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PubMed2003

Angiogenesis in nervous system disorders.

Angiogenesis is a crucial requirement for embryonal development and new vessel formation during adult life. Various disease processes such as cancer, ischemia, vascular malformations, and inflammatory processes also depend on pathological angiogenesis. A better understanding of the complex and coordinated interactions among various angiogenic pathways involved in pathological angiogenesis is necessary to improve our therapeutic approaches to the various disease processes observed in the central nervous system. This review summarizes the current understanding of the role of principal angiogenic factors relevant to neurosurgical abnormalities.

Angiogenesis Modulating Agents↗

PubMed2001

Plasminogen activator inhibitor-1 regulates tumor growth and angiogenesis.

Elevated expression of plasminogen activator inhibitor-1 (PAI-1) in tumors is associated with a poor prognosis in many cancers. Reduced tumor growth and angiogenesis have also been reported in mice deficient in PAI-1. These results suggest that PAI-1 may be required for efficient angiogenesis and tumor growth. In the present study, we demonstrate that PAI-1 can both enhance and inhibit the growth of M21 human melanoma tumors in nude mice and that this appears to be due to PAI-1 regulation of angiogenesis. Quantitative analysis of angiogenesis in a Matrigel implant assay indicated that in PAI-1 null mice angiogenesis was reduced approximately 60% compared with wild-type mice, while in mice overexpressing PAI-1, angiogenesis was increased nearly 3-fold. Furthermore, addition of PAI-1 to implants in wild-type mice enhanced angiogenesis up to 3-fold at low concentrations but inhibited angiogenesis nearly completely at high concentrations. Together, these data demonstrate that PAI-1 is a potent regulator of angiogenesis and hence of tumor growth and suggest that understanding the mechanism of this activity may lead to the development of important new therapeutic agents for controlling pathologic angiogenesis.

Animals↗

PubMed1989

Fibroblast growth factors.

The existence of fibroblast growth factors (FGFs) was proposed over 40 years ago to account for the ability of tissue extracts to stimulate fibroblast proliferation. In the 1970s it became clear that preparations containing FGF activity were in fact pleiotropic, affecting the growth and function of a wide variety of mesenchymal, endocrine and neural cells. Their angiogenic effects have promoted research in cardiology and neurology because of their proposed role in stimulating collateral vascularisation and recovery from ischemia. Their identity with a component of tumour angiogenesis factor activity has stimulated research in oncology and their capacity to enhance wound healing, nerve regeneration and cartilage repair has affected research in neurology, orthopaedic medicine and pathology. The potential therapeutic value of FGFs is just beginning to be realized and will be dependent on a concerted effort to establish their function in the regulation of normal cell homeostasis and the pathophysiology of disease.

Animals↗

PubMed2006

Predicting sentinel lymph node metastases in infiltrating breast carcinoma with vascular invasion.

Sentinel lymph node and clinically negative axillary node status was compared with well-known clinicopathological characteristics such as tumor size, histologic and nuclear grade, lymphovascular invasion, steroid receptor, and HER-2 status in patients with breast cancer (pT1 and pT2). Positive sentinel lymph nodes were found in 29 of 100 patients: 19 with metastases detected by hematoxylin and eosin staining and 10 with micrometastases confirmed by immunohistochemistry with cytokeratin. Positive sentinel lymph nodes were present in larger carcinomas (P < 0.03), more frequently in tumors with negative PR status (P < 0.037) and evident lymphovascular invasion (P < 0.002). Lymphovascular invasion was also associated with breast cancer of higher histologic (P = 0.011) and nuclear grade (P = 0.039). Tumor size and the presence of lymphovascular invasion were found to be significant predictors of pathologically positive sentinel lymph node in T1 and T2.

Adult↗

PubMed1999

Tumor neoangiogenesis in rebiopsied patients with prostatic carcinoma.

