Input:
UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice.

UFT, an anticancer agent that is composed of tegafur (FT) and uracil at a molar ratio of 1:4, is widely used in clinical practice in Japan to treat cancer patients requiring a long-term chemotherapy, and it is associated with few side effects, if any. In this study, we have evaluated the inhibitory effect of UFT against RENCA cell-induced angiogenesis by a dorsal air sac assay. Marked angiogenesis is induced by implantation of a chamber containing RENCA cells into mice. In this model, UFT showed a strong angiogenesis-inhibitory effect, whereas 5-fluorouracil (5-FU) and doxifluridine were less effective. Additional experiments revealed FT to be effective component of UFT; uracil remained ineffective in the inhibition of angiogenesis. Moreover, we have found that gamma-hydroxybutyric acid and gamma-butyrolactone, the metabolites of FT, possess a potent angiogenesis inhibitory effect that is amplified when the compounds are administered by a continuous infusion. This may reflect a transition in blood concentration of each metabolite resulting from the administration of UFT. Similar results were also obtained with respect to 5-FU. It was suggested that UFT has a stronger angiogenesis-inhibitory effect than did other fluorinated pyrimidines, partly due to its pharmacokinetic properties characterized by maintaining of higher and long-lasting blood levels of 5-FU and partly due the inhibitory effects derived from gamma-hydroxybutyric acid and gamma-butyrolactone, UFT-specific metabolites.

angiogenesis

angiogenesis

angiogenesis

angiogenesis

angiogenesis

angiogenesis

angiogenesis

inhibit

UFT

angiogenesis

inhibitory effect

UFT

angiogenesis

inhibitory effect

UFT

angiogenesis

effective

angiogenesis

effective

angiogenesis

doxifluridine

inhibition

angiogenesis

inhibitory effect

gamma-hydroxybutyric acid

angiogenesis

inhibitory effect

gamma-butyrolactone

angiogenesis

inhibitory effect

UFT

angiogenesis

inhibitory effect

angiogenesis

fluorinated pyrimidines

treat

UFT

patients

chemotherapy

patients

implantation

RENCA cells

mice

administered

gamma-hydroxybutyric acid

administered

gamma-butyrolactone

administration

UFT

induced

angiogenesis

renal cell carcinoma

induced

RENCA cell

angiogenesis

induced

angiogenesis

implantation

amplified

gamma-hydroxybutyric acid

amplified

gamma-butyrolactone

ineffective

uracil

inhibition


Input:
Nitric oxide synthase inhibition results in synergistic anti-tumour activity with melphalan and tumour necrosis factor alpha-based isolated limb perfusions.

Nitric oxide (NO) is an important molecule in regulating tumour blood flow and stimulating tumour angiogenesis. Inhibition of NO synthase by L-NAME might induce an anti-tumour effect by limiting nutrients and oxygen to reach tumour tissue or affecting vascular growth. The anti-tumour effect of L-NAME after systemic administration was studied in a renal subcapsular CC531 adenocarcinoma model in rats. Moreover, regional administration of L-NAME, in combination with TNF and melphalan, was studied in an isolated limb perfusion (ILP) model using BN175 soft-tissue sarcomas. Systemic treatment with L-NAME inhibited growth of adenocarcinoma significantly but was accompanied by impaired renal function. In ILP, reduced tumour growth was observed when L-NAME was used alone. In combination with TNF or melphalan, L-NAME increased response rates significantly compared to perfusions without L-NAME (0-64% and 0-63% respectively). An additional anti-tumour effect was demonstrated when L-NAME was added to the synergistic combination of melphalan and TNF (responses increased from 70 to 100%). Inhibition of NO synthase reduces tumour growth both after systemic and regional (ILP) treatment. A synergistic anti-tumour effect of L-NAME is observed in combination with melphalan and/or TNF using ILP. These results indicate a possible role of L-NAME for the treatment of solid tumours in a systemic or regional setting.

angiogenesis

tumour

growth

vascular

growth

adenocarcinoma

growth

tumour

growth

tumour

reach

oxygen

tumour tissue

inhibition

Nitric oxide synthase

activity

tumour

melphalan

Inhibition

NO synthase

L-NAME

effect

tumour

limiting

Inhibition

reach

effect

tumour

L-NAME

inhibited

treatment

growth

impaired

renal

reduced

growth

effect

tumour

added

Inhibition

NO synthase

reduces

Inhibition

growth

effect

tumour

L-NAME

administration

L-NAME

rats

administration

L-NAME

TNF

melphalan

treatment

L-NAME

added

L-NAME

melphalan

TNF

treatment

tumours

results

inhibition

activity

stimulating

Nitric oxide

angiogenesis

induce

effect

limiting

induce

effect

affecting

affecting

Inhibition

growth

role

L-NAME

treatment


Input:
Vascular endothelial growth factor-B and vascular endothelial growth factor-C expression in renal cell carcinomas: regulation by the von Hippel-Lindau gene and hypoxia.

Angiogenesis is essential for tumor growth and metastasis. It is regulated by numerous angiogenic factors, one of the most important being vascular endothelial growth factor (VEGF). Recently VEGF-B and VEGF-C, two new VEGF family members, have been identified that bind to the tyrosine kinase receptors flt-1 (VEGFR1), KDR (VEGFR2), and flt-4 (VEGFR3). Although the importance of VEGF-A has been shown in renal carcinomas, the contribution of these new ligands in kidney tumors is not clear. We have, therefore, measured the mRNA level of VEGF-B and VEGF-C together with their receptors by RNase protection assay (RPA) in 26 normal kidney samples and 45 renal cell cancers. We observed a significant up-regulation of VEGF-B (P = 0.002) but not VEGF-C (P = 0.3) in neoplastic kidney compared with normal tissues. In addition, although VEGF receptors were higher in tumors than normal kidney, there was a significant up-regulation of only flt-1 (P = 0.003) but not KDR (P = 0.12) or flt-4 (P = 0.09). There was also a significant correlation between VEGF-C and both of its receptors flt-4 (P = 0.006) and KDR (P = 0.03) but no association between VEGF-B and its receptor flt-1 (P = 0.23). A significant increase was observed in flt-1 (P  less than  0.001), KDR (P = 0.02), and flt-4 (P = 0.01) but not VEGF-B (P = 0.82) or VEGF-C (P = 0.52) expression in clear cell compared with chromophil (papillary) carcinomas. No significant association was demonstrated between VEGF-B, VEGF-C, flt-1, KDR, and flt-4 with patient sex, patient age, or tumor size (P  greater than  0.05). The effect of von Hippel-Lindau (VHL) gene and hypoxia on VEGF-B and VEGF-C expression in the renal carcinoma cell line 786-0 transfected with wild-type and mutant VHL was determined by growing cells under 21% O2- and 0.1% O2. In wild-type VHL cells, whereas VEGF-A was significantly up-regulated under hypoxic compared with normoxic conditions (P  less than  0.001), expression of VEGF-C was reduced (P  less than  0.002). Nevertheless, the repression of VEGF-C was lost in mutant VHL cell lines under hypoxia. In contrast VEGF-B was not regulated by VHL despite clear up-regulation in vivo. These findings strongly support an enhanced role for this pathway in clear cell carcinomas by regulating angiogenesis and/or lymphangiogenesis. The study shows that clear cell tumors are able to up-regulate angiogenic growth factor receptors more efficiently than chromophil (papillary), that clear cell tumors can use pathways independent of VHL to regulate angiogenesis, and that this combined regulation may account for their more aggressive phenotype, which suggests that targeting VEGFR1 (flt-l) may be particularly effective in these tumor types.

bind

VEGF-B

bind

VEGF-B

KDR

bind

VEGF-B

bind

VEGF-C

bind

VEGF-C

KDR

bind

VEGF-C

Angiogenesis

angiogenic

angiogenesis

lymphangiogenesis

angiogenic

angiogenesis

growing

cells

expression

Vascular endothelial growth factor-B

expression

vascular endothelial growth factor-C

expression

expression

KDR

expression

expression

VEGF-B

expression

VEGF-C

expression

VEGF-B

expression

VEGF-C

expression

VEGF-C

growth

tumor

metastasis

tumor

reduced

expression

repression

VEGF-C

transfected

VHL

essential

Angiogenesis

growth

essential

Angiogenesis

metastasis

up-regulation

VEGF-B

up-regulation

VEGF-C

up-regulation

up-regulation

KDR

up-regulation

increase

expression

up-regulated

VEGF-A

up-regulation

VEGF-B

VHL

effect

von Hippel-Lindau

expression

regulated

VEGF-B

VHL

regulating

angiogenesis

regulating

lymphangiogenesis

regulate

VHL

angiogenesis


Input:
Retinal microangiopathies overlying pigment epithelial detachment in age-related macular degeneration.

PURPOSE: To evaluate alterations in the retinal vasculature overlying pigment epithelial detachments (PED) in exudative age-related macular degeneration (ARMD) using indocyanine green and fluorescein angiography. METHODS: Forty-one patients (41 eyes) with a clinical diagnosis of exudative ARMD with PED underwent simultaneous fluorescein and indocyanine green angiography, also under high (10 degrees ) magnification. Vascular abnormalities in the retina were compared between patients with vascularized (n = 34, group 1) and nonvascularized (n = 7, group 2) PED on indocyanine green angiography and correlated with the size of the PED and the presence of serous retinal detachment. RESULTS: In all, 67 vascular abnormalities were found by indocyanine green angiography and only 22 by fluorescein angiography; this finding was statistically significant (P  less than  0.0001). The finding of retinal vasculopathy (32 patients in group 1 and two patients in group 2) was directly correlated with the presence of choroidal neovascularizations (P = 0.002). There was also a direct correlation between the presence of choroidal neovascularization and size of the PED (P = 0.03). The number of retinal vascular findings was not significantly correlated with serous elevation of the retina. CONCLUSIONS: Retinal vasculopathies may be observed in eyes with PED and are detectable by indocyanine green and fluorescein angiography.

neovascularizations

neovascularization

detachment

pigment epithelial

degeneration

macular

detachments

pigment epithelial

degeneration

macular

detachment

serous retinal

angiography

eyes

fluorescein

indocyanine green

angiography

eyes

indocyanine green

fluorescein

elevation

retina

alterations

retinal vasculature


Input:
Adaptor protein Crk is required for ephrin-B1-induced membrane ruffling and focal complex assembly of human aortic endothelial cells.

