Input:
Adenovirus-mediated gene transfer of endostatin in vivo results in high level of transgene expression and inhibition of tumor growth and metastases.

Inhibition of angiogenesis has been shown to be an effective strategy in cancer therapy in mice. However, its widespread application has been hampered by difficulties in the large-scale production of the antiangiogenic proteins. This limitation may be resolved by in vivo delivery and expression of the antiangiogenic genes. We have constructed a recombinant adenovirus that expresses murine endostatin that is biologically active both in vitro, as determined in endothelial cell proliferation assays, and in vivo, by suppression of angiogenesis induced by vascular endothelial growth factor 165. Persistent high serum levels of endostatin (605-1740 ng/ml; mean, 936 ng/ml) were achieved after systemic administration of the vector to nude mice, which resulted in significant reduction of the growth rates and the volumes of JC breast carcinoma and Lewis lung carcinoma (P  less than  0.001 and P  less than  0.05, respectively). In addition, the endostatin vector treatment completely prevented the formation of pulmonary micrometastases in Lewis lung carcinoma (P = 0.0001). Immunohistochemical staining of the tumors demonstrated a decreased number of blood vessels in the treatment group versus the controls. In conclusion, the present study clearly demonstrates the potential of vector-mediated antiangiogenic gene therapy as a component in cancer therapy.

angiogenesis

angiogenic

angiogenic

angiogenesis

angiogenic

proliferation

endothelial cell

formation

pulmonary micrometastases

expression

endostatin

expresses

endostatin

growth

tumor

growth

JC breast carcinoma

growth

Lewis lung carcinoma

metastases

tumor

inhibition

growth

inhibition

metastases

Inhibition

angiogenesis

suppression

angiogenesis

reduction

growth

prevented

vector treatment

formation

decreased

blood vessels

gene transfer

endostatin

therapy

cancer

constructed

adenovirus

administration

nude mice

vector treatment

endostatin

therapy

cancer

mediated

Adenovirus

gene transfer

results

gene transfer

inhibition

results

gene transfer

expression

induced

angiogenesis

vascular endothelial growth factor 165

resulted

administration

reduction


Input:
Building the vertebrate vasculature: research is going swimmingly.

The vertebrate vasculature develops in remarkably similar fashion in all vertebrates. A cohort of unspecified mesodermal cells differentiates into primitive endothelial cells, which migrate to and occupy positions within the stereotypical blueprint of the primitive vasculature. Once in position, these cells coalesce and form cords, which lumenize and become ensheathed by supporting pericytes and smooth muscle cells. This primitive vascular network is extensively remodeled in some places, and expanded by sprouting in others. Various studies using the mouse, quail/chick, and frog have uncovered a number of signals that guide these complex processes but many gaps still exist in our understanding of the mechanisms by which the embryonic vasculature is built. Because many questions will require in vivo studies to be properly addressed, the zebrafish, with its unique accessibility to analysis by combined embryological, molecular, and genetic methods, should prove invaluable in identifying new molecules involved in blood vessel development and integrating pathways that influence embryonic blood vessel formation.

Building

vasculature

develops

vasculature

differentiates

mesodermal cells

form

cords

lumenize

cords

built

embryonic vasculature

development

blood vessel

formation

blood vessel

migrate

endothelial cells

coalesce

cells

ensheathed

cords

pericytes

ensheathed

cords

smooth muscle cells

remodeled

vascular network


Input:
A small peptide derived from Flt-1 (VEGFR-1) functions as an angiogenic inhibitor.

Vascular endothelial growth factor (VEGF) is an angiogenic stimulator which functions through two endothelial specific tyrosine kinase receptors, Flt-1 and Flk-1. In this work, we show that an 11-amino acid peptide derived from the second immunoglobulin-like domain of Flt-1 functions as an angiogenic inhibitor in chick chorioallantoic membrane and inhibited VEGF-induced vascular permeability in Miles' assay without binding to VEGF directly. Circular dichroism and nuclear magnetic resonance analyses indicate that this peptide forms a stable extended structure in solution, presumably beta-sheet structure and is most likely existing as a dimer. Our results suggest that this small peptide functions as an angiogenic inhibitor by inhibiting VEGF function through a non-VEGF binding mechanism.

binding

VEGF

binding

VEGF

angiogenic

angiogenic

angiogenic

angiogenic

inhibitor

angiogenic

inhibitor

angiogenic

inhibiting

VEGF

stimulator

angiogenic

functions

functions

Vascular endothelial growth factor

functions

Vascular endothelial growth factor


Input:
Coexpression of vascular endothelial growth factor and p53 protein in squamous cell carcinoma of the esophagus.