Tumor neoangiogenesis has proven its prognostic value in malignant tumors of different organs including prostatic adenocarcinoma. The aim of this retrospective study was to disclose the significance of neoangiogenesis in incidental prostatic carcinoma (ICP) after transurethral resection (TURP). The authors examined all patients having ICP diagnosed at the Institute of Pathology, Medical Faculty in Ljubljana during the 1985-1989 period, in whom rebiopsy was performed. Ten of 68 patients were examined to determine how microvessels correlate with the degree of tumor differentiation determined histopathologically, and with Gleason score, stage of disease, and survival time. Microvessels were highlighted by immunostaining endothelial cells for factor VIII-related antigen and counted in a x200 microscope field (0.8012 mm2) in the most active areas of neovascularization. Neoangiogenesis and tumor differentiation degree were then correlated between primary tumors and rebiopsies. Tumor differentiation degree was also correlated with the time of the disease progression. Microvessel counts (MVC) showed no association with the degree of tumor differentiation, Gleason score, disease stage, or patients' survival. The time elapsed to the disease progression was associated with less differentiated tumors (p = 0.004; 0.006). Microvessel counts were significantly higher in rebiopsies compared to initial tumors (p = 0.006), but no differences could be observed in the degree of differentiation. The results showed that the determination of microvessel density in rebiopsied patients had a better prognostic value than the degree of tumor differentiation. Nevertheless, the latter showed an association with the time of the disease progression. The number of patients included in the study was too low to confirm the association of MVC and degree of tumor differentiation in primary tumors.

Adenocarcinoma↗

PubMed2002

Cu/Zn superoxide dismutase plays a role in angiogenesis.

Endothelial cells produce oxygen radicals spontaneously and this process is augmented by hypoxia/reoxygenation. Cu/Zn superoxide dismutase (SOD-1) is an important enzyme in cellular oxygen metabolism. To determine whether alterations in SOD-1 activity affect angiogenesis we used transgenic SOD-1 (Tg-SOD) mice with elevated level of SOD-1. Angiogenesis induced subcutaneously by bFGF in Tg-SOD mice was 3-fold higher than in control non-transgenic (ntg) mice. Oral administration of disulfiram (DSF), an inhibitor of SOD-1, inhibited angiogenesis in Tg-SOD mice as well as in CD1 nude mice. Effects of DSF on cultured cells were also tested. Application of DSF to cultured bovine capillary endothelial (BCE) cells caused inhibition of DNA synthesis and induction of apoptosis. These effects were prevented by addition of antioxidants, further indicating involvement of reactive oxygen species. DSF also reduced the level of glutathione and the production of H(2)O(2) in BCE cells. Moreover, PC12-SOD cells with elevated SOD-1 were less sensitive to DSF treatment then control cells. These data indicate that the effects of DSF are mediated by inhibition of SOD-1 activity. Tumor development is known to largely depend on angiogenesis. We found that oral administration of DSF to mice caused significant inhibition of C6 glioma tumor development and marked reduction (by 10-19-fold) in metastatic growth of Lewis lung carcinoma. The data suggest a role for SOD-1 in angiogenesis, establish DSF as a potential inhibitor of angiogenesis and raise the possibility that attenuating SOD-1 activity may be important in treatment of angiogenesis-dependent pathologies.

Animals↗

PubMed1999

Microvessel density of hepatocellular carcinoma: its relationship with prognosis.