Endothelial cell migration is an essential step in vasculogenesis and angiogenesis, in which receptor tyrosine kinases play a pivotal role. We investigated the mechanism by which ephrin-B1 promotes membrane ruffling in human aortic endothelial cells, because membrane ruffling heralds cell body migration. We especially focused on the role of Crk adaptor protein in EphB-mediated signaling. Using DsRed-tagged Crk and a fluorescent time-lapse microscope, we showed that Crk was recruited to the nascent focal complex after ephrin-B1 stimulation. Furthermore, we found that p130(Cas), but not paxillin, recruited Crk to the nascent focal complex. The necessity of Crk in ephrin-B1-induced membrane ruffling was shown both by the overexpression of dominant negative Crk mutants and by the depletion of Crk by using RNA interference. Then, we examined the role of two major downstream molecules of Crk, Rac1 and Rap1. The dominant negative mutant of Rac1 completely inhibited ephrin-B1-induced membrane ruffling and focal complex assembly. In contrast, rap1GAPII, a negative regulator of Rap1, did not inhibit ephrin-B1-induced membrane ruffling. However, in rap1GAPII-expressing cells, ephrin-B1 did not induce membrane spreading, probably due to instability of the focal complex. These results indicated that Crk plays a critical role in Rac1-induced membrane ruffling and Rap1-mediated nascent focal complex stabilization contributing to ephrin-B1-induced human aortic endothelial cells migration.

assembly

focal complex

assembly

focal complex

vasculogenesis

angiogenesis

expressing

ruffling

membrane

migration

Endothelial cell

ruffling

membrane

ruffling

membrane

migration

cell body

recruited

Crk

nascent focal complex

recruited

Crk

nascent focal complex

ruffling

membrane

ruffling

membrane

ruffling

membrane

spreading

membrane

ruffling

membrane

migration

aortic endothelial cells

depletion

Crk

inhibited

induced

inhibit

ruffling

signaling

tagged

DsRed

Crk

stabilization

nascent focal complex

required

Crk

ruffling

required

Crk

assembly

induced

ruffling

induced

assembly

essential

migration

vasculogenesis

essential

migration

angiogenesis

promotes

ruffling

mediated

EphB

signaling

stimulation

recruited

recruited

recruited

recruited

paxillin

recruited

necessity

Crk

ruffling

induced

ruffling

induced

ruffling

induced

assembly

induced

ruffling

induce

spreading

induced

ruffling

induced

migration

play a pivotal role

vasculogenesis

receptor tyrosine kinases

play a pivotal role

angiogenesis

receptor tyrosine kinases

role

Crk

signaling

plays a critical role

Crk

ruffling

plays a critical role

Crk

stabilization

mediated

stabilization

contributing

Crk

migration


Input:
Postoperative progression of pulmonary metastasis in osteosarcoma.

Early relapse with distant metastasis often is observed in patients with cancer after resection of the primary tumor. It is considered that resection of the primary tumor induces activation of systemic angiogenesis and enhances progression of remote metastasis. The authors show that resection of the primary osteosarcoma tumor enhances progression of pulmonary metastasis in animal osteosarcoma models. Matrigel plug neovascularization assay revealed that systemic angiogenic activity was elevated after primary tumor removal (tumor intact group, 1.61 +/- 0.21 g/dL; tumor removed group, 4.92 +/- 0.35 g/dL). In addition, serum concentration of the angiogenesis inhibitor, endostatin, decreased significantly after primary tumor removal. Treatment with the antiangiogenic reagent TNP-470 suppressed postoperative progression of pulmonary metastasis. These results indicate the possibility that activation of angiogenic activity after resection of osteosarcoma tumors enhances progression of pulmonary metastasis. The current data also suggest that administration of antiangiogenic reagents can prevent progression of pulmonary metastasis in osteosarcoma postoperatively.

angiogenesis

neovascularization

angiogenic

angiogenesis

angiogenic

angiogenic

angiogenic

metastasis

pulmonary

osteosarcoma

metastasis

tumor

metastasis

tumor

metastasis

osteosarcoma tumor

pulmonary

metastasis

tumor

pulmonary

metastasis

osteosarcoma tumors

pulmonary

metastasis

pulmonary

osteosarcoma

decreased

endostatin

suppressed

Treatment

progression

prevent

administration

progression

resection

tumor

resection

tumor

resection

osteosarcoma tumor

removal

tumor

removal

tumor

Treatment

resection

osteosarcoma tumors

administration

osteosarcoma

progression

metastasis

induces

resection

activation

activation

angiogenesis

enhances

resection

progression

progression

metastasis

enhances

resection

progression

progression

metastasis

elevated

angiogenic

progression

metastasis

activation

angiogenic

enhances

activation

progression

progression

metastasis

progression

metastasis


Input:
Antiapoptotic effect of coagulation factor VIIa.

Binding of factor VIIa (FVIIa) to its cellular receptor tissue factor (TF) was previously shown to induce various intracellular signaling events, which were thought to be responsible for TF-mediated biologic effects, including angiogenesis, tumor metastasis, and restenosis. To understand the mechanisms behind these processes, we have examined the effect of FVIIa on apoptosis. Serum deprivation-induced apoptosis of BHK(+TF) cells was characterized by apoptotic blebs, nuclei with chromatin-condensed bodies, DNA degradation, and activation of caspase 3. FVIIa markedly decreased the number of cells with apoptotic morphology and prevented the DNA degradation as measured by means of TdT-mediated dUTP nick end labeling (TUNEL). The antiapoptotic effect of FVIIa was confirmed by the observation that FVIIa attenuated caspase 3 activation. FVIIa-induced antiapoptotic effect was dependent on its proteolytic activity and TF but independent of factor Xa and thrombin. FVIIa-induced cell survival correlated with the activation of Akt and was inhibited markedly by the specific PI3-kinase inhibitor, LY294002. Blocking the activation of p44/42 mitogen-activated protein kinase (MAPK) by the specific mitogen-induced extracellular kinase (MEK) inhibitor, U0126, impaired modestly the ability of FVIIa to promote cell survival. In conclusion, FVIIa binding to TF provided protection against apoptosis induced by growth factor deprivation, primarily through activation of PI3-kinase/Akt pathway, and to a lesser extent, p44/42 MAPK pathway.

Binding

factor VIIa

tissue factor

binding

FVIIa

TF

angiogenesis

apoptosis

BHK(+TF) cells

survival

cell

survival

cell

metastasis

tumor

attenuated

FVIIa

activation

Blocking

activation

impaired

Blocking

promote

pathway

Akt

pathway

p44/42 MAPK

induce

Binding

angiogenesis

induce

Binding

metastasis

mediated

TF

angiogenesis

mediated

TF

metastasis

induced

apoptosis

activation

caspase 3

activation

caspase 3

induced

FVIIa

survival

activation

Akt

activation

p44/42 mitogen-activated protein kinase

promote

FVIIa

survival

activation

pathway

activation

pathway


Input:
Laser treatment of eccentric leaks in central serous chorioretinopathy resulting in disappearance of untreated juxtafoveal leaks.

In central serous chorioretinopathy (CSCR) laser treatment of leaking points close to the macular center should be avoided because of the possibility of producing juxtafoveal scotoma and stimulating choroidal neovascularization. Nine eyes of nine consecutive patients with CSCR had two or more leaking points within a macular detachment, one of which was foveal or near to the fovea. Photocoagulation with green argon laser was performed in all eyes, treating all the leaking points except for the central one. Visual symptoms regressed after treatment, and the serous detachment was resolved 10 days to 4 weeks after photocoagulation in all cases. Fluorescein angiography showed no leakage at either the central leakage point or the leakage point that had been treated. These results led us to believe that the central or dependent leak in our cases was not sufficient to maintain the serous detachment by itself. An alternative hypothesis is that the untreated leak did not represent real fluid movement but only diffusion of fluorescein molecules, or a false leak. In cases of CSCR with multiple leaks within a single macular detachment, we believe that a foveal leak may be a dependent or false leak and that direct treatment is not necessary.

neovascularization

detachment

macular

detachment

macular

stimulating

neovascularization


Input:
Angiopoietin/tie-2 as mediators of angiogenesis: a role in congestive heart failure?

Angiogenic factors, in particular vascular endothelial growth factor (VEGF) and the angiopoietins, Ang-1 and -2, have recently generated significant interest, especially in oncology. The process of angiogenesis is also thought to occur in response to ischaemic conditions, which lie at the core of cardiovascular disease states such as coronary artery disease and congestive heart failure. However, current data do not conclusively show evidence of angiogenesis per se in these conditions, despite (for example) the presence of high levels of VEGF and Ang-2. High levels of these angiogenic factors in heart disease also have not translated into clinically significant new vessel formation, as in accelerated cancer growth or proliferative retinopathy. Indeed, we would hypothesize that these angiogenic markers--especially the angiopoietins--do not necessarily translate into new vessel formation in congestive heart failure (CHF), but may well reflect disturbances of endothelial integrity in CHF.

angiogenesis

Angiogenic

angiogenesis

angiogenesis

angiogenic

angiogenic

disturbances

endothelial

formation

vessel

formation

vessel

growth

cancer

presence

VEGF

presence

accelerated

growth

translate

angiopoietins

formation

reflect

angiopoietins

disturbances


Input:
Hypothesis: Induced angiogenesis after surgery in premenopausal node-positive breast cancer patients is a major underlying reason why adjuvant chemotherapy works particularly well for those patients.

BACKGROUND: We suggest that surgical extirpation of primary breast cancer among other effects accelerates relapse for some premenopausal node-positive patients. These accelerated relapses occur within 10 months of surgery for untreated patients. The mechanism proposed is a stimulation of angiogenesis for distant dormant micrometastases. This has been suggested as one of the mechanisms to explain the mammography paradox for women aged 40-49 years. We could imagine that it also plays a role in adjuvant chemotherapy effectiveness since, perhaps not coincidentally, this is most beneficial for premenopausal node-positive patients. HYPOTHESIS: We speculate that there is a burst of angiogenesis of distant dormant micrometastases after surgery in approximately 20% of premenopausal node-positive patients. We also speculate that this synchronizes them into a temporal highly chemosensitive state and is the underlying reason why adjuvant chemotherapy works particularly well for that patient category. Furthermore, this may explain why cancer in younger patients is more often 'aggressive'. TESTING THE HYPOTHESIS: Stimulation of dormant micrometastases by primary tumor removal is known to occur in animal models. However, we need to determine whether it happens in breast cancer. Transient circulating levels of angioactive molecules and serial high-resolution imaging studies of focal angiogenesis might help. IMPLICATIONS: Short-course cytotoxic chemotherapy after surgery has probably reached its zenith, and other strategies, perhaps antiangiogenic methods, are needed to successfully treat more patients. In addition, the hypothesis predicts that early detection, which is designed to find more patients without involved lymph nodes, may not be a synergistic strategy with adjuvant chemotherapy, which works best with positive lymph node patients.

angiogenesis

angiogenesis

distant dormant micrometastases

angiogenesis

distant dormant micrometastases

angioactive

angiogenesis

angiogenic

surgery

patients

chemotherapy

patients

surgical extirpation

breast cancer

surgery

patients

untreated

patients

chemotherapy

patients

surgery

patients

chemotherapy

patient

removal

tumor

treat

patients

chemotherapy

patients

Induced

angiogenesis

stimulation

angiogenesis

burst

angiogenesis

Stimulation

dormant micrometastases

removal


Input:
Vascular endothelial growth factor (VEGF) in seizures: a double-edged sword.

