, is known to potently induce cellular transformation through activation of PDGF receptor (PDGFR)-beta. In this work, we have determined the transformation efficacy of PDGF-D in comparison with that of PDGF-C and PDGF-B. PDGF-D is a potent transforming growth factor for NIH/3T3 cells, and the transformed cells displayed stress fibre reorganization, increased proliferation rate, anchorage-independent growth in soft agar, ability to induce tumours in nude mice, and upregulation of vascular endothelial growth factor. Morphological analyses of the vasculatures from the PDGF-isoform-expressing tumours revealed marked differences suggesting differential signalling through the two PDGF receptors in tumour vessel development and remodelling. In summary, these results suggest that PDGF-D induce cellular transformation and promote tumour growth by accelerating the proliferation rate of the tumour cells, and by stimulation of tumour neovascularization.


Subject(s)
Angiogenesis Inducing Agents/physiology , Cell Transformation, Neoplastic , Lymphokines , Platelet-Derived Growth Factor/physiology , 3T3 Cells/pathology , Actins/metabolism , Actins/ultrastructure , Animals , Carcinogenicity Tests , Cell Division/genetics , Down-Regulation , Female , Gene Expression Regulation , Humans , Mice , Mice, Inbred BALB C , Neovascularization, Pathologic , Proto-Oncogene Proteins c-sis/physiology , Receptor, Platelet-Derived Growth Factor alpha/genetics , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Receptor, Platelet-Derived Growth Factor beta/genetics , Receptor, Platelet-Derived Growth Factor beta/metabolism , Tumor Stem Cell Assay
15.
J Control Release ; 87(1-3): 49-56, 2003 Feb 21.
Article in English | MEDLINE | ID: mdl-12618022

ABSTRACT

Therapeutic angiogenesis is a promising approach to treat patients with cardiovascular disease, and will likely be critical to engineering large tissues. Many growth factors have been found to play significant roles in angiogenesis, and vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are the most extensively investigated angiogenic factors to date. However, the appropriate dose to obtain a desired response and the effectiveness of each factor, relative to the other, in promoting angiogenesis at a specific site in the body remains unclear. We have used alginate hydrogels as localized delivery vehicles for VEGF and bFGF, and compared the ability of these factors to promote new blood vessel formation in the subcutaneous tissue of severe combined immunodeficient (SCID) mice. We have found that the thickness of a granulation tissue layer formed around the gel and the number of blood vessels in the layer increased with the dose of VEGF in the gel, but the density of new blood vessels remained relatively constant. Sustained and localized delivery of bFGF from the gels, while similarly leading to an increase in the density of blood vessels in the granulation tissue, did not lead to as high of a blood vessel density as VEGF. The results of this study support previous studies demonstrating the utility of both VEGF and bFGF in promoting angiogenesis, and suggest VEGF is more appropriate for creating a dense bed of new blood vessels in this model.


Subject(s)
Angiogenesis Inducing Agents/administration & dosage , Fibroblast Growth Factor 2/administration & dosage , Neovascularization, Physiologic/drug effects , Vascular Endothelial Growth Factor A , Angiogenesis Inducing Agents/physiology , Animals , Delayed-Action Preparations/administration & dosage , Dose-Response Relationship, Drug , Fibroblast Growth Factor 2/physiology , Humans , Hydrogels/administration & dosage , Mice , Mice, SCID , Neovascularization, Physiologic/physiology
17.
Blood ; 102(2): 638-45, 2003 Jul 15.
Article in English | MEDLINE | ID: mdl-12649156

ABSTRACT

Patients with multiple myeloma (MM) have increased bone marrow (BM) angiogenesis; however, the proangiogenic properties of myeloma cells and the mechanisms of MM-induced angiogenesis are not completely clarified. The angiopoietin system has been identified as critical in the regulation of vessel formation. In this study we have demonstrated that myeloma cells express several proangiogenic factors, and, in particular, we found that angiopoietin-1 (Ang-1), but not its antagonist Ang-2, was expressed by several human myeloma cell lines (HMCLs) at the mRNA and the protein levels. In a transwell coculture system, we observed that myeloma cells up-regulated the Ang-1 receptor Tie2 in human BM endothelial cells. Moreover, in an experimental model of angiogenesis, the conditioned medium of HMCLs significantly stimulated vessel formation compared with control or vascular endothelial growth factor (VEGF) treatment. The presence of anti-Tie2 blocking antibody completely blunted the proangiogenic effect of XG-6. Finally, our in vitro results were supported by the in vivo finding of Ang-1, but not Ang-2, mRNA and protein expression in purified MM cells obtained from approximately 47% of patients and by high BM angiogenesis in patients with MM positive for Ang-1, suggesting that the angiopoietin system could be involved, at least in part, in MM-induced angiogenesis.