PURPOSE: To elucidate the relationship between angiogenesis and prognosis after curative resection of hepatocellular carcinoma (HCC). METHODS: An immunohistochemical study using anti-CD34 monoclonal antibody was carried out on surgical specimens from 78 HCC patients who had undergone curative resection; microvessel density (MVD) was counted and the overall survival and disease-free survival were analyzed retrospectively. RESULTS: Blood vessels in the tumor were strongly stained by anti-CD34 antibody, but not those in the surrounding liver parenchyma. There were three types of tumor vessels: capillary-like (n = 59), sinusoid-like (n = 16) and mixed-type (n = 3). The median MVD count was 100 per field. The HCC were designated as hypovascular (n = 36) with an MVD count below 100, and hypervascular (n = 42) with an MVD count of 100 or more per field. The 5-year survival and disease-free survival rates were 49.7% and 42.8% respectively, and statistical analysis showed that the MVD level was not correlated with tumor size, capsule status, Edmondson's grade, alpha-fetoprotein level, associated cirrhosis, gamma-glutamyltransferase, and serum HBsAg status. The sinusoid-like tumor vessels appeared more frequently in the more differentiated tumors (P<0.05). No statistical difference in overall and disease-free survival between different MVD levels and microvessel types was found. Tumor size was the only predicting factor in the entire series. In patients with small HCC (< or =5 cm, n = 40), 5-year survival and disease-free survival rates were 58.9% and 52.7% respectively, higher than the values in large HCC (39.8% and 32.0% respectively, P<0.05). The MVD level was an independent predicting factor of disease-free survival, 5-year disease-free survival in the hypovascular group (74.6%) being better than that in the hypervascular group (34.7%, P<0.05). CONCLUSIONS: The MVD level was not related to tumor size, capsule statuo, Edmondson's grade, alpha-fetoprotein level, associated cirrhosis, gamma-glutamyltransferase and serum HBsAg status. In the entire series, tumor size was the only factor influencing survival after curative resection. However, in patients with small HCC, the MVD level was an independent factor of disease-free survival. The pathological and clinical implications of different types of tumor vessels in HCC remain to be studied.

Adult↗

PubMed2006

Alternative splicing in angiogenesis: the vascular endothelial growth factor paradigm.

Alternative splicing, first discovered in the 1970s, has emerged as one of the key generators of proteomic diversity. Not surprisingly, alternative splicing is increasingly linked to the etiology of cancer. This is illustrated by vascular endothelial growth factor (VEGF), the dominant angiogenic factor. Recently, an antiangiogenic family of VEGF isoforms was discovered, and termed VEGF(xxx)b. VEGF(xxx)b isoforms arise from an alternative 3' splice site in exon 8, and differ by a mere six amino acids at the C-terminus. These alternative six amino acids radically change the functional properties of VEGF. VEGF(xxx)b isoform expression is regulated in human tissues and development, and disregulated in many pathological states including cancer. Understanding what regulates VEGF(xxx)b alternative splicing, and therefore the balance of pro- and antiangiogenic isoforms is of great importance and will be explored in detail over the next few years.

Alternative Splicing↗

PubMed2001

Myocardial ischemia and infarction: growth of ideas.

This report reviews the author's involvement in the growth of ideas and basic concepts in myocardial ischemia resulting in the histological changes of myocardial infarction. Concepts arising from the study of myocardial substrate utilization, activation of the inducible form of nitric oxide synthase and production of prostacyclin and thromboxane in the infarcted heart are presented. New approaches are discussed dealing with the effects of nonsteroidal anti-inflammatory drugs on myocardial production of nitric oxide and prostanoids, and with the relevance of the inducible form of cyclooxygenase. The review also records a number of significant similarities between angiogenesis in the ischemic heart and some cancers. Angiogenesis in both instances originates from inflammatory reactions, illustrating how different tissues and organs such as ischemic heart muscle and cancer react to similar pathological stimuli in an identical manner. This multifocal approach opens new concepts on myocardial ischemia and cancer.

Animals↗

PubMed1993

The histology of lumbar intervertebral disc herniation. The significance of small blood vessels in the extruded tissue.

Six hundred surgical cases of lumbar intervertebral disc herniation were evaluated histologically for the presence of blood vessels. These patients ranged in age from 12 to 77 years. Blood vessels were observed in 57 of 101 cases of complete prolapse type of herniated disc (56.4%), 12 of 32 cases of incomplete prolapse type of herniated disc (37.5%), and 53 of 467 cases of protrusion type of intervertebral disc herniation (11.3%). The presence of blood vessels in intervertebral discs was also investigated in postmortem specimens. Blood vessels were observed in 293 of 616 intervertebral discs (T10-L5), in individuals older than 40 years of age from 100 postmortem spines. The specimen age range was 16-89 years. Most of the blood vessels seen in the extruded tissue, exposed to the epidural space in cases of complete and incomplete prolapse type of herniation, are thought to have been newly formed after herniation occurred. As invasion of the intervertebral disc by blood vessels was found to occur with the advance of age, it is possible that such blood vessels become extruded with the intervertebral disc tissue. The intervertebral disc may herniate posteriorly in three basic patterns. The first pattern is "protrusion type of herniated disc." In protrusion hernia type there is abnormal posterior bulging of the anulus fibrosus. The disc pathology is predominantly nucleus pulposus, and the peripheral layer of the anulus fibrosus remains attached to the vertebral body bony rim, however.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed2003