Vascular endothelial growth factor (VEGF) is a vascular growth factor which induces angiogenesis (the development of new blood vessels), vascular permeability, and inflammation. In brain, receptors for VEGF have been localized to vascular endothelium, neurons, and glia. VEGF is upregulated after hypoxic injury to the brain, which can occur during cerebral ischemia or high-altitude edema, and has been implicated in the blood-brain barrier breakdown associated with these conditions. Given its recently-described role as an inflammatory mediator, VEGF could also contribute to the inflammatory responses observed in cerebral ischemia. After seizures, blood-brain barrier breakdown and inflammation is also observed in brain, albeit on a lower scale than that observed after stroke. Recent evidence has suggested a role for inflammation in seizure disorders. We have described striking increases in VEGF protein in both neurons and glia after pilocarpine-induced status epilepticus in the brain. Increases in VEGF could contribute to the blood-brain barrier breakdown and inflammation observed after seizures. However, VEGF has also been shown to be neuroprotective across several experimental paradigms, and hence could potentially protect vulnerable cells from damage associated with seizures. Therefore, the role of VEGF after seizures could be either protective or destructive. Although only further research will determine the exact nature of VEGF's role after seizures, preliminary data indicate that VEGF plays a protective role after seizures.

angiogenesis

breakdown

blood-brain barrier

breakdown

blood-brain barrier

breakdown

blood-brain barrier

damage

cells

development

blood vessels

protect

damage

induces

Vascular endothelial growth factor

angiogenesis

upregulated

VEGF

increases

VEGF

Increases

VEGF

contribute

Increases

breakdown


Input:
Safety of verteporfin for treatment of subfoveal choroidal neovascular membranes associated with age-related macular degeneration.

Photodynamic therapy (PDT) is a novel treatment entity that exploits the photophysical properties of various photosensitive chemical entities which, upon light activation, results in targeted photooxidation and subsequent tissue destruction. The antiangiogenic properties of PDT have been adapted for treatment of subfoveal choroidal neovascular membranes due to disease states such as age-related macular degeneration (AMD). Historically, PDT has been limited by a lack of suitable photosensitive dyes. However, agents such as verteporfin, a second-generation benzoporphyrin derivative, appear to be free from the extensive phototoxicity that limited the success of previous agents. Verteporfin has a high affinity for choroidal neovascular membranes, typically found with exudative AMD, and upon photoactivation results in targeted microvascular damage and thrombus formation with resultant vessel occlusion. Scrutiny of diagnostic indicators for verteporfin administration, including critical angiographic evaluation of lesion size and visual acuity, is essential to treatment success. Large lesions with relatively good visual acuity (20/50 or better) may be at particular risk for marked vision loss following verteporfin administration. Lesion composition also appears to influence visual outcome with verteporfin use. The safety of verteporfin is directly dependent upon the appropriate integration of dosage, infusion and light activation required for a suitable pharmacotherapeutic outcome. When used appropriately, and with adequate patient education regarding photosensitivity, the risk-benefit of verteporfin for the medical treatment of neovascular AMD is favourable.

affinity

Verteporfin

choroidal neovascular membranes

angiogenic

degeneration

macular

destruction

tissue

degeneration

macular

damage

microvascular

formation

thrombus

properties

angiogenic

treatment

verteporfin

subfoveal choroidal neovascular membranes

treatment

subfoveal choroidal neovascular membranes

administration

verteporfin

administration

verteporfin

use

Lesion

verteporfin

treatment

verteporfin

results

formation

results

damage


Input:
Retrospective case series of juxtafoveal choroidal neovascularization treated with photodynamic therapy with verteporfin.

PURPOSE: To describe visual acuity and angiographic outcomes of juxtafoveal choroidal neovascularization (CNV) treated with photodynamic therapy and verteporfin (PDT). METHODS: Four hundred eighty-four consecutive eyes of 446 patients treated with PDT from January 1, 2001, to June 30, 2002, were identified from billing records. Fluorescein angiograms were reviewed retrospectively to identify juxtafoveal CNV. Eligible patients had CNV in which the central boundary of the lesion was between 1 and 199 microm from the geometric center of the foveal avascular zone (FAZ). Patient charts were reviewed for visual acuity of the treated eye before PDT and at 6- and 12-month follow-up examinations. Presence of subfoveal CNV at 6 and 12 months of follow-up was determined by review of fluorescein angiograms. A lesion was considered subfoveal if it extended underneath the geometric center of the FAZ. RESULTS: Twenty-one eyes had juxtafoveal CNV. Median change in visual acuity both 6 and 12 months after the initial PDT was 0 lines (n = 18 at 6 months, range -14 to + 8 lines; n = 17 at 12 months, range -18 to + 7 lines). Eleven lesions progressed to a subfoveal location by 12 months. Visual acuity in eyes with progressive lesions decreased a median of 4 lines of vision. CONCLUSIONS: Despite a small sample size and limited length of follow-up, this study shows that visual acuity on average can remain stable for at least 12 months after PDT of juxtafoveal lesions. Growth through the foveal center still can occur, however, and this can be associated with substantial visual loss.

neovascularization

neovascularization

CNV

CNV

CNV

CNV

CNV

progressed

lesions

treated

neovascularization

verteporfin

treated

CNV

verteporfin

treated

eyes

treated

eye


Input:
An evaluation of low molecular weight heparin and hyperbaric oxygen treatment in the prevention of intra-abdominal adhesions and wound healing.

BACKGROUND: Abdominal surgery can lead to intra-abdominal adhesions with significant morbidity and mortality. To prevent adhesions, an experimental study was planned to designate the effects of low molecular weight (LMW) heparins and hyperbaric oxygen (HBO) therapy both on the formation of adhesions and wound healing. METHODS: Thirty-eight Wistar albino rats underwent laparotomy to cause intra-abdominal adhesions by mechanical abrasion of the cecum and ethanol application. The rats were divided into 4 groups. In the control group (group 1) no further management was undertaken. Group 2 was treated by Enoxaparine Na, group 3 received HBO therapy, and group 4 was given both enoxaparine Na and HBO treatment. RESULTS: There was a statistically significant difference between the control and enoxaparine Na groups regarding adhesions. Statistically significant differences were observed between groups 1 and 4 and between groups 1 and 3 regarding the hydroxyproline content of the abdominal wounds. In the pathologic analysis of the abdominal wounds, there was no statistically significant difference between any of the groups, including the control group, regarding inflammation. Statistically significant differences were observed regarding angiogenesis between the control group and groups 3 and 4. There was also a statistically significant difference regarding fibrosis between groups 1 and 4. CONCLUSIONS: Enoxaparine Na decreased intra-abdominal adhesions, and HBO therapy had no beneficial effect on adhesions. Enoxaparine Na had no harmful effects on wound healing, and HBO therapy increased the process of wound healing.

angiogenesis

treatment

low molecular weight heparin

treatment

hyperbaric oxygen

therapy

low molecular weight (LMW) heparins

therapy

hyperbaric oxygen

underwent

Wistar albino rats

abrasion

cecum

application

ethanol

treated

Enoxaparine Na

therapy

HBO

treatment

enoxaparine Na

HBO

therapy

HBO

therapy

HBO


Input:
VEGF-targeted therapy: therapeutic potential and recent advances.

After over 30 years of theorizing, the use of angiogenesis inhibitors as anticancer therapy has finally moved from the realm of research to reality. Normal adult vasculature is generally quiescent in nature, with endothelial cells dividing approximately every 10 years. In contrast, the growth of tumors requires constant vascular growth and remodeling in order for solid tumors to grow beyond 1-2 mm(3) in size. Vascular endothelial growth factor (VEGF) and its receptors are key regulators of the process of angiogenesis, which makes them attractive therapeutic targets. A multitude of VEGF-targeted inhibitory agents are currently being investigated for the treatment of cancer. This review article focuses on recent developments in the use of angiogenesis inhibitors for the treatment of breast, lung, and colorectal cancers.

angiogenesis

angiogenesis

angiogenesis

dividing

endothelial cells

growth

tumors

growth

vascular

grow

solid tumors

treatment

breast

treatment

lung

treatment

colorectal cancers

requires

growth

growth

requires

growth

remodeling

remodeling

vascular


Input:
Thrombospondins, metallo proteases and thrombospondin receptors messenger RNA and protein expression in different tumour sublines of the Dunning prostate cancer model.

Thrombospondin is a potent inhibitor of angiogenesis and might therefore be important in controlling tumour growth. TSP interacts with a number of proteases and receptors and in this way inhibits stimulation of angiogenesis. An earlier study showed that thrombospondin is expressed in benign prostatic hyperplasia (BPH) and high-grade prostatic intraepithelial neoplasia (PIN) but is absent in prostate cancer. The present study was therefore designed to evaluate the expression of thrombospondin 1 and 2 (TSP-1, TSP-2), TSP receptors CD36 and CD47, and matrix-metalloproteases 2 and 9 (MMP-, MMP-9) in a rat prostate cancer model. By using immunohistochemistry, Western blot, and real-time PCR the expression patterns of TSP-1, TSP-2, CD36, CD47, MMP-2, and MMP-9 were investigated in normal rat prostate tissue and five malignant Dunning sublines tissue. TSP-1 mRNA levels were decreased in all tumours compared with normal prostate. However, there was no difference in expression of TSP-2 and CD36 mRNA in these samples. MMP-2 was increased with malignancy, but no expression of MMP-9 was seen. The CD47 receptor did slightly increase with malignancy except for H3327. The results showed that thrombospondin is expressed in normal prostate but not in prostate tumours in a rat model. Simultaneously, MMP-2 expression increases with malignancy.

interacts

TSP

angiogenesis

angiogenesis

expression

Thrombospondins

expression

metallo proteases

expression

thrombospondin receptors

expressed

thrombospondin

absent

thrombospondin

expression

thrombospondin 1

expression

expression

expression

expression

matrix-metalloproteases 2

expression

expression

expression

expression

expression

expression

expression

expression

expressed

thrombospondin

expression

growth

tumour

inhibits

TSP

stimulation

decreased

stimulation

angiogenesis

increased

increase

CD47 receptor

increases

expression

controlling

Thrombospondin

growth

expression

Thrombospondins

expression

metallo proteases

expression

thrombospondin receptors

expression

expression


Input:
Minimal contribution of marrow-derived endothelial precursors to tumor vasculature.

During embryogenesis, vascular and hemopoietic cells originate from a common precursor, the hemangioblast. Recent evidence suggests the existence of endothelial precursors in adult bone marrow cells, but it is unclear whether those precursors have a role in tumor neovascularization. In this report, we demonstrate that murine bone marrow contains endothelial progenitors, which arise from a cell with self-renewing capacity, and can integrate into tumor microvasculature, albeit at a very low frequency. A transgenic double-reporter strategy allowed us to demonstrate definitively that tumor bone marrow-derived endothelial cells arise by transdifferentiation of marrow progenitors rather than by cell fusion. Single cell transplants showed that a common precursor contributes to both the hemopoietic and endothelial lineages, thus demonstrating the presence of an adult hemangioblast. Furthermore, we demonstrate that increased vascular endothelial growth factor (VEGF)-A secretion by tumor cells, as well as activation of VEGF receptor-2 in bone marrow cells does not alter the mobilization and incorporation of marrow-derived endothelial progenitors into tumor vasculature. Finally, in human umbilical cord blood cells, we show that endothelial precursors make up only approximately 1 in 10(7) mononuclear cells but are highly enriched in the CD133+ cell population. By ruling out cell fusion, we clearly demonstrate the existence of an adult hemangioblast, but the differentiation of marrow stem cells toward the endothelial lineage is an extremely rare event. Furthermore, we show that VEGF-A stimulation of hemopoietic cells does not significantly alter this process.

neovascularization

tumor

originate

vascular

originate

hemopoietic cells

transdifferentiation

marrow progenitors

fusion

cell

fusion

cell

differentiation

marrow stem cells

existence

endothelial precursors

secretion

vascular endothelial growth factor (VEGF)-A

tumor cells

incorporation

marrow-derived endothelial progenitors

tumor vasculature

existence

hemangioblast

transplants

cell

increased

secretion

activation

VEGF receptor-2

stimulation

VEGF-A

hemopoietic cells

contribution

marrow-derived endothelial precursors

tumor vasculature

have a role

endothelial precursors

neovascularization

contributes

hemopoietic

contributes

endothelial lineages


Input:
High-Dose celecoxib and metronomic "low-dose" cyclophosphamide is an effective and safe therapy in patients with relapsed and refractory aggressive histology non-Hodgkin's lymphoma.

