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At least 1,207 records · Page 67Linked to original sources
PubMed1995

The modulation of granulomatous tissue and tumour angiogenesis by diclofenac in combination with hyaluronan (HYAL EX-0001).

In a novel application, hyaluronan has been utilized as a delivery system for topical and i.v. therapeutics. Clinical trials and case reports show that topical diclofenac delivered in hyaluronan (HYAL CT-1101) is effective against basal-cell carcinoma and actinic keratosis. The effect of this drug formulation on tumour growth and angiogenesis, as well as granulomatous tissue angiogenesis, has been investigated experimentally. The evidence that hyaluronan has a permissive effect on the inhibition of granulomatous tissue angiogenesis by diclofenac (as assessed by the carminel/gelatin vascular casting method) when injected into the lesion or applied topically is reviewed. Topical diclofenac in hyaluronan also induces a regression of the existing neo-vasculature of granulomatous tissue when applied therapeutically. The diclofenac formulated in hyaluronan was also found to be profoundly effective against the development of subcutaneous Colon-26 tumours in syngeneic balb/c mice (T/C ratio after 12 days topical application of 0.174, p < 0.0001). Analysis of the tumour vasculature showed that vascular development was retarded by 12 days. This was shown by the reduction in the tumour density of carmine in the vascular casts, as well as reduced blood-vessel density visualized by rat anti-mouse CD31 immunohistology. Hyaluronan alone had a significant effect on tumour development with a 50% inhibition of tumour growth and only a transient reduction in vascularity. The effects noted when diclofenac is formulated in hyaluronan, and applied topically, could be related to trans-dermal delivery and deposition properties of hyaluronan, and to the binding properties of hyaluronan to areas of pathology with high expression of hyaluronan receptors such as RHAMM, ICAM-1, and CD44.

Animals↗
PubMed2004

Variable oxygen and retinal VEGF levels: correlation with incidence and severity of pathology in a rat model of oxygen-induced retinopathy.

Retinal capillary quiescence is regulated by a delicate balance between proangiogenic and anti-angiogenic factors. Pathological angiogenesis is the result of a shift in this balance towards proangiogenic influences. Pathological angiogenesis is produced in a rat model of oxygen-induced retinopathy (OIR) by exposing newborn rat pups to alternating periods of hyperoxia and hypoxia. Based upon previous work, two similar exposure paradigms were investigated and compared, exposure of rat pups to alternating periods of 45 and 12.5% oxygen, and to alternating periods of 40 and 15% oxygen. The resulting retinal pathology was assessed by measurement of retinal clock hours with pathological blood vessel growth and the percentage of the retina that is avascular. The 45 and 12.5% exposure produced significantly greater incidence and severity of pathology than the 40 and 15% protocol. To explain the difference in pathology between these two very similar exposure protocols, retinal levels of proangiogenic vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) and anti-angiogenic pigment epithelium-derived factor (PEDF) were measured by ELISA and western blot analysis at 0, 2, and 6 days post-exposure. In whole retinal lysates, there were no significant differences in VEGFR2 and PEDF levels. However, VEGF levels were approximately 48 and 78% higher on post-oxygen exposure day 0 and 2, respectively, in the group treated with alternating periods of 45 and 12.5% oxygen compared to the group treated with alternating periods of 40 and 15% oxygen. There was no significant difference in VEGF levels between these two groups on day 6 post-exposure. Therefore, the difference in pathology observed between these two experimental paradigms is associated with differences in whole retinal VEGF levels, but not changes in whole retinal VEGFR2 or PEDF levels. The results of this study suggest the existence of a threshold in the rat model of OIR, such that a small change in blood oxygen profile triggers a disproportionate increase in subsequent neovascularization, which is accompanied by more dramatic changes of retinal VEGF level than VEGFR2 or PEDF level. If a similar threshold exists for humans, it could explain why some oxygen-treated premature infants develop retinopathy and others do not, despite similar gestational ages, birth weights and clinical courses.