[Expression of PTEN-encoding product in different stages of carcinogenesis and progression of gastric carcinoma].

OBJECTIVE: To illustrate the significance of expression of phosphatase and tensin homologue derived from chromosome ten (PTEN) encoding product in normal mucosa, intestinal metaplasia (IM), dysplasia and carcinoma of the stomach, and to evaluate its clinical implication in tumorigenesis and progression of gastric carcinoma. METHODS: Formalin-fixed and paraffin-embedded tissues from 184 cases of gastric carcinoma, its adjacent normal mucosa, IM and dysplasia were evaluated for the expression of PTEN by SABC immunohistochemistry. PTEN expression was assessed as to tumor stage, lymph node metastasis, Lauren's classification and WHO histological classification of gastric carcinoma. Expression of VEGF protein was also studied in 60 cases of gastric carcinoma, with its correlation with PTEN concerned. RESULTS: The positive rates of PTEN protein were 100% (102/102), 98.5% (65/66), 66.7% (4/6) and 47.8% (88/184) in normal mucosa, IM, dysplasia and carcinoma of stomach, respectively. The positive rates in the last two groups were lower than the first two (P < 0.01). PTEN was less expressed in advanced gastric carcinoma than in early ones (42.9% vs 67.6%, P < 0.01). The positive rate of PTEN protein was lower in gastric carcinoma with lymph node metastasis than without (40.3% vs 63.3%, P < 0.01). PTEN was less expressed in diffuse-type gastric carcinoma than in intestinal-type (41.5% vs 57.8%, P < 0.05). Signet ring cell carcinoma expressed PTEN stood the lowest (25.0%, 7/28), which was less than well and moderately differentiated ones (61.8%, 21/34) (P < 0.01). Expression of PTEN was inversely correlated with expression of VEGF though without any significance (P > 0.05). CONCLUSION: Loss or reduced expression of PTEN protein is common in carcinogenesis and progression of gastric cancer. Altered expression of PTEN may contribute to carcinogenesis and progression of gastric cancer by increasing angiogenesis, cellular adhesion and mobility and so on. PTEN may be an objective marker for pathologically biological behavior of gastric carcinoma.

Adult↗

PubMedDate not supplied

Myofibroblast induction and microvascular alteration in scleroderma lung fibrosis.

OBJECTIVE: Scleroderma (SSc) is an autoimmune connective tissue disorder characterized by progressive fibrosis of the skin and internal organs. The leading cause of death in SSc patients is pulmonary dysfunction as a result of interstitial fibrosis and pulmonary vasculopathy. Our objective was to evaluate histopathological abnormalities associated with the development of pulmonary fibrosis in SSc. METHODS: Postmortem SSc lung tissue from various stages of fibrosis and tissue from normal lung were analyzed by Masson's trichrome staining and immunohistochemistry. Monoclonal antibodies against smooth muscle-alpha actin (myofibroblast marker), von Willebrand Factor, platelet endothelial cell adhesion molecule-1 (endothelial cell markers), or caldesmon (smooth muscle cell marker) were employed. RESULTS: We found that in the early active stages of SSc lung fibrosis two major types of cellular abnormalities occur. One is the induction of a large number of smooth muscle alpha-actin-positive myofibroblasts in interstitia. The other is the excessive formation of alveolar capillaries (hypervascularity) accompanied by an increase in the number of microvascular endothelial cells. The vascular abnormality also involves the development of microvessels that are irregular in size and shape. However, the population of myofibroblasts and capillary endothelial cells decline as the fibrosis progresses to its most marked, later stages. CONCLUSION: We conclude that the induction of myofibroblasts and the overdevelopment of capillary microvessels characterize the progression of lung fibrosis in SSc. Using these histological alterations as criteria, therefore we have divided the fibrosis formed in the SSc lungs into four pathological stages. These results suggest that both fibroblast overproliferation and vascular abnormality play an important role in the pathogenesis of lung fibrosis in SSc.