PURPOSE: Angiogenesis is increased in aggressive histology non-Hodgkin's lymphoma and may be a target with selective cyclooxygenase-2 inhibition and metronomic chemotherapy. EXPERIMENTAL DESIGN: We assessed response, toxicity, and biomarkers of angiogenesis to low-dose cyclophosphamide (50 mg p.o. o.d.) and high-dose celecoxib (400 mg p.o. b.i.d.) in adult patients with relapsed or refractory aggressive non-Hodgkin's lymphoma in a multicenter phase II prospective study. RESULTS: Thirty-two of 35 patients (median age, 62 years) are evaluable for response. Patients had primarily relapsed diffuse large B-cell lymphoma (63%) were heavily pretreated (median of three regimens) and high risk (79% international prognostic index,  greater than or=2) and 34% were relapsed after autologous stem cell transplant. With a median follow-up of 8.4 months, the overall best response rate is 37% (2 complete clinical response/complete clinical response unconfirmed and 9 partial response), with 22% achieving stable disease. Median overall and progression-free survivals are 14.4 and 4.7 months, respectively. The median response duration was 8.2 months. The most common toxicity was skin rash (40%); myelosuppression and gastrointestinal side effects were uncommon. Three patients developed deep vein thromboses and two heavily pretreated patients developed treatment-related acute myelogenous leukemia or myelodysplasia after 3.7 and 12 months of therapy. Circulating endothelial cells and their precursors declined and remained low in responders, whereas plasma vascular endothelial growth factor trended to decline in responding patients but increase in nonresponders. Trough celecoxib levels achieved targeted "antiangiogenic" levels. CONCLUSIONS: Low-dose cyclophosphamide and high-dose celecoxib is well tolerated and active in pretreated aggressive non-Hodgkin's lymphoma. Close surveillance for arterial and venous thrombotic events is recommended. The decline in circulating endothelial cells and their precursors suggests that this combination may be working by inhibiting angiogenesis but should be validated in a larger patient sample.

Angiogenesis

angiogenesis

angiogenic

angiogenesis

inhibition

Angiogenesis

decline

vascular endothelial growth factor

targeted

celecoxib

angiogenic

decline

endothelial cells

inhibiting

cyclophosphamide

angiogenesis

inhibiting

celecoxib

angiogenesis

therapy

celecoxib

patients

therapy

cyclophosphamide

patients

chemotherapy

non-Hodgkin's lymphoma

pretreated

Patients

transplant

Patients

stem cell

pretreated

patients

treatment

patients

therapy

patients

pretreated

cyclophosphamide

non-Hodgkin's lymphoma

pretreated

celecoxib

non-Hodgkin's lymphoma

increased

Angiogenesis

increase

vascular endothelial growth factor


Input:
Photodynamic therapy with verteporfin for subfoveal choroidal neovascularization secondary to pathologic myopia: long-term study.

PURPOSE: To assess the safety and effectiveness of photodynamic therapy (PDT) with verteporfin for subfoveal choroidal neovascularization (CNV) secondary to pathologic myopia (PM). METHODS: Sixty-two patients (62 eyes) with PM underwent PDT according to the guidelines of the Verteporfin in Photodynamic Therapy Study. Clinical evaluations performed at all study visits included measurement of best-corrected Snellen visual acuity, slit-lamp biomicroscopy, and fundus fluorescein angiography. Patients were followed up at 1 month and 3 months after treatment and thereafter at 3-month intervals. RESULTS: The final visual acuity of the study patients, after a median follow-up of 31 months, improved by  greater than or=1 Snellen lines in 8 patients (13%), deteriorated in 20 (32%), and remained stable in 34 (55%). The baseline visual acuity was similar in the various study groups. The final mean visual acuity in group A (55 years of age or younger) was 20/80 and significantly (P=0.006) better than that (20/138) in group B (older than 55 years of age). The mean final visual acuity in eyes with higher refractive error at baseline (greater than -17 diopters) was significantly better (P=0.014) than that in eyes with lower refractive error (-6 to -10 diopters). CNV size did not affect visual outcomes. CONCLUSION: PDT preserves vision in patients with CNV associated with PM. Younger patients and eyes with higher refractive error appear more likely to benefit from PDT with verteporfin.

neovascularization

neovascularization

CNV

CNV

CNV

Photodynamic therapy

verteporfin

photodynamic therapy

verteporfin

PDT

patients

Photodynamic Therapy

patients

Verteporfin

angiography

fundus

fluorescein

treatment

Patients

PDT

patients

PDT

patients

verteporfin

PDT

eyes

verteporfin


Input:
Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy.

Maternal endothelial dysfunction in preeclampsia is associated with increased soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor and placental growth factor. Angiotensin II (Ang II) is a potent vasoconstrictor that increases concomitant with sFlt-1 during pregnancy. Therefore, we speculated that Ang II may promote the expression of sFlt-1 in pregnancy. Here we report that infusion of Ang II significantly increases circulating levels of sFlt-1 in pregnant mice, thereby demonstrating that Ang II is a regulator of sFlt-1 secretion in vivo. Furthermore, Ang II stimulated sFlt-1 production in a dose- and time-dependent manner from human villous explants and cultured trophoblasts but not from endothelial cells, suggesting that trophoblasts are the primary source of sFlt-1 during pregnancy. As expected, Ang II-induced sFlt-1 secretion resulted in the inhibition of endothelial cell migration and in vitro tube formation. In vitro and in vivo studies with losartan, small interfering RNA specific for calcineurin and FK506 demonstrated that Ang II-mediated sFlt-1 release was via Ang II type 1 receptor activation and calcineurin signaling, respectively. These findings reveal a previously unrecognized regulatory role for Ang II on sFlt-1 expression in murine and human pregnancy and suggest that elevated sFlt-1 levels in preeclampsia may be caused by a dysregulation of the local renin/angiotensin system.

dysfunction

endothelial

formation

tube

expression

production

expression

Ang II

expression

release

fms-Like tyrosine kinase-1

circulating

vascular endothelial growth factor

circulating

placental growth factor

circulating

secretion

secretion

migration

endothelial cell

release

dysregulation

system

calcineurin signaling pathway

calcineurin signaling

system

renin

angiotensin

infusion

Ang II

induces

induces

release

increased

fms-like tyrosine kinase-1

increases

Angiotensin II

promote

Ang II

expression

increases

infusion

circulating

stimulated

Ang II

production

induced

Ang II

secretion

inhibition

induced

migration

inhibition

induced

formation

mediated

release

activation

activation

Ang II type 1 receptor

elevated

caused

elevated

dysregulation

induces

Angiotensin II

calcineurin signaling pathway

mediated

Ang II

activation

regulatory role

expression


Input:
Ectopic decorin expression up-regulates VEGF expression in mouse cerebral endothelial cells via activation of the transcription factors Sp1, HIF1alpha, and Stat3.

We demonstrate that a proteoglycan decorin (DCN) up-regulates the vascular endothelial growth factor (VEGF) expression with activation of VEGF regulating transcription factors Sp1, hypoxia-inducible factor 1alpha (HIF1alpha), and signal transducer and activator of transcription 3 (Stat3) via epidermal growth factor receptor (EGFR), mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2), and protein kinase B (AKT) pathways in DCN transfected mouse cerebral endothelial (MCE) cells. Treatment with pharmacological inhibitors and small interfering RNAs reveal that induction and activation of Sp1, HIF1alpha, and Stat3 facilitate their nuclear localization and binding to their specific motifs of the VEGF promoter and induce VEGF expression via two independent pathways, DCN/EGFR/phosphoinositide-3 kinase/AKT and DCN/EGFR/ERK1/2, respectively, in DCN synthesizing MCE cells. The cell type specific glycosylation protects Sp1 and HIF1alpha from proteosome degradation and plays an important and novel role in the regulation of VEGF in DCN transfected MCE cells. Induction of gelatinases (matrix metalloproteinase 2 and 9), the serine protease tissue plasminogen activator and plasmin by DCN transfection in MCE cells leads to extracellular proteolysis and to release of matrix-bound VEGF and activation of angiogenesis. In this study, we demonstrate that two independent downstream signal pathways, DCN/EGFR/ERK1/2 and DCN/EGFR/phosphoinositide-3 kinase/AKT, mediate up-regulation and activation of transcription factors of VEGF such as HIF1alpha, Stat3, and Sp1 and increase VEGF transcription and angiogenesis in MCE cells.

binding

VEGF

promoter

binding

VEGF

promoter

binding

VEGF

promoter

bound

VEGF

angiogenesis

angiogenesis

degradation

degradation

release

VEGF

expression

decorin

expression

VEGF

expression

vascular endothelial growth factor

expression

VEGF

synthesizing

DCN

localization

localization

localization

protects

degradation

pathways

epidermal growth factor receptor

pathways

mitogen-activated protein kinase extracellular signal-regulated kinase 1/2

pathways

protein kinase B

pathways

DCN

EGFR

pathways

DCN

EGFR

phosphoinositide-3 kinase

AKT

signal pathways

DCN

EGFR

signal pathways

DCN

EGFR

phosphoinositide-3 kinase

AKT

transfected

DCN

cerebral endothelial (MCE) cells

transfected

DCN

MCE cells

transfection

DCN

MCE cells

up-regulates

expression

activation

activation

expression

activation

expression

activation

expression

up-regulates

expression

pathways

activation

pathways

activation

hypoxia-inducible factor 1alpha

pathways

activation

signal transducer and activator of transcription 3

pathways

induction

pathways

induction

pathways

induction

pathways

activation

pathways

activation

pathways

activation

pathways

induce

expression

pathways

Induction

matrix metalloproteinase 2

transfection

Induction

transfection

Induction

tissue plasminogen activator

transfection

Induction

plasmin

transfection

leads

Induction

release

leads

Induction

activation

activation

angiogenesis

mediate

signal pathways

up-regulation

mediate

signal pathways

activation

mediate

signal pathways

increase

up-regulation

up-regulation

up-regulation

activation

activation

activation

increase

transcription

increase

angiogenesis

up-regulates

decorin

pathways

activation

decorin

pathways

regulating

VEGF

regulating

VEGF

hypoxia-inducible factor 1alpha

regulating

VEGF

signal transducer and activator of transcription 3

regulation

VEGF

transcription

VEGF


Input:
Effects of spironolactone on corneal allograft survival in the rat.