Animals↗
PubMed2003

Tie2 receptor tyrosine kinase, a major mediator of tumor necrosis factor alpha-induced angiogenesis in rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is an inflammatory disease and an angiogenic disease. However, the molecular mechanisms promoting angiogenesis in RA are not clearly identified. Our objective was to study the role of an endothelium-specific receptor tyrosine kinase, Tie2, in angiogenesis of inflammatory arthritis. METHODS: Expression of Tie2 and its ligand, angiopoietin 1 (Ang1), in human synovium was examined by immunohistochemistry and Western blot. A novel synovium vascular window model was established to study the role of Tie2 in angiogenesis in vivo. Primary cultured endothelial cells and synoviocytes were used to study tumor necrosis factor alpha (TNF alpha)-induced Tie2 and Ang1 expression. RESULTS: Tie2 was implicated in pathologic angiogenesis. We observed that Tie2 and Ang1 were elevated in human RA synovium. Using a novel collagen-induced arthritis synovial window model, we demonstrated that Tie2 signaling regulated arthritis angiogenesis in vivo. We also showed that Tie2 mediated TNF alpha-induced angiogenesis in a mouse cornea assay. In addition, we observed that TNF alpha can regulate Tie2 activation in multiple ways that may involve interactions between endothelial cells and synoviocytes. TNF alpha up-regulates Tie2 in endothelial cells through nuclear factor kappa B, and it up-regulates Ang1 in synoviocytes. These findings suggest paracrine regulation of angiogenesis between endothelial cells and synoviocytes. CONCLUSION: This study demonstrates that Tie2 regulates angiogenesis in inflammatory synovium. Tie2 signaling is an important angiogenic mediator that links the proinflammatory cytokine TNF alpha to pathologic angiogenesis.

Angiogenesis Inducing Agents↗
PubMed1995

Angiogenesis in pre-eclampsia.

OBJECTIVE: To study the angiogenetic activity of decidua basalis from primigravid women with pre-eclampsia. STUDY DESIGN: Fresh fragments of decidua basalis from 10 primigravid women with pre-eclampsia and from 10 healthy, control primigravid women, were grafted onto the chick embryo chorioallantoic membrane (CAM) at the 6th incubation day. Four days later the CAMs were fixed and the angiogenic response of the CAMs was assessed on histologic sections by a planimetric point-count method. RESULTS: Decidua from pre-eclamptic pregnancies induced angiogenesis to a greater extent than that from normotensive pregnancies. CONCLUSIONS: Angiogenesis might be stimulated in pre-eclampsia through endothelia and decidua changes induced by the pathological condition which, in turn, would lead to a greater expression of angiogenic factors also present in normal condition.

Allantois↗
PubMed2005

Endometrial volume and vascularity measurements by transvaginal three-dimensional ultrasonography and power Doppler angiography in stimulated and tumoral endometria: intraobserver reproducibility.

OBJECTIVES: To assess intraobserver reproducibility of the endometrial volume (EV) and 3D power Doppler indices (vascularization index, VI; flow index, FI; and vascularization flow index, VFI) of the endometrium and subendometrial area using three-dimensional power Doppler angiography (3D-PDA). METHODS: Twenty-five women on the hCG day after controlled ovarian stimulation and 15 patients presenting with uterine bleeding and suspicious endometrial thickening (10 endometrial cancers and 5 endometrial hyperplasias) were scanned. Eighty volume data sets were analyzed using the VOCAL imaging program. EV and VI, FI and VFI of the endometrium and subendometrium (5 mm shell) were manually calculated in the longitudinal and coronal planes with 15 degrees and 9 degrees rotation steps. Intraclass correlation coefficient (ICC) and 95% confidence intervals were used to assess reliability. RESULTS.: EV measurements were highly reproducible (ICC > or = 0.97) without significant differences between planes and rotation steps. Endometrial and subendometrial VI, FI, and VFI presented ICCs above 0.90 with the exception of the subendometrial FI (ICC > or = 0.80). There were no significant differences according to measurement plane and rotation step except for subendometrial VFI. Nevertheless, 3D power Doppler indices calculated in the coronal plane and 9 degrees rotation step obtained the highest ICC. ICCs for 3D-PDA indices from the tumoral endometria were significantly higher than those calculated from the stimulated endometria. CONCLUSIONS: Endometrial volume and endometrial and subendometrial 3D power Doppler indices have an acceptable reproducibility, significantly higher in tumoral endometria. The reliability of measurements does not seem to be significantly influenced by the rotation plane and degrees of rotation. These results support that 3D-PDA and VOCAL are reliable methods to evaluate the physiological and pathological changes of the endometrium.

Adult↗
PubMed1990

Carcinoma in situ of the cornea.

Carcinoma in situ of the cornea is part of a pathological entity, which covers all conjunctival and corneal epithelial neoplasiae (CIN). The clinicopathological characteristics of this rare ocular tumor will be demonstrated.

Adult↗
PubMed2002

Peptidomimetics and angiogenesis.