Adult↗

PubMed2002

Expression of TGFbeta2 but not TGFbeta1 correlates with the deposition of scar tissue in the lesioned spinal cord.

Transforming growth factor-betas (TGFbetas) are implicated in fibrotic pathologies. TGFbeta1 and -beta2 expression is increased around the glial/fibrotic scar in the injured brain. Moreover, local injection of TGFbeta antagonists into cerebral wounds reduces glial scarring. Here, we monitored expression of TGFbeta1 and -beta2 mRNA and protein in the spinal cord after transection of the dorsal funiculi. Levels of TGFbeta1 mRNA were most elevated over the acute inflammatory phase, while TGFbeta2 mRNA levels were raised locally about the wound, particularly in astrocytes and neovascular endothelial cells, over the subacute period of scarring. TGFbeta protein production also increased after injury. Both TGFbeta1 and TGFbeta2 were found in hematogenous inflammatory cells, while TGFbeta1 was also neuron-associated, and high levels of TGFbeta2 were localized to multiple cell types in the wound, including reactive astrocytes, during the period of glial/collagen scar formation. The cellular localization and temporal pattern of expression of TGFbeta after spinal cord injury suggest that TGFbeta1 modulates the inflammatory and neuronal responses, while TGFbeta2 regulates glial/collagen scarring.

Animals↗

PubMed1998

Expression of VEGF in routinely fixed material using a new monoclonal antibody VG1.

The aim of this study was to raise and characterize a monoclonal antibody reactive with VEGF (vascular endothelial growth factor) in routinely fixed specimens and to use it to investigate its tissue distribution in normal and pathological specimens. Recombinant VEGF 189 protein was used to raise a monoclonal antibody. The specificity of the antibody was confirmed using COS cells transfected with cDNA coding for VEGF 121, 165 and 189 protein and by western blotting studies. The resulting antibody VG1 was shown to react with the 121, 165 and 189 isoforms of VEGF protein in routinely processed material. In normal tissues, there was strong staining of endometrial and salivary glands and of the mucosa of the gastro-intestinal tract. In tumours, a proportion of the neoplastic cells in lung and breast cancer and in melanoma were labelled. In all tissues, whether normal or malignant, striking VEGF positivity was seen in plasma in vessels and stroma. This study has shown that antibody VG1 detects the 121, 165 and 189 VEGF isoforms in routinely fixed specimens. The results of the normal tissue and tumour labelling are in agreement with other studies using alternative methods of detection. This should be a useful and reliable reagent for studies of VEGF and angiogenesis in human pathological material.

Animals↗

PubMed2002

Selection of high affinity human neutralizing antibodies to VEGFR2 from a large antibody phage display library for antiangiogenesis therapy.

Compelling evidence suggests that vascular endothelial growth factor (VEGF) and its receptors play an important role in angiogenesis associated with tumor growth and metastasis. VEGF exerts its biologic activities through 2 transmembrane tyrosine kinase receptors: the fms-like tyrosine kinase receptor (Flt-1, or VEGFR1) and kinase insert domain-containing receptor (KDR or VEGFR2). We have previously produced a panel of antibodies directed against KDR from mice immunized with the recombinant form receptor. These antibodies efficiently neutralized VEGF-induced KDR activation and mitogenesis of human umbilical vascular endothelial cells (HUVEC). Murine antibodies, however, may not be suitable candidates for human therapy because of their propensity to elicit human anti-mouse antibody response. Here we isolated several high-affinity human Fab antibody fragments directed against KDR from an antibody phage display library constructed from the pooled B lymphocytes of nonimmunized healthy human donors. These human Fab fragments bind specifically to KDR with nanomolar affinity and block KDR/VEGF interaction with IC(50) of approximately 2-20 nM. Further, they effectively inhibit VEGF-stimulated mitogenesis of HUVEC and migration of human leukemia cells. Epitope mapping studies demonstrated that all neutralizing human antibodies bound the epitope(s) located within the first 3 N-terminal immunoglobulin-like domains of KDR, the same region that encompasses the binding site of VEGF. Our results suggest that these human anti-KDR antibodies may have potential application in the treatment of cancer and other diseases in which pathologic angiogenesis occurs.