PURPOSE: Spironolactone has recently been shown to have suppressive effects on several immunoactive and proinflammatory cytokines. In this study, we investigated the effects of spironolactone on the prevention of corneal allograft rejection in a MHC class I/II mismatch rat corneal transplant model. METHODS: Grafted animals for corneal survival analysis were assigned to receive either spironolactone suspension (orally, 100 mg/kg/day, n = 7), phosphate-buffered saline (PBS, orally, same volume as spironolactone, n = 9) or remained untreated (n = 16). Additional grafted rats treated with spironolactone (n = 6) or PBS (n = 8) were sacrificed on day 12 for quantitative RT-PCR analysis for mechanistic studies. RESULTS: Mean (+/-SEM) graft survival was significantly prolonged in animals receiving spironolactone (14.9 +/- 2.0 days) compared with both PBS-treated (12.3 +/- 1.2 days, p = 0.007) and untreated controls (13.0 +/- 1.0 days, p = 0.01). We found a decrease in corneal neovascularization in spironolactone-treated rats compared with the PBS-treated group, although the difference was not statistically significant. Spironolactone affected both systemic (down-regulation of CD25+ cells in spleen) and local immune response (up-regulation of IL-10 in cornea). CONCLUSION: We present initial results demonstrating anti-inflammatory effects of spironolactone.

neovascularization

corneal

survival

corneal allograft

rejection

corneal allograft

survival

corneal

survival

graft

prevention

rejection

decrease

neovascularization

down-regulation

CD25+ cells

transplant

rat

corneal

grafted

rats

treated

rats

spironolactone

treated

rats

PBS

sacrificed

rats

receiving

spironolactone

treated

graft

PBS

untreated

graft

treated

spironolactone

rats

treated

rats

PBS

prolonged

survival

receiving

up-regulation

Effects

spironolactone

survival

effects

spironolactone

prevention

affected

Spironolactone

down-regulation

affected

Spironolactone

up-regulation


Input:
A new autosomal dominant vascular retinopathy syndrome.

We describe a new syndrome with autosomal dominant transmission whose most striking feature is vascular retinopathy. The retinopathy is often associated with migraine, Raynaud's phenomenon and mental changes, mainly forgetfulness, aggression and depression. To define this syndrome we collected medical data on 110 family members. General ophthalmological examination and fluorescein angiography were performed in 61 persons. The retinopathy, as diagnosed in 22 persons, is characterized by central and peripheral microangiopathy, areas of capillary non-perfusion, haemorrhages, cotton wool spots and, in a more advanced stage, occlusion of large retinal vessels, which can induce a neovascular response. A vascular occlusive disorder may be the common aetiological factor of the various manifestation of this syndrome.

neovascular response

angiography

fluorescein

persons

induce

neovascular response


Input:
The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis.

Solid tumors express a range of factors required to sustain their growth and promote their dissemination. Among these are vascular endothelial growth factor-A (VEGF-A), the key angiogenic stimulant, and VEGF-C, a primary mediator of lymphangiogenesis. Small molecule tyrosine kinase inhibitors offer the potential to inhibit more than one kinase and impede tumor growth by multiple mechanisms. However, their potency toward individual targets can vary. Cediranib (RECENTIN; AZD2171) is an inhibitor of VEGF signaling that has been shown in experimental models to prevent VEGF-A-induced angiogenesis and primary tumor growth, yet the effects of cediranib on VEGF receptor (VEGFR)-3-mediated endothelial cell function and lymphangiogenesis are unknown. To better understand the activity of cediranib against VEGFR-3 and its associated signaling events compared with its activity against VEGFR-2, we used the receptor-specific ligands VEGF-E and VEGF-C156S. In human endothelial cells, cediranib inhibited VEGF-E-induced phosphorylation of VEGFR-2 and VEGF-C156S-induced phosphorylation of VEGFR-3 at concentrations of  less than /=1nmol/L and inhibited activation of downstream signaling molecules. Additionally, cediranib blocked VEGF-C156S-induced and VEGF-E-induced proliferation, survival, and migration of lymphatic and blood vascular endothelial cells. In vivo, cediranib (6 mg/kg/d) prevented angiogenesis and lymphangiogenesis induced by VEGF-E-expressing and VEGF-C156S-expressing adenoviruses, respectively. Cediranib (6 mg/kg/day) also blocked angiogenesis and lymphangiogenesis induced by adenoviruses expressing VEGF-A or VEGF-C and compromised the blood and lymphatic vasculatures of VEGF-C-expressing tumors. Cediranib may, therefore, be an effective means of preventing tumor progression, not only by inhibiting VEGFR-2 activity and angiogenesis, but also by concomitantly inhibiting VEGFR-3 activity and lymphangiogenesis.

angiogenic

angiogenesis

angiogenesis

angiogenesis

angiogenesis

proliferation

lymphatic

proliferation

blood vascular endothelial cells

survival

lymphatic

survival

blood vascular endothelial cells

progression

tumor

expressing

VEGF-E

expressing

expressing

VEGF-A

expressing

VEGF-C

expressing

VEGF-C

growth

tumor

growth

tumor

migration

lymphatic

migration

blood vascular endothelial cells

blocks

cediranib

vascular endothelial growth factor receptor-3

impede

tyrosine kinase inhibitors

growth

prevent

Cediranib

angiogenesis

prevent

Cediranib

growth

inhibited

cediranib

phosphorylation

inhibited

cediranib

phosphorylation

blocked

cediranib

proliferation

blocked

cediranib

survival

blocked

cediranib

migration

prevented

cediranib

angiogenesis

blocked

Cediranib

angiogenesis

preventing

progression

inhibiting

preventing

progression

inhibiting

inhibiting

Cediranib

inhibiting

Cediranib

angiogenesis

inhibiting

signaling

VEGF

phosphorylation

phosphorylation

induced

vascular endothelial growth factor receptor-3

induced

VEGF-A

angiogenesis

induced

VEGF-E

phosphorylation

induced

phosphorylation

induced

proliferation

induced

survival

induced

migration

induced

VEGF-E

proliferation

induced

VEGF-E

survival

induced

VEGF-E

migration

induced

angiogenesis

adenoviruses

effects

cediranib

endothelial cell

mediated

VEGF receptor (VEGFR)-3

endothelial cell


Input:
Bevacizumab and irinotecan therapy in glioblastoma multiforme: a series of 13 cases.

OBJECT: Endothelial proliferation has been recognized as a marker of high-grade or aggressive glioma. Bevacizumab is a humanized immunoglobulin G1 monoclonal antibody to vascular endothelial growth factor that has been shown to have activity in malignant gliomas when combined with irinotecan. The authors report on a case series of 13 patients with recurrent heavily pretreated malignant glioma that was treated with the combination of bevacizumab and irinotecan. METHODS: Standard therapy with primary resection followed by adjuvant chemotherapy and radiation had failed in all patients. The median number of therapies applied, including initial surgery, was 5 (range 3-7 therapies). Nine patients were started on bevacizumab at a dose of 5 mg/m2 every 2 weeks. Four patients received bevacizumab at a dose of 10 mg/m2; irinotecan was given at a dose of 125 mg/m2 every week for 3 weeks. RESULTS: Of the 13 treated patients, 10 (77%) had a radiologically demonstrated partial response and 3 (23%) had stable disease. Six patients (46%) had a clinical response. The median time to disease progression while on treatment was 24 weeks. The median overall survival was 27 weeks. The disease progressed in 8 patients, despite an initial response. Five patients are still responding to therapy. Six of the 8 patients whose disease progressed have died. Bevacizumab was discontinued in 2 patients because of nonfatal intracranial bleeding. CONCLUSIONS: The combination of bevacizumab and irinotecan is safe and has excellent activity even in this relapsed, heavily pretreated population of patients with high-grade malignant glioma, most of whom would not be candidates for clinical trials.

proliferation

Endothelial

died

patients

therapy

Bevacizumab

glioblastoma multiforme

therapy

irinotecan

glioblastoma multiforme

pretreated

patients

treated

glioma

bevacizumab

irinotecan

chemotherapy

patients

radiation

patients

started

patients

bevacizumab

received

patients

bevacizumab

given

patients

irinotecan

treated

patients

discontinued

Bevacizumab

patients

pretreated

patients

have activity

Bevacizumab

gliomas


Input:
Endosialin/TEM 1/CD248 is a pericyte marker of embryonic and tumor neovascularization.

The formation of functional, mature blood vessels depends on the interaction between endothelial cells and pericytes. Commonality exists in the processes involved in vasculature development between tissues whether healthy or diseased. Endosialin/TEM 1 is a cell membrane protein that is expressed in blood vessels during embryogenesis and tumorigenesis but not in normal mature vessels. Antibodies developed to human endosialin were used to investigate endosialin expression and function in human prenatal brain pericytes and pericytes residing in tumors. Anti-endosialin was capable of preventing pericyte tube formation in culture and inhibited migration. Brain pericytes in culture had higher levels of endosialin/TEM 1 than TEMs-2, -3, -4, -5, -7, and -8. Immunocytochemistry revealed that endosialin was present in the cytoplasmic body and in the elongated extensions essential to pericyte function. Transgenic mice engineered to express human endosialin bred on an immunocompromised background allowed the growth of human tumor xenografts. In human colon carcinoma Colo205 and HT29 xenografts grown in human endosialin-transgenic mice, endosialin expression was largely confined to NG2-expressing perivascular cells and not CD31-positive endothelial cells. Similar methods applied to human ovarian and colon tumors confirmed endosialin expression by pericytes. The data indicate that endosialin is strongly expressed by pericytes during periods of active angiogenesis during embryonic and tumor development. Anti-endosialin antibodies may have value in identifying vasculature in malignant tissues. With the appropriate agent, targeting endosialin may interfere with blood vessel growth during tumor development.

interaction

endothelial cells

pericytes

neovascularization

tumor

angiogenesis

formation

blood vessels

development

vasculature

formation

pericyte tube

development

tumor

development

tumor

expressed

TEM 1

expression

endosialin

express

endosialin

expression

endosialin

expressing

positive

expression

endosialin

expressed

endosialin

growth

tumor xenografts

grown

colon carcinoma Colo205

grown

growth

blood vessel

present

endosialin

preventing

Anti-endosialin

formation

interfere

targeting

growth

Transgenic

mice

endosialin

transgenic

endosialin

mice

targeting

endosialin

depends

formation

interaction


Input:
Efficient inhibition of ovarian cancer growth and prolonged survival by transfection with a novel pro-apoptotic gene, hPNAS-4, in a mouse model. In vivo and in vitro results.

OBJECTIVE: We transfected ovarian cancer cells and administered recombinant plasmid encoding hPNAS-4 to nude mice bearing ovarian cancer, aiming to evaluate the effect of hPNAS-4 against ovarian cancer in vitro and in vivo. METHODS: Ovarian cancer SKOV3 cells were transfected with hPNAS-4-plasmid, and cell proliferation was evaluated by MTT assay; apoptosis was examined by DNA ladder, Hoechst33258 staining and flow-cytometric assays. Nude mice bearing ovarian cancers were treated with hPNAS-4-p/liposome. Tumor growth was determined and survival was recorded. TUNEL assay and microvessel density was assessed to evaluate apoptosis and angiogenesis. RESULTS: Both inhibition of proliferation (p < 0.05) and induction of apoptosis (p < 0.05) were observed in SKOV3 cells transfected with hPNAS-4-p in vitro. In hPNAS-4-p-treated tumor cells in vivo, tumor growth significantly decreased, while the survival time of tumor-bearing mice was prolonged compared with control groups (p < 0.05). Increased apoptosis of tumor cells and decreased angiogenesis in tumor tissue were also observed. CONCLUSIONS: Our promising results on the potential antitumor effects of hPNAS-4 on ovarian cancer in vitro and in vivo may be explained, in part, by the induction of apoptosis and inhibition of angiogenesis. Consequently, hPNAS-4 has potential as a new gene therapy for human ovarian cancer.

angiogenesis

angiogenesis

tumor tissue

angiogenesis

proliferation

cell

proliferation

SKOV3 cells

survival

mouse

apoptosis

Ovarian cancer SKOV3 cells

apoptosis

SKOV3 cells

survival

mice

apoptosis

tumor cells

apoptosis

ovarian cancer

growth

ovarian cancer

growth

Tumor

growth

tumor

inhibition

growth

transfection

inhibition

survival

transfection

inhibition

proliferation

decreased

growth

decreased

angiogenesis

effects

tumor

effects

ovarian cancer

induction

effects

ovarian cancer

inhibition

inhibition

angiogenesis

transfection

transfected

ovarian cancer cells

administered

nude mice

transfected

Ovarian cancer SKOV3 cells

treated

Nude mice

liposome

transfected

SKOV3 cells

treated

tumor cells

gene therapy

ovarian cancer

induction

apoptosis

prolonged

survival

Increased

apoptosis

induction

apoptosis

effect

ovarian cancer


Input:
The in vivo properties of STX243: a potent angiogenesis inhibitor in breast cancer.

