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Angiogenesis in normal, hyperplastic, and neoplastic endometrium.
The purpose of this study was to quantify vascular density in the stroma of normal, hyperplastic, and neoplastic endometria and to explore its relationship to other prognostic features of endometrioid adenocarcinoma. Curettage specimens of proliferative and mid-secretory endometrium; simple, complex, and atypical endometrial hyperplasia; and grade I endometrioid adenocarcinoma were stained with Factor VIII-related antigen. The number of vessels per mm2 of stroma was calculated for each case. The stroma of mid-secretory and hyperplastic endometrium was more vascular than that of proliferative endometrium. The stroma of adenocarcinoma, though reduced in proportion to the epithelium, was significantly more vascular than that of normal or hyperplastic endometrium. Stromal vascular density was not related to the depth of invasion, the presence of lymphovascular space permeation, or the state of the adjacent endometrium, whether atrophic or hyperplastic.
Crystallization of the receptor binding domain of vascular endothelial growth factor.
Vascular endothelial growth factor (VEGF) is a potent angiogenic factor with a unique specificity for vascular endothelial cells. In addition to its role in vasculogenesis and embryonic angiogenesis, VEGF is implicated in pathologic neovascularization associated with tumors and diabetic retinopathy. Four different constructs of a short variant of VEGF sufficient for receptor binding were overexpressed in Escherichia coli, refolded, purified, and crystallized in five different space groups. In order to facilitate the production of heavy atom derivatives, single cysteine mutants were designed based on the crystal structure of platelet-derived growth factor. A construct consisting of residues 8 to 109 was crystallized in space group P2(1), with cell parameters a = 55.6 A, b = 60.4 A, c = 77.7 A, beta = 90.0 degrees, and four monomers in the asymmetric unit. Native and derivative data were collected for two of the cysteine mutants as well as for wild-type VEGF.
Phage antibodies with pan-species recognition of the oncofoetal angiogenesis marker fibronectin ED-B domain.
Fibronectin (FN) exists in several polymorphic forms due to alternative splicing. The B-FN isoform (with ED-B domain inserted by splicing) is present in the stroma of foetal and neoplastic tissues and in adult and neoplastic blood vessels during angiogenesis but is undetectable in mature vessels. This isoform, therefore, represents a promising marker for angiogenesis, as already shown using the mouse monoclonal antibody (MAb) BC-1 directed against an epitope on human B-FN. However, this MAb does not directly recognise the human ED-B domain nor does it recognise B-FN of other species; therefore, it cannot be used as a marker of angiogenesis in animal models. In principle, antibodies directed against the human ED-B domain should provide pan-species markers for angiogenesis as the sequence of this domain is highly conserved in different species (and identical in humans and mice). As it has proved difficult to obtain such antibodies by hybridoma technology, we used phage display technology. Here, we describe the isolation of human antibody fragments against the human ED-B domain that bind to human, mouse and chicken B-FN. As shown by immunohistochemistry, the antibody fragments stain human neoplastic tissues and the human, mouse and chicken neovasculature.
Angiogenic potential of malignant and non-malignant human breast tissues in an in vivo angiogenesis model.
Tumors need to acquire an angiogenic phenotype for outgrowth and metastasis formation. Limited information on the angiogenic potential of specific tissues, especially human breast tissues is available. Here we describe an in vivo model, using the dorsal skin fold chamber in immunodeficient nude mice, where various tissues of human breast origin were xenografted and evaluated for their angiogenesis-inducing potential. We found that angiogenesis was abundantly induced by all breast carcinoma tissue samples. Similar angiogenesis was induced by tissue samples from breasts with hyperplasia and apocrine metaplasia. Histologically normal tissues adjacent to the tumor induced angiogenesis in 66% of the cases. Angiogenesis was not induced by control tissues from normal healthy breasts, obtained after cosmetic breast reduction. Angiogenesis induction parallelled VEGF production by the tumor cells. The tissue induced neovascularization, found both around and in the human tissue, was functional since a tail vein injection of albumin-FITC revealed positive tumor microcirculation within 5 min, while the tumor tissue still consisted of vital human epithelial cells after 14 days.