Amino Acid Sequence↗

PubMed2001

Thymidine phosphorylase/platelet-derived endothelial cell growth factor (PD-ECGF) associated with prognosis in renal cell carcinoma.

We investigated the correlation between thymidine phosphorylase (TP)/platelet-derived endothelial cell growth factor (PD-ECGF) expression, angiogenesis, and prognosis in renal cell carcinoma (RCC) patients. We prepared paraffin block specimens from 56 postradical nephrectomy RCC patients. The preparations were immunohistochemically stained using anti-CD34 antibody and anti-TP antibody. Angiogenic findings were evaluated based on both microvessel density (MVD) and renal arteriography findings as classified by Roosen et al. TP expression showed heterogeneity in 56 patients: 11 (19.6%) were negative, 28 (50.0%) weak, and 17 (30.4%) positive. There was no correlation between TP expression, MVD, and renal arteriography. There was no TP expression in chromophobe types. Univariate analysis showed a significant correlation between survival and TP expression, patient age, tumor infiltration type, pathologic T- and N-stages, venous involvement, distant metastasis, and tumor grade. There was no correlation between survival and MVD or renal arteriography. Multivariate analysis showed a significant correlation between survival and pathologic T-stage, distant metastasis, tumor infiltration type, and TP expression. TP expression in RCC may be an independent prognostic factor rather than just an index for angiogenesis.

Adult↗

PubMed1991

Angiogenesis in arteries: review.

The inner parts of the walls of large blood vessels do not normally contain intrinsic vasculature. In pathologic conditions such as arteriosclerosis or thrombosis, angiogenesis occurs, and may have significant clinical consequences. This review attempts to relate the little that is known about the factors specific to vascular walls which regulate angiogenesis to more general knowledge of the phenomenon.

Animals↗

PubMed2005

Inhibitors of cytochrome P450 4A suppress angiogenic responses.

Cytochrome P450 enzymes of the 4A family (CYP4A) convert arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) in blood vessels of several vascular beds. The present study examined the effects of inhibiting the formation of 20-HETE with N-hydroxy-N'-(4-butyl-2-methylphenol) formamidine (HET0016) on the mitogenic response of vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells (HUVECs) in vitro, and on growth factor-induced angiogenesis in the cornea of rats in vivo. HET0016 (10 micromol/L and 20 microg, respectively) abolished the mitogenic response to VEGF in HUVECs and the angiogenic response to VEGF, basic fibroblast growth factor, and epidermal growth factor in vivo by 80 to 90% (P < 0.001). Dibromododecenyl methylsulfonimide (DDMS), a structurally and mechanistically different inhibitor of 20-HETE synthesis, also abolished angiogenic responses when tested with VEGF. Additionally, administration of the stable 20-HETE agonist, 20-hydroxyeicosa-6(Z) 15(Z)-dienoic acid (WIT003) induced mitogenesis in HUVECs and angiogenesis in the rat cornea in vivo. We studied the ability of HET0016 to alter the angiogenic response in the rat cornea to human glioblastoma cancer cells (U251). When administered locally into the cornea, HET0016 (20 microg) reduced the angiogenic response to U251 cancer cells by 70%. These results suggest that a product of CYP4A product, possibly 20-HETE, plays a critical role in the regulation of angiogenesis and may provide a useful target for reduction of pathological angiogenesis.

Amides↗