The steroidal-based drug 2-ethyloestradiol-3,17-O,O-bis-sulphamate (STX243) has been developed as a potent antiangiogenic and antitumour compound. The objective of this study was to ascertain whether STX243 is more active in vivo than the clinically relevant drug 2-methoxyoestradiol (2-MeOE2) and the structurally similar compound 2-MeOE2-3,17-O,O-bis-sulphamate (STX140). The tumour growth inhibition efficacy, antiangiogenic potential and pharmacokinetics of STX243 were examined using four in vivo models. Both STX243 and STX140 were capable of retarding the growth of MDA-MB-231 xenograft tumours (72 and 63%, respectively), whereas no inhibition was observed for animals treated with 2-MeOE2. Further tumour inhibition studies showed that STX243 was also active against MCF-7 paclitaxel-resistant tumours. Using a Matrigel plug-based model, in vivo angiogenesis was restricted with STX243 and STX140 (50 and 72%, respectively, using a 10 mg kg(-1) oral dose), thereby showing the antiangiogenic activity of both compounds. The pharmacokinetics of STX243 were examined at two different doses using adult female rats. The compound was orally bioavailable (31% after a single 10 mg kg(-1) dose) and resistant to metabolism. These results show that STX243 is a potent in vivo drug and could be clinically effective at treating a number of oncological conditions.

angiogenesis

angiogenic

angiogenic

angiogenesis

angiogenic

growth

tumour

growth

MDA-MB-231 xenograft tumours

inhibition

growth

potential

angiogenic

retarding

growth

retarding

growth

inhibition

tumour

restricted

angiogenesis

restricted

angiogenesis

activity

angiogenic

activity

angiogenic

treated

active against

MCF-7 paclitaxel-resistant tumours


Input:
Grape seed extract inhibits angiogenesis via suppression of the vascular endothelial growth factor receptor signaling pathway.

Blockade of angiogenesis is an important approach for cancer treatment and prevention. Vascular endothelial growth factor (VEGF) is one of the most critical factors that induce angiogenesis and has thus become an attractive target for antiangiogenesis treatment. However, most current anti-VEGF agents often cause some side effects when given chronically. Identification of naturally occurring VEGF inhibitors derived from diet would be one alternative approach with an advantage of known safety. Grape seed extract (GSE), a widely used dietary supplement, is known to have antitumor activity. In this study, we have explored the activity of GSE on VEGF receptor and angiogenesis. We found that GSE could directly inhibit the kinase activity of purified VEGF receptor 2, a novel activity of GSE that has not been characterized. GSE could also inhibit the VEGF receptor/mitogen-activated protein kinase-mediated signaling pathway in endothelial cells. As a result, GSE could inhibit VEGF-induced endothelial cell proliferation and migration as well as sprout formation from aorta ring. In vivo assay further showed that GSE could inhibit tumor growth and tumor angiogenesis of MDA-MB-231 breast cancer cells in mice. Consistent with the in vitro data, GSE treatment of tumor-bearing mice led to concomitant reduction of blood vessel density and phosphorylation of mitogen-activated protein kinase. Depletion of polyphenol with polyvinylpyrrolidone abolished the antiangiogenic activity of GSE, suggesting a water-soluble fraction of polyphenol in GSE is responsible for the antiangiogenic activity. Taken together, this study indicates that GSE is a well-tolerated and inexpensive natural VEGF inhibitor and could potentially be useful in cancer prevention or treatment.

angiogenesis

angiogenesis

angiogenesis

angiogenesis

angiogenesis

angiogenesis

tumor

angiogenic

angiogenic

proliferation

endothelial cell

formation

sprout

growth

tumor

migration

endothelial cell

inhibits

Grape seed extract

angiogenesis

suppression

Grape seed extract

signaling pathway

Blockade

angiogenesis

prevention

cancer

treatment

Vascular endothelial growth factor

angiogenesis

activity

Grape seed extract

tumor

inhibit

GSE

VEGF receptor 2

inhibit

signaling pathway

inhibit

GSE

proliferation

inhibit

GSE

migration

inhibit

GSE

formation

inhibit

GSE

growth

inhibit

GSE

angiogenesis

reduction

blood vessel

Depletion

polyphenol

polyvinylpyrrolidone

abolished

Depletion

activity

activity

angiogenic

GSE

activity

GSE

angiogenic

prevention

GSE

cancer

signaling pathway

vascular endothelial growth factor receptor

signaling pathway

phosphorylation

mitogen-activated protein kinase

treatment

cancer

treatment

GSE

mice

treatment

GSE

cancer

induce

Vascular endothelial growth factor

angiogenesis

mediated

VEGF receptor

signaling pathway

mediated

mitogen-activated protein kinase

signaling pathway

induced

VEGF

proliferation

induced

VEGF

migration

led

treatment

reduction

led

treatment

phosphorylation

responsible

polyphenol

activity


Input:
Role of the interferon-inducible IFI16 gene in the induction of ICAM-1 by TNF-alpha.

The Interferon-inducible gene IFI16, a member of the HIN200 family, is activated by oxidative stress and cell density, in addition to Interferons, and it is implicated in the regulation of endothelial cell proliferation and vessel formation in vitro. We have previously shown that IFI16 is required for proinflammatory gene stimulation by IFN-gamma through the NF-kappaB complex. To examine whether IFI16 induction might be extended to other proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, we used the strategy of the RNA interference to knock down IFI16 expression, and analyze the capability of TNF-alpha to stimulate intercellular adhesion molecule-1 (ICAM-1 or CD54) expression in the absence of functional IFI16. Our studies demonstrate that IFI16 mediates ICAM-1 stimulation by TNF-alpha through the NF-kappaB pathway, thus reinforcing the role of the IFI16 molecule in the inflammation process.

proliferation

endothelial cell

formation

vessel

expression

expression

expression

pathway

NF-kappaB

knock down

inducible

interferon

induction

TNF-alpha

inducible

Interferon

activated

Interferons

induction

extended

induction

tumor necrosis factor (TNF)-alpha

stimulate

TNF-alpha

expression

stimulation

TNF-alpha

Role

induction

regulation

proliferation

regulation

formation

mediates

pathway

mediates

mediates

stimulation


Input:
Impact of tumor cell VEGF expression on the in vivo efficacy of vandetanib (ZACTIMA; ZD6474).

VEGF is the key player in tumor angiogenesis. In the current study, the impact of VEGF expression on the response of tumors to the VEGFR2 associated tyrosine kinase inhibitor vandetanib was evaluated. MATERIALS AND METHODS: Human colon carcinoma (HT29) and murine squamous carcinoma (SCCVII) clonal cell lines expressing varying levels of VEGF were established and their response to vandetanib was assessed in tissue culture and as solid tumors. RESULTS: Vandetanib treatment had no effect on tumor cell clonogenic cell survival in vitro but doses >or=10 nM significantly reduced endothelial cell migration. In vivo, tumors derived from cell clones expressing high levels of VEGF displayed significantly enhanced angiogenesis and more aggressive growth. An intradermal angiogenesis assay was used to demonstrate that a 4-day treatment with vandetanib (50 mg/kg/day) was able to significantly inhibit blood vessel growth induced by both parental and high VEGF-expressing tumor cell clones. In the HT29 tumor model, treatment response to vandetanib (50 mg/kg/day, Monday-Friday for 2 weeks) was greatest in xenografts derived from the highest VEGF-expressing cell clones. A similar trend was noted in the SCCVII tumor model. The present findings indicate that vandetanib therapy effectively counteracted the aggressive feature of tumor growth resulting from VEGF over-expressing tumor cells and suggest that such tumors may be particularly well suited for anti-VEGF interventions.

associated

vandetanib

angiogenesis

tumor

angiogenesis

tumors

angiogenesis

intradermal

survival

cell

expression

VEGF

expression

VEGF

expressing

VEGF

expressing

VEGF

expressing

VEGF

expressing

VEGF

over-expressing

VEGF

growth

tumors

growth

blood vessel

growth

tumor

migration

endothelial cell

reduced

treatment

migration

inhibit

treatment

growth

counteracted

therapy

growth

interventions

VEGF

treatment

Vandetanib

tumor cell

treatment

vandetanib

treatment

HT29 tumor

therapy

vandetanib

enhanced

tumors

angiogenesis

enhanced

tumors

growth

induced

growth

tumor cell

response

tumors

vandetanib

response

expressing

vandetanib

effect

treatment

survival

response

HT29 tumor

vandetanib


Input:
The Down syndrome critical region gene 1 short variant promoters direct vascular bed-specific gene expression during inflammation in mice.

Down syndrome critical region gene 1 (DSCR-1) short variant (DSCR-1s) is an inhibitor of calcineurin/NFAT signaling encoded by exons 4-7 of DSCR1. We previously reported that VEGF induces DSCR-1s expression in endothelial cells, which in turn negatively feeds back to attenuate endothelial cell activation. Here, in order to characterize the role of the promoter that drives DSCR-1s expression in mediating inducible expression in vivo and to determine the functional relevance of DSCR-1s in inflammation, we targeted a DNA construct containing 1.7 kb of the human DSCR1s promoter coupled to the lacZ reporter to the hypoxanthine guanine phosphoribosyl transferase (Hprt) locus of mice. We determined that lacZ was uniformly expressed in the endothelium of transgenic embryos but was markedly downregulated postnatally. Systemic administration of VEGF or LPS in adult mice resulted in cyclosporine A-sensitive reactivation of the DSCR1s promoter and endogenous gene expression in a subset of organs, including the heart and brain. The DSCR1s promoter was similarly induced in the endothelium of tumor xenografts. In a mouse model of endotoxemia, DSCR-1s-deficient mice demonstrated increased sepsis mortality, whereas adenovirus-mediated DSCR-1s overexpression protected against LPS-induced lethality. Collectively, these data suggest that the DSCR1s promoter directs vascular bed-specific expression in activated endothelium and that DSCR-1s serves to dampen the host response to infection.

expression

expression

expressed

lacZ

deficient

overexpression

expression

attenuate

induces

activation

downregulated

expressed

signaling

calcineurin

NFAT

targeted

lacZ

mice

coupled

lacZ

administration

VEGF

mice

administration

LPS

mice

induces

VEGF

expression

activation

endothelial cell

resulted

administration

reactivation

reactivation

promoter

induced

promoter

mediated

adenovirus

overexpression

activated

endothelium

sensitive

cyclosporine A

reactivation


Input:
Nicked {beta}2-glycoprotein I binds angiostatin 4.5 (plasminogen kringle 1-5) and attenuates its antiangiogenic property.