Expression of multiple angiogenic cytokines in cultured normal human prostate epithelial cells: predominance of vascular endothelial growth factor.
The cytokines that regulate angiogenesis in normal and malignant prostate tissue are not well studied. Using an RT-PCR-based screen, we observed that cultured, low-passage normal human prostate epithelial cells (PrECs) express a variety of cytokines which have been shown to have angiogenic and/or endothelial cell-activating properties in various systems. These include vascular endothelial growth factor (VEGF), basic fibroblastic growth factor (bFGF), transforming growth factor-alpha (TGF-alpha), transforming growth factor-beta (TGF-beta), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). Expression of VEGF, bFGF, GM-CSF, G-CSF, TGF-alpha and TNF-alpha in these cells was confirmed by immunohistochemistry. Culture medium conditioned by normal human PrECs for periods of up to 96 hr were found to contain VEGF, GM-CSF, G-CSF, IL-8, TGF-beta1 and TGF-beta2 but not TNF-alpha or bFGF, as determined by ELISA. Of these, VEGF was by far the most prominently expressed angiogenic cytokine (approx. 2,500 pg/ml conditioned medium at 96 hr vs. 30 to 100 pg/ml conditioned medium for the other cytokines). PrEC-conditioned medium induced an approximately 2-fold stimulation of [3H]-thymidine incorporation in cultured human umbilical cord endothelial cells (HUVECs) deprived of the endothelial growth factors VEGF and bFGF; this stimulation was abolished by neutralizing antibodies directed against VEGF but not bFGF, IL-8, GM-CSF or TNF-alpha. VEGF expression by PrECs was not markedly altered by administration or deprivation of other angiogenic cytokines for which these cells have receptors, suggesting that there is not a hierarchy of cytokines controlling its expression; however, retinoic acid, a component of PrEC growth medium, was found to modestly suppress VEGF at physiological concentrations (0.1 ng/ml). These data suggest that normal PrECs express a variety of angiogenic cytokines, most prominently VEGF, to recruit a supporting vasculature, even in culture. Our data also suggest that the ability of malignant PrECs to stimulate angiogenesis may be intrinsic and does not need to be acquired during oncogenesis.
Inhibition of angiogenesis and breast cancer xenograft tumor growth by VEGI, a novel cytokine of the TNF superfamily.
Recently, we reported a novel protein of the tumor necrosis factor (TNF) superfamily, named vascular endothelial cell growth inhibitor (VEGI), which is expressed predominantly in endothelial cells. When a secreted form of this new protein was overexpressed in mouse colon cancer cells, the growth of tumors formed by these cells in black mice was inhibited. We now report that recombinant VEGI inhibits the proliferation of endothelial cells but not that of other types of cells examined. The protein also inhibits formation of capillary-like structures by endothelial cells in collagen gels, and the growth of capillaries into collagen gels placed on the chick chorioallantoic membrane. The anticancer potential of VEGI was examined in a breast cancer xenograft tumor model in which the cancer cells were co-injected with Chinese hamster ovary cells overexpressing a secreted form of the protein. The co-injection resulted in potent inhibition of xenograft tumor growth. Our findings are consistent with the view that VEGI is an endothelial cell-specific negative regulator of angiogenesis.
Selenium-induced inhibition of angiogenesis in mammary cancer at chemopreventive levels of intake.