Angiogenesis is the sprouting of new blood capillaries from surrounding preexisting blood vessels. This process is fundamental for embryonic development, wound healing and inflammation. In healthy adults angiogenesis is of minor importance. However, aberrant angiogenesis is essentially involved in disorders as diabetic retinopathy, rheumatoid arthritis and tumor growth, and blocking angiogenesis has emerged as a promising target for antagonizing these diseases. Therefore the development of new anti-angiogenic drugs is of great interest in academic and industrial research. This review focuses on the employment of peptidomimetics in inhibiting pathologic angiogenesis. It will survey the individual aspects of angiogenesis where the usage of peptidomimetics is favored and will consider the current progresses on this field.

Angiogenesis Inhibitors↗
PubMed1992

Platelet-derived growth factor is angiogenic in vivo.

PDGF receptors have recently been found to be expressed in microvascular endothelium in vivo under circumstances of endothelial cell activation and angiogenesis suggesting that PDGF may have a direct effect on endothelial cells. We have tested the angiogenic activity of PDGF-AA and -BB homodimers in the chick chorioallantoic membrane in vivo. PDGF-BB was found to consistently induce an angiogenic response whereas PDGF-AA was less active. Morphological analyses revealed that there was little inflammation associated with this response but an increase in vessel density suggested a direct effect of PDGF on embryonic chorioallantoic endothelial cells. In vitro, PDGF-BB was found to be more potent than PDGF-AA in stimulating the chemotaxis of rat brain capillary endothelial cells. This is consistent with a direct effect of PDGF on endothelial cells. Thus, this novel angiogenic activity of PDGF has implications for several developmental and pathological events in which PDGF, particularly the B-chain, is expressed.

Allantois↗
PubMed2002

The prognostic molecular markers in hepatocellular carcinoma.

The prognosis of hepatocellular carcinoma (HCC) still remains dismal, although many advances in its clinical study have been made. It is important for tumor control to identify the factors that predispose patients to death. With new discoveries in cancer biology, the pathological and biological prognostic factors of HCC have been studied quite extensively. Analyzing molecular markers (biomarkers) with prognostic significance is a complementary method. A large number of molecular factors have been shown to associate with the invasiveness of HCC, and have potential prognostic significance. One important aspect is the analysis of molecular markers for the cellular malignancy phenotype. These include alterations in DNA ploidy, cellular proliferation markers (PCNA, Ki-67, Mcm2, MIB1, MIA, and CSE1L/CAS protein), nuclear morphology, the p53 gene and its related molecule MD M2, other cell cycle regulators (cyclin A, cyclin D, cyclin E, cdc2, p27, p73), oncogenes and their receptors (such as ras, c-myc, c-fms, HGF, c-met, and erb-B receptor family members), apoptosis related factors (Fas and FasL), as well as telomerase activity. Another important aspect is the analysis of molecular markers involved in the process of cancer invasion and metastasis. Adhesion molecules (E-cadherin, catenins, serum intercellular adhesion molecule-1, CD44 variants), proteinases involved in the degradation of extracellular matrix (MMP-2, MMP-9, uPA, uPAR, PAI), as well as other molecules have been regarded as biomarkers for the malignant phenotype of HCC, and are related to prognosis and therapeutic outcomes. Tumor angiogenesis is critical to both the growth and metastasis of cancers including HCC, and has drawn much attention in recent years. Many angiogenesis-related markers, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF), thrombospondin (TSP), angiogenin, pleiotrophin, and endostatin (ES) levels, as well as intratumor microvessel density (MVD) have been evaluated and found to be of prognostic significance. Body fluid (particularly blood and urinary) testing for biomarkers is easily accessible and useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum, and its genetic alterations in HCC are other important trends. More attention should be paid to these two areas in future. As the progress of the human genome project advances, so does a clearer understanding of tumor biology, and more and more new prognostic markers with high sensitivity and specificity will be found and used in clinical assays. However, the combination of some items, i.e., the pathological features and some biomarkers mentioned above, seems to be more practical for now.

Apoptosis↗
PubMed2006

Molecular addresses of tumors: selection by in vivo phage display.