Angiostatin was first discovered as a plasminogen fragment with antitumor/antiangiogenic property. One of the angiostatin isoforms, that is, angiostatin 4.5 (AS4.5), consisting of plasminogen kringle 1 to 4 and a most part of kringle 5, is produced by autoproteolysis and present in human plasma. beta2-glycoprotein I (beta2GPI) is proteolytically cleaved by plasmin in its domain V (nicked beta2GPI), resulting in binding to plasminogen. Antiangiogenic properties have been recently reported in nicked beta2GPI as well as in intact beta2GPI at higher concentrations. In the present study, we found significant binding of nicked beta2GPI to AS4.5 (K(D) = 3.27 x 10(6) M(-1)). Via this binding, nicked beta2GPI attenuates the antiangiogenic functions of AS4.5 in the proliferation of arterial/venous endothelial cells, in the extracellular matrix invasion and the tube formation of venous endothelial cells, and in vivo angiogenesis. In contrast, intact beta2GPI does not bind to AS4.5 or inhibit its antiangiogenic activity. Thus, nicked beta2GPI exerts dual effects on angiogenesis, that is, nicked beta2GPI promotes angiogenesis in the presence of AS4.5, whereas nicked beta2GPI inhibits angiogenesis at concentrations high enough to neutralize AS4.5. Our data suggest that plasmin-nicked beta2GPI promotes angiogenesis by interacting with plasmin-generated AS4.5 in sites of increased fibrinolysis such as thrombus.

binds

Nicked {beta}2-glycoprotein I

angiostatin 4.5

binding

nicked beta2GPI

plasminogen

binding

nicked beta2GPI

binding

nicked beta2GPI

bind

interacting

plasmin-nicked beta2GPI

plasmin-generated AS4.5

angiogenic

angiogenic

angiogenic

angiogenic

angiogenesis

angiogenic

angiogenesis

angiogenesis

angiogenesis

angiogenesis

proliferation

arterial

proliferation

venous endothelial cells

formation

tube

invasion

arterial

extracellular matrix

invasion

venous endothelial cells

extracellular matrix

attenuates

Nicked {beta}2-glycoprotein I

property

property

Nicked {beta}2-glycoprotein I

angiogenic

property

plasminogen fragment

tumor

property

plasminogen fragment

angiogenic

properties

angiogenic

nicked beta2GPI

properties

angiogenic

attenuates

nicked beta2GPI

functions

functions

angiogenic

inhibit

activity

activity

angiogenic

inhibits

nicked beta2GPI

angiogenesis

cleaved

cleaved

plasmin

domain V

resulting

cleaved

binding

promotes

nicked beta2GPI

angiogenesis

autoproteolysis

angiostatin 4.5

cleaved

beta2-glycoprotein I

promotes

angiogenesis

interacting


Input:
[An experimental study on angiogenesis of non-vascularized autogenous bone graft with vascular bundle implantation]

OBJECTIVE: To investigate the effect of vascular bundle implantation in autogenous bone graft on angiogenesis. METHODS: Thirty-six New Zealand white rabbits were evaluated in this study. A portion of bilateral radial bones of a rabbit were removed as free bone grafts, whose periostea were peeled off. In test group, the external maxillary artery bundle was passed through the marrow cavity of the bone. In control group, there was no vascular bundle implantation. Each bone was placed in masseter muscle separately. The rabbits were sacrificed and the specimens were procured at 3 days, 1, 2, 3, 4 and 6 weeks after surgery for histological observation, Chinese ink perfusion and CD34 immunohistochemistry. Microvessel density (MVD) was assessed in order to evaluate angiogenesis of autogenous bone grafts. RESULTS: The bone grafts were found revascularization in 3 days after surgery in the test group, whereas at 2 weeks in the control group. In 3 days, 1 week, 2 weeks, 3 weeks and 4 weeks after surgery, the MVD of test group was significantly higher than that of control group. In 4 weeks after surgery, angiogenesis of test group reached to peak. CONCLUSION: Vascular bundle implantation improved angiogenesis in non-vascularized autogenous bone graft in this study.

angiogenesis

autogenous bone graft

vascularized

autogenous bone graft

angiogenesis

autogenous bone graft

angiogenesis

Microvessel

autogenous bone grafts

revascularization

bone grafts

angiogenesis

angiogenesis

autogenous bone graft

vascularized

autogenous bone graft

implantation

autogenous bone graft

vascular bundle

implantation

vascular bundle

removed

bilateral radial bones

peeled off

periostea

implantation

vascular bundle

placed

bone

masseter muscle

sacrificed

rabbits

implantation

Vascular bundle

improved

implantation

angiogenesis

effect

implantation

angiogenesis


Input:
Dopamine regulates phosphorylation of VEGF receptor 2 by engaging Src-homology-2-domain-containing protein tyrosine phosphatase 2.

Vascular endothelial growth factor (VEGF)-induced receptor phosphorylation is the crucial step for initiating downstream signaling pathways that lead to angiogenesis or related pathophysiological outcomes. Our previous studies have shown that the neurotransmitter dopamine could inhibit VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR-2), endothelial cell proliferation, migration, microvascular permeability, and thus, angiogenesis. In this study, we address the mechanism by which VEGFR-2 phosphorylation is regulated by dopamine. Here, we demonstrate that D2 dopamine receptor (D2DR) colocalizes with VEGFR-2 at the cell surface. Dopamine pretreatment increases the translocation and colocalization of Src-homology-2-domain-containing protein tyrosine phosphatase (SHP-2) with D2DR at the cell surface. Dopamine administration leads to increased VEGF-induced phosphorylation of SHP-2 and this increased phosphorylation parallels the increased phosphatase activity of SHP-2. Active SHP-2 then dephosphorylates VEGFR-2 at Y951, Y996 and Y1059, but not Y1175. We also observe that SHP-2 knockdown impairs the dopamine-regulated inhibition of VEGF-induced phosphorylation of VEGFR-2 and, subsequently, Src phosphorylation and migration. Our data establish a novel role for SHP-2 phosphatase in the dopamine-mediated regulation of VEGFR-2 phosphorylation.

angiogenesis

angiogenesis

proliferation

endothelial cell

dephosphorylates

dephosphorylates

dephosphorylates

dephosphorylates

migration

endothelial cell

colocalizes

D2 dopamine receptor

cell surface

translocation

Src-homology-2-domain-containing protein tyrosine phosphatase

colocalization

Src-homology-2-domain-containing protein tyrosine phosphatase

cell surface

migration

Src

inhibit

dopamine

phosphorylation

inhibit

dopamine

proliferation

inhibit

dopamine

migration

inhibit

dopamine

microvascular

inhibit

dopamine

angiogenesis

impairs

knockdown

inhibition

impairs

knockdown

phosphorylation

impairs

knockdown

migration

inhibition

dopamine

phosphorylation

phosphorylation

VEGF receptor 2

phosphorylation

VEGF receptor 2

phosphorylation

phosphorylation

phosphorylation

phosphorylation

phosphorylation

Src

phosphorylation

pretreatment

Dopamine

administration

Dopamine

knockdown

lead

angiogenesis

induced

VEGF

phosphorylation

increases

pretreatment

translocation

increases

pretreatment

colocalization

leads

administration

increased

increased

phosphorylation

induced

VEGF

phosphorylation

increased

phosphorylation

increased

dephosphorylates

dephosphorylates

induced

VEGF

phosphorylation

regulates

phosphorylation

engaging

engaging

Dopamine

Src-homology-2-domain-containing protein tyrosine phosphatase 2

regulated

phosphorylation

dopamine

role

SHP-2 phosphatase

regulation

regulation

dopamine

phosphorylation


Input:
Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1.

Cancer stem cells (CSC) are predicted to be critical drivers of tumor progression due to their self-renewal capacity and limitless proliferative potential. An emerging area of research suggests that CSC may also support tumor progression by promoting tumor angiogenesis. To investigate how CSC contribute to tumor vascular development, we used an approach comparing tumor xenografts of the C6 glioma cell line containing either a low or a high fraction of CSC. Compared with CSC-low tumors, CSC-high tumors exhibited increased microvessel density and blood perfusion and induced increased mobilization and tumor recruitment of bone marrow-derived endothelial progenitor cells (EPC). CSC-high C6 cell cultures also induced higher levels of endothelial cell proliferation and tubule organization in vitro compared with CSC-low cultures. CSC-high cultures and tumors expressed increased levels of the proangiogenic factors vascular endothelial growth factor and stromal-derived factor 1, and when signaling by either factor was blocked, all aspects of angiogenesis observed in CSC-high cultures and tumors, including microvessel density, perfusion, EPC mobilization/recruitment, and stimulation of endothelial cell activity, were reduced to levels comparable with those observed in CSC-low cultures/tumors. These results suggest that CSC contribute to tumor angiogenesis by promoting both local endothelial cell activity and systemic angiogenic processes involving bone marrow-derived EPC in a vascular endothelial growth factor-dependent and stromal-derived factor 1-dependent manner.

angiogenesis

tumor

vasculogenesis

tumor

angiogenesis

tumor

angiogenic

angiogenesis

tumors

angiogenesis

tumor

angiogenic

proliferative

Cancer stem cells

proliferation

endothelial cell

progression

tumor

progression

tumor

development

vascular

organization

tubule

expressed

vascular endothelial growth factor

expressed

stromal-derived factor 1

mobilization

endothelial progenitor cells

recruitment

tumor

endothelial progenitor cells

mobilization/recruitment

EPC

blocked

vascular endothelial growth factor

blocked

stromal-derived factor 1

reduced

blocked

microvessel

reduced

blocked

mobilization/recruitment

reduced

blocked

stimulation

promote

promote

angiogenesis

promote

promote

vasculogenesis

support

progression

promoting

promoting

CSC

angiogenesis

increased

CSC-low tumors

microvessel

increased

CSC-high tumors

microvessel

induced

CSC-low tumors

mobilization

induced

CSC-low tumors

recruitment

induced

CSC-high tumors

mobilization

induced

CSC-high tumors

recruitment

induced

CSC-high C6 cell cultures

proliferation

induced

CSC-high C6 cell cultures

organization

increased

expressed

stimulation

endothelial cell

promoting

CSC

endothelial cell

promoting

CSC

angiogenic

dependent

contribute

vascular endothelial growth factor

dependent

contribute

stromal-derived factor 1

promote

Glioma tumor stem-like cells

stromal-derived factor 1

promote

Glioma tumor stem-like cells

vascular endothelial growth factor

contribute

CSC

development

contribute

angiogenesis

promoting


Input:
Inducible nitric oxide synthase modulates angiogenesis in ischemic hindlimb of rat.