The trace element nutrient selenium (Se) has been shown to possess cancer-preventive activity in both animal models and humans, but the mechanisms by which this occurs remain to be elucidated. Because angiogenesis is obligatory for the genesis and growth of solid cancers, we investigated, in the study presented here, the hypothesis that Se may exert its cancer-preventive activity, at least in part, by inhibiting cancer-associated angiogenesis. The effects of chemopreventive levels of Se on the intra-tumoral microvessel density and the expression of vascular endothelial growth factor in 1-methyl-1-nitrosourea-induced rat mammary carcinomas and on the proliferation and survival and matrix metalloproteinase activity of human umbilical vein endothelial cells in vitro were examined. Increased Se intake as Se-enriched garlic, sodium selenite, or Se-methylselenocysteine led to a significant reduction of intra-tumoral microvessel density in mammary carcinomas, irrespective of the manner by which Se was provided: continuous exposure (7-wk feeding) with a chemoprevention protocol or acute bolus exposure (3 d) after carcinomas had established. Compared with the untreated controls, significantly lower levels of vascular endothelial growth factor expression were observed in a sizeable proportion of the Se-treated carcinomas. In contrast to the mammary carcinomas, the microvessel density of the uninvolved mammary glands was not altered by Se treatment. In cell culture, direct exposure of human umbilical vein endothelial cells to Se induced cell death predominantly through apoptosis, decreased the gelatinolytic activities of matrix metalloproteinase-2, or both. These results indicate a potential for Se metabolites to inhibit key attributes (proliferation, survival, and matrix degradation) of endothelial cells critical for angiogenic sprouting. Therefore, inhibition of angiogenesis associated with cancer may be a novel mechanism for the anticancer activity of Se in vivo, and multiple mechanisms are probably involved in mediating the anti-angiogenic activity.
Vascular remodelling during the normal and malignant life cycle of the mammary gland.
The mammary gland life cycle is exemplified by massive, physiologically dictated changes in cell number and composition, architecture, and functionality. These drastic upheavals, by necessity, also involve the mammary endothelium, which undergoes angiogenic expansion during pregnancy and lactation followed by ordered regression during involution. In this review, we summarise data obtained using the Mercox methyl methacrylate corrosion cast technique to analyse the mammary gland vasculature during normal development and carcinogenesis. Concomitant with epithelial cell expansion, the mammary vasculature grows during the first half of pregnancy by sprouting angiogenesis whereas the last half of pregnancy and lactation are characterised by the non-proliferative intussusceptive angiogenesis. The vasculature of the lactating gland is composed of a well-developed capillary meshwork enveloping the secretory alveoli with basket-like honeycomb structures. During involution, regression of the vasculature is achieved by regional collapse of the honeycomb structures, capillary retraction, and endothelial attenuation. This process appears partly to involve apoptosis. However, an additional mechanism involving remodelling without cell death, which we have termed angiomeiosis, must exist to explain the morphological observations. Interestingly, in mammary tumours of neuT transgenic mice, both sprouting and intussusceptive angiogenesis was observed simultaneously in the same nodules, a finding with potential implications for cancer therapy. The underlying molecular mechanisms controlling angiogenic modulation in the mammary gland, particularly angiogenic regression and the endothelial:parenchymal interplay, are poorly understood. However, the data summarised in this review indicate that precisely these molecular mechanisms offer novel alternatives for specific and effective treatment of breast cancer.
Retinal and choroidal neovascularization.
The unique vascular supply of the retina, the ability to visualize the vasculature in vivo, and the ability to selectively express genes in the retina make the retina an ideal model system to study molecular mechanisms of angiogenesis. In addition, this area of investigation has great clinical significance, because retinal and choroidal neovascularization are the most common causes of severe visual loss in developed countries and new treatments are needed. As a result, interest in ocular neovascularization is rapidly growing and there has been considerable recent progress. Use of genetically engineered mice in recently developed murine models provides a means to investigate the role of individual gene products in neovascularization in two distinct vascular beds, the retinal vasculature and the choroidal vasculature. It appears that angiogenesis in different vascular beds has common themes, but also has tissue-specific aspects. This review summarizes recent progress in the field of ocular neovascularization and the prospects that it provides for the development of new treatments.
HGF/SF in angiogenesis.
Hepatocyte growth factor/scatter factor (HGF/SF) is a mesenchyme-derived cytokine that stimulates motility and invasiveness of epithelial and cancer cells. These responses are transduced through the c-met proto-oncogene product, a transmembrane tyrosine kinase that functions as the HGF/SF receptor. We have shown that HGF/SF is a potent angiogenic molecule and that its angiogenic activity is mediated primarily through direct actions on vascular endothelial cells. These include stimulation of cell migration, proliferation, protease production, invasion, and organization into capillary-like tubes. We further showed that HGF/SF is overexpressed in invasive human cancers, including breast cancer, relative to non-invasive cancers and benign conditions. In invasive breast cancers, the content of HGF/SF is strongly correlated with that of von Willebrand's factor, a marker of vascular endothelial cells. Furthermore, transfection of breast cancer and glioma cell lines with HGF/SF cDNA greatly enhanced the ability of these cells to grow as tumours in orthotopic sites in syngeneic or immunocompromized host animals. The increased growth rate of the HGF/SF-transfected cells was attributable, in part, to increased tumour angiogenesis. These findings suggest that HGF/SF may function as a tumour progression factor, in part by stimulating tumour cell invasiveness and in part by stimulating angiogenesis.