In vivo phage display has been used extensively to screen for novel targets of tumor therapy. Phage display peptide libraries can express random peptides or protein fragments and the aim of phage display is to identify peptide molecules that bind stably to a given target. Angiogenesis is essential to tumor development. Both blood and lymphatic vessels of tumors are different from those of normal tissues. Phage display has been used to analyze the structure and molecular diversity of tumor vasculature and to select tumor-specific antigens which have revealed stage- and type-specific markers of tumor blood vessels. Furthermore, peptides identified by in vivo phage display also work as vehicles to transport cargo therapeutic reagents to tumors. These peptides and their corresponding cellular proteins and ligands may provide molecular tools to selectively target the addresses of tumors and their pathological blood vessels and might increase the efficacy of therapy while decreasing side effects.

Amino Acid Sequence↗
PubMed1990

Comparison of Dolichos biflorus lectin and other lectin-horseradish peroxidase conjugates in staining of cutaneous blood vessels in the hairless mini-pig.

Angiogenesis is necessary for normal growth, wound healing, and plays a key role in many pathologic processes. A variety of endothelial markers have been used to investigate angiogenesis. Unfortunately, excellent markers for vascular endothelium in human tissues exhibit little or no staining of endothelia in tissues of other animal species, including the pig. We are interested in the hairless Yucatan strain of mini-pig as an animal model for studying cutaneous wound healing because its skin is histologically and functionally very similar to that of man. Hoping to find a specific marker to identify vascular endothelium in the mini-pig, we therefore screened a battery of 11 different lectin-horseradish peroxidase conjugates. Based on specificity and staining intensity, Dolichos biflorus agglutinin (DBA) was chosen from this battery to investigate vascular changes in the healing of cutaneous wounds in the mini-pig. When compared with routine histologic sections stained with hematoxylin and eosin, blood vessels were much easier to identify in sections stained histochemically with DBA. Lectin histochemistry was particularly useful in investigations of early events in angiogenesis during wound healing when newly derived capillary buds and minute blood vessels were obscured in normal histologic sections by an inflammatory cell infiltrate associated with the healing wound. Ultrastructural lectin cytochemistry revealed staining along the luminal surface and the basolateral plasmalemma of endothelial cells. Histochemical staining with DBA promises to provide a useful method for further investigation of angiogenesis and other vascular phenomena in a variety of normal and pathologic processes using the hairless Yucatan strain of mini-pig as the animal model.

Animals↗
PubMed2003

Activation of vascular endothelial growth factor receptor-1 sustains angiogenesis and Bcl-2 expression via the phosphatidylinositol 3-kinase pathway in endothelial cells.

Vascular insufficiency and retinal ischemia precede many proliferative retinopathies and stimulate secretion of various vasoactive growth factors, including vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF). It is unclear, however, how PlGF, which is elevated in proliferative diabetic retinopathy and is a VEGF homolog that binds only to VEGF receptor (VEGFR)-1, promotes pathological angiogenesis. When primary microvascular endothelial cells were grown on collagen gels, PlGF-containing ligands upregulated Bcl-2 expression and stimulated the formation of capillary-like tube networks that were retained for up to 14 days in culture. The inhibition of VEGFR-1 results in a dramatic decrease in the number of capillary connections, indicating that VEGFR-1 ligands promote branching angiogenesis. In contrast, VEGF-induced tube formations and Bcl-2 expression were significantly decreased at the end of this period. Flow cytometry analysis of annexin-V/propidium iodide-stained cells revealed that PlGF and PlGF/VEGF heterodimer inhibited apoptosis in serum-deprived endothelial cells. These two growth factors stimulated a survival signaling pathway phosphatidylinositol 3-kinase (PI3K), as identified by increased Akt phosphorylation and because blocking PI3K signalling by adenovirus-mediated overexpression of wild-type phosphatase and tensin homolog on chromosome 10 (PTEN) disrupted angiogenesis and decreased Bcl-2 expression by PlGF and PlGF/VEGF heterodimer, whereas a dominant-negative PTEN mutant enhanced endothelial sprout formation and Bcl-2 expression. Together, these findings indicate that PlGF-containing ligands contribute to pathological angiogenesis by prolonging cell survival signals and maintaining vascular networks.

Animals↗
PubMedDate not supplied

[Changes in endometrial vascularisation due to hormone therapy in menopause].

Hysteroscopic and histopathologic endometrial study by commune and immunohistochemical techniques on 2 groups of menopausal women on HRT-sequential (24 months) and continuous combined (12 months) compared to pretherapy or a control untreated group showed the changes of endometrial superficial microvascular net-work, with new blood vessels and ecquimosis/subepithelial haemorrhages. Endometrial neoangiogenesis varied according to progestogens/progesterone: type (less on dydrogesterone, more important on cyproterone acetate, medroxyprogesterone acetate, norethisterone), dose (large doses of medroxyprogesterone acetate induce greater changes in sequential HRT, and small doses induce less changes), time (minimum when progestogen is cyclic at 3 months). The vascular changes are more accentuate in the first year of HRT. The correlation between the number of new vessels and type of endometrial pathology showed that the neoangiogenesis is greater in secretory and atrophic endometrium.