BACKGROUND: Angiogenesis plays an important role in maintaining adequate oxygen delivery, and nitric oxide (NO) is a potential regulator of angiogenesis. NO is synthesized through three isoforms of NO synthase (NOS). It is hypothesized that the NO derived from inducible NOS (iNOS) may promote survival of ischemic tissue through angiogenesis. To test this hypothesis, we investigated the effect of iNOS deficiency (by L-NIL) on angiogenesis in a hindlimb ischemia model. METHODS: Thirty-two male wistar rats randomly divided into four groups. In groups 1 & 2, hindlimb ischemia was induced by ligation of femoral artery and they received L-NIL and saline respectively. The animals in groups 3 and 4 also received L-NIL and saline respectively without surgical procedure. After 21 days, the serum concentration of nitrite, capillary density and expression of HIF1alpha were determined. RESULTS: Serum nitrite levels were significantly lower in L-NIL groups (p<0.05). The capillary density in group 1 (ischemia+L-NIL) was significantly different from group 2 (ischemia+saline); group 1: 360.33+/-77.02, group 2: 549+/-81.85 /mm2, p<0.05) .In addition, expression of HIF1alpha was significantly increased in ischemic groups (p<0.05). CONCLUSION: Selective inhibition of iNOS by L-NIL inhibits angiogenesis in a hindlimb ischemic rat model. In addition, ischemia induces expression of HIF1alpha in hypoxic tissue.

angiogenesis

Angiogenesis

angiogenesis

angiogenesis

angiogenesis

hindlimb

angiogenesis

hindlimb

survival

ischemic tissue

expression

expression

expression

delivery

oxygen

inhibition

iNOS

L-NIL

inhibits

inhibition

angiogenesis

ligation

femoral artery

received

L-NIL

received

saline

received

L-NIL

received

saline

promote

promote

survival

increased

expression

induces

expression

modulates

Inducible nitric oxide synthase

angiogenesis

plays an important role

Angiogenesis

maintaining

maintaining

delivery

promote

NO

angiogenesis

synthesized

NO


Input:
[Intraepithelial neoplasm of the uterine cervix and angiogenesis: morphologic study]

Thirty uterine cervix specimens sampled following conization or total hysterectomy were studied using histology, histoenzymology (vessel phosphatase alkaline activity), and immunohistochemistry (demonstration of laminin and type IV collagen in epithelium and vessel basement membranes). Pathologic conditions included dystrophia, moderate dysplasia, severe dysplasia, and intraepithelial carcinoma. Results were compared to findings in a control group. We found that the severity of vascular abnormalities correlated positively with the severity of histologic epithelial lesions; this finding is consistent with colposcopic results. Anarchic angiogenesis with large, moniliform, tortuous vessels was seen in severe dysplasias and carcinomas. The vascular anomalies seem to precede the development of histologic lesions in some instances. Histogenesis of the abnormal vessels may involve production of an angiogenic factor by the cancerized epithelia.

angiogenesis

angiogenesis

vessels

carcinomas

angiogenic

Histogenesis

abnormal vessels

conization

uterine cervix

hysterectomy

uterine cervix


Input:
Conjunctival hypoxia in diabetes mellitus.

A frequently cited theory for the pathogenesis of neovascularization in diabetic retinopathy is that retinal hypoxia and/or ischemia release a factor which stimulates neovascularization. To the authors' knowledge, there is no direct in vivo evidence in the human proving this theory. One hundred and twenty-two diabetic subjects were studied to see whether worsening retinopathy was associated with changes in conjunctival oxygen tension (pO2). Diabetics without retinopathy had a conjunctival pO2 which was similar to an age-matched normal population. Diabetics with only background retinopathy had a significantly lower conjunctival pO2 than those without retinopathy (P less than 0.01). Diabetics with proliferative retinopathy showed a conjunctival pO2 that was significantly lower than either of the first two groups (P less than 0.05). The lowest value of all was found in patients with rubeosis iridis. Duration of diabetes alone did not correlate significantly to conjunctival pO2. These findings support the hypoxic theory of diabetic neovascular retinopathy.

neovascularization

neovascularization

neovascular

stimulates

neovascularization

changes

conjunctival


Input:
New functions of epidermal growth factor: stimulation of capillary endothelial cell migration and matrix dependent proliferation.

The proliferative response of bovine retinal capillary endothelial cells to EGF is dependent upon attaching the cells to a matrix of fibronectin. Bovine capillary endothelial cells are also stimulated to actively migrate when exposed to EGF in vitro. These activities provide an explanation for the angiogenic properties of EGF in vivo. Capillary cell migration and proliferation are proposed as sensitive quantifiable bioassays to explore the functional domains of the EGF molecule. Studies on the inactivation of these properties of EGF by specific cleavage of the molecule with CNBr or proteases suggest that an intact loop composed in part by amino acid residues 20 to 31 is essential for at least some functions.

attaching

retinal capillary endothelial cells

cells

matrix

angiogenic

cleavage

EGF

proliferation

capillary endothelial cell

proliferative

retinal capillary endothelial cells

proliferation

Capillary cell

migration

capillary endothelial cell

migrate

capillary endothelial cells

migration

Capillary cell

inactivation

EGF

cleavage

exposed

capillary endothelial cells

EGF

stimulation

epidermal growth factor

proliferation

stimulation

epidermal growth factor

migration

dependent

matrix

proliferation

dependent

response

attaching

stimulated

migrate

exposed

cleavage

cleavage

CNBr

response

proliferative

EGF


Input:
Angiogenesis: initiation and control.

From in vivo experiments using new methods such as the rabbit cornea, it is now becoming clear that the growth of a capillary involves an ordered sequence of events that includes lysis of the basement membrane of a parent venule, directional migration of capillary endothelial cells toward the angiogenic stimulus, lumen formation, development of branches, and anastomosis of the tip of one tube with another to form a loop. It is also clear that diffusible angiogenic stimuli can be released not only from most solid tumors, but also from at least three non-neoplastic cells. These include activated macrophages, sensitized lymphocytes, and adipocytes. Other normal tissues can also stimulate angiogenesis, but the type of cell giving rise to the angiogenic stimulus is unknown, and the period of angiogenic stimulation is brief. With the recent ability to clone capillary endothelial cells and to carry them in long-term culture, it has been possible to further delineate the mechanism of capillary growth. In vitro studies have shown that the mast cell seems to behave as a helper cell for capillary endothelial cells, in some way speeding up their rate of directional migration. At this writing, heparin appears to be the principal mast cell factor responsible for this effect on capillary endothelial cells. One theoretical possibility is that mast cells may prepare the matrix, perhaps by slow release of heparin, so that capillary sprouts can more easily move through it toward their angiogenic target. While the study of angiogenesis as a phenomenon is still in an early phase, it has become possible, by using a combination of in vitro and in vivo techniques, to more thoroughly understand the initiation and control of capillary growth.

Angiogenesis

angiogenic

angiogenic

angiogenesis

angiogenic

angiogenic

angiogenic

capillary sprouts

angiogenesis

lysis

basement membrane

formation

lumen

development

branches

anastomosis

tube

prepare

matrix

growth

capillary

growth

capillary

growth

capillary

migration

capillary endothelial cells

migration

capillary endothelial cells

release

mast cells

heparin

move

capillary sprouts

clone

capillary endothelial cells

culture

capillary endothelial cells

initiation

Angiogenesis

activated

macrophages

stimulate

normal tissues

angiogenesis

stimulation

angiogenic

speeding up

mast cell

migration

initiation

growth

control

Angiogenesis

involves

growth

lysis

involves

growth

migration

involves

growth

formation

involves

growth

development

involves

growth

anastomosis

effect

capillary endothelial cells

control

growth


Input:
Protection from experimental ocular herpetic keratitis by a heat-killed virus vaccine.

New Zealand white rabbits were given limbal inoculations of a heat-killed suspension of herpes simplex virus (HSV) in a lysate of human embryonic kidney cells. At intervals of four to 14 days, the animals were challenged by intrastromal inoculation with 10,000 plaque-forming units of viable HSV. Epithelial keratitis, disciform edema, and necrotizing keratitis with neovascularization of the cornea developed in control animals. Epithelial keratitis and corneal edema also developed in the immunized animals during the first week after virus challenge, but these symptoms rapidly resolved during the following weeks. The absence of iritis, neovascularization, and necrotizing keratitis in the corneas of the immunized animals was particularly striking.

neovascularization

cornea

neovascularization

corneas

developed

cornea

developed

corneal edema

inoculations

New Zealand white rabbits

herpes simplex virus

inoculation

HSV


Input:
Molecular mediators of interactions with extracellular matrix components in metastasis and angiogenesis.

Metastasis and tumor angiogenesis are invasive phenomena and share many common properties at the physiological level and some similarities at the molecular level. Each consists of repetitive cycles of interaction with adjacent extracellular matrix components by mediating cellular adhesion, matrix dissolution, and cellular motility to achieve metastasis of cancer cells or neovascularization of tumors. Molecular factors which implement this triad of events are reviewed, as are several signal transduction components which may regulate them. Some potentially promising prognostic, diagnostic, and therapeutic modalities for tumor angiogenesis and metastatic disease are also discussed.

interactions

extracellular matrix components

interaction

extracellular matrix components

adhesion

cellular

angiogenesis

angiogenesis

tumor

neovascularization

tumors

angiogenesis

tumor

matrix dissolution

matrix

motility

cellular

metastasis

cancer cells

mediating

adhesion

mediating

matrix dissolution

mediating

motility

mediating

neovascularization


Input:
High density of somatostatin receptors in veins surrounding human cancer tissue: role in tumor-host interaction?

Somatostatin receptors were detected in peritumoral veins of various human cancer tissue specimens. Vascular and neoplastic tissue from 14 colonic adenocarcinomas, 13 carcinoids, 6 renal-cell carcinomas and 7 malignant lymphomas were analyzed for somatostatin receptors by use of quantitative receptor autoradiography. In colonic carcinoma specimens, the peritumoral vessels expressed a high density of somatostatin receptors, whereas the neoplastic tissue itself was receptor-negative in many cases. In contrast, the incidence and density of somatostatin receptors in peritumoral vessels was low in well-differentiated gastrointestinal and bronchial carcinoids, in contrast to the high density of such receptors in the carcinoid tumor tissue. Autochthonous vessels surrounding other tumors such as renal-cell carcinomas or malignant lymphomas also frequently expressed somatostatin receptors. In all cases, the somatostatin receptors were localized in veins, particularly in the smooth-muscle cell layer. They exhibited specific and high-affinity binding of somatostatin-14, somatostatin-28 and octreotide, suggesting a preferential expression of the SSTR2 receptor subtype. Since the vessels of normal non-neoplastic human tissues, e.g. of intestine or lymphatic organs, have few somatostatin receptors, the increased somatostatin receptor expression in peritumoral vessels observed in this study may be linked to the neoplastic process itself. The results suggest that somatostatin and somatostatin receptors may play a regulatory role for hemodynamic tumor-host interactions, possibly involving tumor stroma generation, tumor environment, angiogenesis and, particularly, vascular drainage of poorly differentiated neoplasms.

interaction

tumor

binding

somatostatin receptors

binding

somatostatin receptors

binding

somatostatin receptors

octreotide

interactions

tumor

angiogenesis

differentiated

gastrointestinal

differentiated

bronchial carcinoids

generation

tumor stroma

differentiated

neoplasms

expressed

somatostatin receptors

negative

somatostatin receptors

expressed

somatostatin receptors

expression

SSTR2 receptor

expression

somatostatin receptor

detected

Somatostatin receptors

veins

localized

somatostatin receptors

smooth-muscle cell

increased

expression

role

somatostatin receptors

interaction

play a regulatory role

somatostatin

interactions

play a regulatory role

somatostatin receptors

interactions

involving

somatostatin

generation

involving

somatostatin

angiogenesis

involving

somatostatin receptors

generation

involving

somatostatin receptors

angiogenesis