Chorioallantoic membrane capillary bed: a useful target for studying angiogenesis and anti-angiogenesis in vivo.
The chick embryo chorioallantoic membrane (CAM) is an extraembryonic membrane that is commonly used in vivo to study both angiogenesis and anti-angiogenesis. This review 1) summarizes the current knowledge about the structure of the CAM's capillary bed; 2) discusses the controversy about the existence of a single blood sinus or a capillary plexus underlying the chorionic epithelium; 3) describes a new model of the CAM vascular growth, namely the intussusceptive mode; 4) reports findings regarding the role played by endogenous fibroblast growth factor-2 in CAM vascularization; and 5) addresses the use and limitations of the CAM as a model for studying angiogenesis and anti-angiogenesis.
Teratogen update: pseudoephedrine.
Pseudoephedrine is contained in decongestants such as the Sudafed line of products. It is an alpha-adrenergic receptor agonist, which causes blood vessel constriction, including the therapeutic effect of reducing airflow resistance in the nasal cavity. Pseudoephedrine is one of the most commonly used medications in pregnancy, with an estimated 25% of women exposed. It has been demonstrated that alpha-adrenergic receptor agonists slow uterine blood flow, but their effects have not been studied in relation to most reproductive outcomes in animals or humans. Two analyses of health maintenance organization pharmacy data identified 9 malformed infants among 902 first-trimester pseudoephedrine exposures, suggesting no association with birth defects overall; however, studies of such data sets often lack sufficient power to identify risks for specific birth defects. The related compounds, epinephrine, ephedrine, and phenylephrine, have been associated with hemorrhages and cardiovascular and limb malformations in animal models. Risk of ventricular septal defects was associated with decongestant use in pregnant women in 1 recent study. The vasoconstrictive effects of these drugs raise the hypothesis that their use in early pregnancy might increase the risk of vascular disruption defects. Case-control studies, which often do have power to identify risks related to specific birth defects, have explored this hypothesis. Decongestant use in the first trimester has been associated with small increases in risks of 3 defects thought to arise, at least in some instances, from vascular disruption-gastroschisis, small intestinal atresia, and hemifacial microsomia. These findings are somewhat consistent in terms of magnitude of effect and suggest that risks are even greater among women also exposed to the vasoconstrictive effects of cigarette smoking. There are, however, limitations to these studies, including the possibilities of inaccurate recall of exposures and confounding by indication. In addition, the majority of decongestant use is in oral form and the question of whether intranasal formulations carry risk has not been adequately addressed.
The role of thrombospondin-1 in tumor progression and angiogenesis.
Thrombospondin (TSP-1) is a large glycoprotein secreted by platelets and synthesized by many cell types, including endothelial and tumor cells. Although controversy exists about the biological function of TSP-1, the following observations suggest that TSP-1 may potentiate tumor progression. (1) Tumor metastases in mice are promoted by TSP-1 and inhibited by anti-TSP-1 antibodies. (2) TSP-1 promotes tumor cell adhesion, migration and invasion. (3) TSP-1 promotes angiogenesis in the rat aorta model. (4) TSP-1 up-regulates the plasminogen activator system through a mechanism involving the activation of TGF-beta 1. (5) Human tumors express increased levels of the CSVTCG-specific TSP-1 receptor. (6) Tumor stroma is enriched in TSP-1. (7) Cancer patients have high blood levels of TSP-1. (8) Poor patient survival correlates with a higher expression of the CSVTCG-specific TSP-1 receptor on tumor cells. In this paper we discuss the evidence that TSP-1 promotes tumor progression and present a hypothetical scheme for its mechanism of action.