Subject(s)
Angiogenesis Inducing Agents/physiology , Membrane Glycoproteins/physiology , Multiple Myeloma/metabolism , Neoplasm Proteins/physiology , Neovascularization, Pathologic/metabolism , Proto-Oncogene Proteins , Adult , Angiogenesis Inducing Agents/analysis , Angiogenesis Inducing Agents/biosynthesis , Angiogenesis Inducing Agents/genetics , Angiopoietin-1 , Angiopoietin-2 , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Bone Marrow Cells/metabolism , Coculture Techniques , Culture Media, Conditioned/pharmacology , Endothelial Growth Factors/pharmacology , Endothelium/metabolism , Gene Expression Regulation, Neoplastic , Humans , Intercellular Signaling Peptides and Proteins/pharmacology , Leukemia, Plasma Cell/metabolism , Leukemia, Plasma Cell/pathology , Lymphokines/pharmacology , Membrane Glycoproteins/biosynthesis , Membrane Glycoproteins/genetics , Middle Aged , Multiple Myeloma/blood supply , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Neovascularization, Pathologic/genetics , RNA, Messenger/biosynthesis , RNA, Neoplasm/biosynthesis , Receptor, TIE-2 , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
18.
Ann Thorac Surg ; 75(2): S685-90, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12607713

ABSTRACT

Therapeutic angiogenesis, in the form of growth factor protein administration or gene therapy, has emerged as a new method of treatment for patients with severe, inoperable coronary artery disease. Improved myocardial perfusion and function after administration of angiogenic growth factors has been demonstrated in animal models of chronic myocardial ischemia. Recently, preliminary clinical trials using growth factor proteins or genes encoding these angiogenic factors have demonstrated clinical and other objective evidence of relevant angiogenesis. A recent study reported beneficial long-term effects of therapeutic angiogenesis using fibroblast growth factor (FGF)-2 protein in terms of freedom from angina and perfusion on single-photon emission computed tomographic imaging. Thus, therapeutic angiogenesis has the potential to extend treatment options to patients who are not optimal candidates for conventional methods of myocardial revascularization. However, endogenous antiangiogenic influences, intrinsic lack of response of patients with severe endothelial dysfunction, and other limitations will need to be overcome before angiogenesis becomes a standard therapy for the treatment of patients with severe coronary disease.


Subject(s)
Angiogenesis Inducing Agents/physiology , Cardiac Surgical Procedures , Coronary Disease/therapy , Endothelial Growth Factors/therapeutic use , Fibroblast Growth Factor 2/therapeutic use , Genetic Therapy , Intercellular Signaling Peptides and Proteins/therapeutic use , Lymphokines/therapeutic use , Neovascularization, Physiologic/physiology , Protein Isoforms/therapeutic use , Animals , Coronary Artery Bypass , Coronary Disease/diagnostic imaging , Coronary Disease/physiopathology , Drug Delivery Systems , Endothelial Growth Factors/administration & dosage , Fibroblast Growth Factor 1/administration & dosage , Fibroblast Growth Factor 2/administration & dosage , Humans , Intercellular Signaling Peptides and Proteins/administration & dosage , Lymphokines/administration & dosage , Protein Isoforms/administration & dosage , Tomography, Emission-Computed, Single-Photon , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
19.
Biotechniques ; 34(1): 178-83, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12545557

ABSTRACT

The chicken chorioallantoic membrane (CAM) assay represents one of the most widely used in vivo screening assay for genes with angiogenic (blood vessel-inducing) or angiostatic (inhibition of vessel formation or their destruction) activities. Here we show that adenovirus gene transfer vectors infect cells in the CAM and lead to expression of the viral transgene. Furthermore, infection with an adenovirus vector containing the human vascular endothelial growth factor gene induced the formation of new blood vessels. This improved method saves a considerable amount of time in the identification of genes that can influence blood vessel formation because the expensive and time-consuming production and purification of recombinant protein can be omitted.


Subject(s)
Adenoviruses, Human/genetics , Allantois/physiology , Chorion/physiology , Neovascularization, Physiologic/genetics , Transfection/methods , Vascular Endothelial Growth Factor A , Allantois/blood supply , Allantois/cytology , Angiogenesis Inducing Agents/genetics , Angiogenesis Inducing Agents/physiology , Angiogenesis Inhibitors , Animals , Chick Embryo , Chorion/blood supply , Chorion/cytology , Feasibility Studies , Gene Expression Profiling/methods , Gene Expression Regulation/physiology , Genetic Vectors , Humans , Lac Operon/genetics , Neovascularization, Physiologic/physiology , Transgenes
20.
Cardiol Clin ; 20(4): 633-43, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12472049

ABSTRACT

Advances in vascular biology and the study of molecular pathophysiology have enabled the design and initial testing of therapeutic principles for cardiovascular intervention at the level of gene expression. This approach can offer an avenue to greatly impact the onset and progression of vascular disease at its roots. Early translations of basic research into human clinical protocols might provide novel alternatives for patients without traditional therapeutic options and might provide means of improving and prolonging the success of standard therapies. As the understanding of the genetic basis of vascular disease continues to grow and the tools for in vivo genetic manipulation continue to improve, vascular gene therapies might someday become a part of routine patient care.


Subject(s)
Arteriosclerosis/therapy , Angiogenesis Inducing Agents/physiology , Angioplasty/adverse effects , Arteriosclerosis/genetics , Arteriosclerosis/pathology , Bioprosthesis , Coronary Artery Bypass , Coronary Restenosis/prevention & control , Genetic Therapy/methods , Graft Occlusion, Vascular/prevention & control , Graft Survival/physiology , Humans , Hyperlipidemias/prevention & control , Neovascularization, Physiologic/physiology
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