Adult↗
PubMed2000

Correlation between neovascularisation and neuroendocrine differentiation in prostatic carcinoma.

Neuroendocrine (NE) differentiated tumor cells are found in almost all prostatic carcinomas. Prostatic carcinomas with a high NE differentiation have a poor prognosis and increased metastatic potential. A relationship between the neovascularisation density in the tumor and the metastatic potential in prostatic carcinoma is well known. NE cells and microvessels were demonstrated immunohistochemically on 102 radical prostatectomy specimens using antibodies against Chromogranin A and CD34. Standard areas (7.9 mm2) of maximal Chromogranin A expression and highest vascularisation were determined and topographically related by light microscopy. Area density of microvessels was evaluated morphometrically. NE tumor cells were present in all prostatic carcinomas studied. High grade prostatic carcinomas expressed significantly more NE tumor cells and exhibited a higher neovascularisation than low grade carcinomas. There was significantly higher neovascularisation in high grade tumors with many, as compared to high grade tumors with few, NE tumor cells. Poorer pathological staging correlated with increased neovascularisation and stronger NE differentiation. A topographical relationship between the area of maximal NE tumor cells and the area of highest neovascularisation was found in 80.4% of all cases. An analysis of variance revealed a large number of NE tumor cells as the only predictor of an increased neovascularisation (p = 0.0006). These observations support the concept that increased neovascularisation is influenced not only by poor pathological grading but also by a high NE differentiation.

Adenocarcinoma↗
PubMed1991

Angiotensin and the regulation of cellular growth. Pathophysiologic implications for cardiovascular and noncardiovascular tissues.

Components of the renin-angiotensin system can be found in the vasculature, although in most cases it is unclear how much, if any, of this renin in the vasculature is locally synthesized. Over recent years, a variety of novel actions of angiotensin II have been delineated which suggest that in appropriate physiologic or pathologic circumstances vascular angiotensin II can play an important role in determining vascular structure. Moreover, angiotensin II may play a role in neoplastic growth of vascular and nonvascular tissues.

Angiotensin II↗
PubMed2006

Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis.

The chemokine stroma-derived factor (SDF-1/CXCL12) plays multiple roles in tumor pathogenesis. It has been demonstrated that CXCL12 promotes tumor growth and malignancy, enhances tumor angiogenesis, participates in tumor metastasis, and contributes to immunosuppressive networks within the tumor microenvironment. Therefore, it stands to reason that the CXCL12/CXCR4 pathway is an important target for the development of novel anti-cancer therapies. In this review, we consider the pathological nature and characteristics of the CXCL12/CXCR4 pathway in the tumor microenvironment. Strategies for therapeutically targeting the CXCL12/CXCR4 axis also are discussed.

Cell Transformation, Neoplastic↗
PubMed2006

From proteins to nucleic acid-based drugs: the role of biotech in anti-VEGF therapy.

Cancer cells, by releasing pro-angiogenic factors, stimulate the growth of the thick capillary net necessary for the nourishment of the tumor mass. The battle to defeat cancer uses today different approaches based on the inhibition of pathological angiogenesis: several compounds, either synthetic or biotech, aimed at this complex process, are under development. Vascular endothelial growth factor (VEGF) is considered the main target for an anti-cancer therapy based on angiogenesis inhibition; the goal is to block the interaction between this cytokine and its receptors in order to stop the intracellular signaling pathways leading to endothelium remodeling. FDA recently approved two drugs specifically aimed at VEGF, bevacizumab, a humanized monoclonal antibody, and pegaptinib, a pegylated aptamer with application in ophthalmic pathologies. These two approvals validate anti-VEGF therapy for clinical use, and show how biotech companies are investing on angiogenesis using different approaches, i.e. exploiting protein drugs and oligonucleotide-based therapeutics. Monoclonal antibodies, as well as other high molecular weight products like cytokine-traps, aptamers and short interfering RNA (siRNA), are designed to target VEGF and its receptors. Their design, production and clinical advancement in cancer and other pathological conditions linked to angiogenesis will be specifically addressed in this review.

Angiogenesis Inhibitors↗