DNA chip analysis of comprehensive food function: inhibition of angiogenesis and telomerase activity with unsaturated vitamin E, tocotrienol.
Inhibition of angiogenesis and telomerase activity with vitamin E compounds, especially for tocotrienol (T3), has been investigated. Nutrigenomic tools have been used for elucidating the bioactive mechanisms of T3. In the cell culture experiments, T3 reduced the vascular endothelial growth factor (VEGF)-stimulated tube formation by human umbilical vein endothelial cells (HUVEC). Among T3 isomers, delta-T3 appeared the highest activity. The T3 inhibited the new blood vessels formation on the growing chick embryo chorioallantoic membrane (CAM assay for an in vivo model of angiogenesis). In contrast, tocopherol did not. The findings suggested that the T3 has potential use for reducing angiogenic disorder. DNA chip analysis revealed that T3 specifically down-regulates the expression of VEGF receptor (VEGFR) in endothelial cells. It is well-known that VEGF regulates angiogenesis by binding to VEGFR. Therefore, T3 could block the intracellular signaling of VEGF via down-regulation of VEGFR, which resulted in the inhibition of angiogenesis. On the other hand, DNA chip analysis also revealed that T3 down-regulates the expression of protein kinase C (PKC) in the cultured HUVEC. Since PKC is involved with the control of telomerase activity, T3 has potential to act as anti-telomerase inhibitor via PKC inhibition. In this manner, DNA chip technology provides efficient access to genetic information regarding food function and its mechanism.
VEGF coordinates interaction of pericytes and endothelial cells during vasculogenesis and experimental angiogenesis.
Biological activities of vascular endothelial growth factor (VEGF) have been studied extensively in endothelial cells (ECs), but few data are available regarding its effects on pericytes. In murine embryoid body cultures, VEGF-induced expression of desmin and alpha-smooth muscle actin (alpha-SMA) in CD-31+ cells. The number of CD-31+/desmin+ vascular chords increased with VEGF treatment time and peaked during a differentiation window between 6 and 9 days after plating. In vivo, VEGF-induced elongation and migration of desmin-positive pericytes and coverage of angiogenic capillaries, as revealed by analysis of Sambucus nigra lectin-stained vascular beds of the chick chorioallantoic membrane. VEGF also caused significant decrease of intercapillary spaces, an indicator for intussusceptive vascular growth. These VEGF-mediated effects point at a more intricate interaction between ECs and pericytes cells than previously demonstrated and suggest that pericytes may be derived from EC progenitors in vitro and not only stabilize capillaries but also participate in vascular remodeling in vivo.
Competing pathways of iron chelation: angiogenesis or anti-tumor activity: targeting different molecules to induce specific effects.
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Irradiated C6 glioma cells induce angiogenesis in vivo and activate endothelial cells in vitro.
Malignant gliomas are angiogenesis dependent and present a remarkable degree of resistance to radiotherapy. In the present work, we studied the effect of irradiation of C6 glioma cells on their proliferation and activation in vitro and on glioma cell-induced angiogenesis in vivo and in vitro. Irradiation of C6 glioma cells decreased cell proliferation in a dose-dependent manner. Interestingly, metalloproteinase-2 and -9 expression and secretion, as well as integrin alpha(v) expression, increased with elevated doses of X rays 48 hr after irradiation and was mostly evident at the higher doses used. When pre-irradiated C6 cells were implanted on nonirradiated chicken embryo chorioallantoic membranes (CAMs), there was a significant dose-dependent increase in tumor induced angiogenesis, compared to angiogenesis induced by nonirradiated cells. Similar results were obtained when C6 cells were irradiated 48 hr after their inoculation onto nonirradiated CAMs. In the same line, conditioned medium from irradiated C6 cells significantly increased endothelial cell proliferation and migration in vitro, in a manner dependent on the dose of X rays. These results explain at least in part the low effectiveness of radiation therapy of malignant gliomas and support the notion that inhibition of angiogenesis in parallel with radiotherapy may represent a new therapeutic approach.