OBJECTIVE: p53 plays a role in tumor angiogenesis, and vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. The aim of the present study was to clarify how expression of p53 protein participates in angiogenesis, and whether the coexpression of VEGF and p53 protein has a significance for angiogenesis and the clinicopathological features in esophageal squamous cell carcinoma (SCC). METHODS: Tissues samples were taken from 60 patients with esophageal SCC after surgery. The expression of VEGF and p53 protein in these SCC was examined immunohistochemically. Microvessel density (MVD) was determined by counting microvessels in tumor sections stained for Factor VIII-related antigen. Ki-67 labeling index (LI) was calculated, based on Ki-67 antigen immunostaining, as a proliferative marker. Apoptotic index (AI) was calculated, based on the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling, to evaluate apoptosis. RESULTS: VEGF expression was observed in 58.3%, and p53 protein expression was observed in 61.7% of the 60 patients. VEGF and p53 protein were significantly coexpressed in 26 (43.4%). Histological venous invasion (p  less than  0.01) and distant metastasis (p  less than  0.05) were significantly correlated with p53 protein expression. The two parameters were more frequently observed in the SCC with VEGF/p53 coexpression than in those without the coexpression. The MVD and Ki-67 LI were significantly higher (p  less than  0.01 and p  less than  0.001), and the AI was significantly lower (p  less than  0.001) in the SCC with p53 protein expression than in the SCC without it. The MVD and Ki-67 LI were higher, and the AI was lower in the SCC with VEGF/p53 coexpression than in those without the coexpression. The 5-yr survival rate in patients with the coexpression was poorer than in the other patients. CONCLUSION: These results suggest that mutant p53 expression is associated with angiogenesis and distant metastasis in esophageal SCC, and that the coexpression of p53 and VEGF may play an important role in angiogenesis, and have important clinical significance.

angiogenesis

tumor

angiogenesis

tumor

angiogenesis

angiogenesis

angiogenesis

esophageal SCC

angiogenesis

Coexpression

vascular endothelial growth factor

expression

coexpression

VEGF

expression

VEGF

expression

expression

VEGF

expression

coexpressed

VEGF

expression

coexpression

VEGF

coexpression

VEGF

expression

coexpression

VEGF

coexpression

VEGF

coexpression

VEGF

expression

coexpression

VEGF

invasion

venous

taken

Tissues samples

surgery

patients

plays a role

angiogenesis

plays a key role

vascular endothelial growth factor

angiogenesis

participates

expression

angiogenesis

significance

coexpression

angiogenesis

significance

coexpression

esophageal squamous cell carcinoma

play an important role

coexpression

angiogenesis


Input:
Troponin I inhibits capillary endothelial cell proliferation by interaction with the cell's bFGF receptor.

Troponin I (TnI) is a novel cartilage-derived angiogenesis inhibitor, first demonstrated by Moses et al. (1999, Proc. Natl. Acad. Sci. USA 2645-2650) to inhibit endothelial cell proliferation and angiogenesis, both in vivo and in vitro, and to inhibit metastasis of a wide variety of tumors in vivo. Despite convincing evidence of its efficacy, little is known about the mechanism of action of TnI as an anti-proliferative and anti-angiogenic agent. In the current article we demonstrate that TnI inhibits both bFGF-stimulated and basal levels of endothelial cell proliferation, and we hypothesize that this inhibition is occurring, at least in part, via an interaction of TnI with the cell-surface bFGF receptor on capillary endothelial cells. We further support this hypothesis by providing the first evidence that TnI can act on nonendothelial as well as endothelial cells and by demonstrating that this inhibitory action is specific for the bFGF receptor on the target cells. Preliminary data suggest that TnI may be competing with bFGF for interaction with the bFGF receptor on responsive cells.

interaction

Troponin I

bFGF receptor

interaction

TnI

bFGF receptor

interaction

bFGF

bFGF receptor

angiogenesis

angiogenesis

angiogenic

proliferation

capillary endothelial cell

proliferation

endothelial cell

proliferation

endothelial cell

metastasis

tumors

inhibits

proliferation

interaction

inhibit

Troponin I

proliferation

inhibit

Troponin I

angiogenesis

inhibit

Troponin I

metastasis

inhibits

TnI

proliferation

inhibition

proliferation

interaction

inhibitory action

TnI

bFGF receptor

competing

TnI

interaction

stimulated

bFGF

proliferation

act

TnI

nonendothelial

act

TnI

endothelial cells


Input:
Clinical significance of plasma endostatin in acute myeloid leukemia/myelodysplastic syndrome.

BACKGROUND: Endostatin, a C-terminal fragment of collagen XVIII, is an endogenous angiogenesis inhibitor. While endostatin is being investigated for its usefulness in treating solid tumors, its significance in hematologic malignancies is unknown. METHODS: The authors evaluated plasma endostatin (PE) levels using an enzyme linked immunoassay in 71 patients with acute myeloid leukemia (AML) and 43 patients with myelodysplastic syndrome (MDS), and correlated PE with various clinical parameters. RESULTS: There was no significant difference in the median PE level between AML/MDS patients and the normal controls. Nevertheless, patients who achieved complete remission (CR) had a significantly lower median PE level compared to those who did not. In multivariate analysis, PE was found to be a significant (P = 0.03) predictor of overall survival (OS) with adjustment of the other baseline covariates, including patient age, history of antecedent hematologic disorders, and the use of protective environments. The prognostic value of PE was also evaluated by dividing MDS/AML patients into high and low PE groups using the median PE level of normal controls as the cut-off. The authors found that patients in the high PE group survived for a significantly shorter time than those patients in the low PE group. CONCLUSIONS: PE is a useful prognostic predictor of CR and OS for AML/MDS patients. The mechanism underlying the association between high PE and poor clinical outcome is unclear, although it may be related to the possible PE reflection of tumor burden.

angiogenesis

survived

patients

treating

endostatin

solid tumors

enzyme linked immunoassay

plasma endostatin


Input:
Modulation of angiogenesis and progelatinase a by thrombin receptor mimetics and antagonists.

The angiogenic action of thrombin has been shown to be mediated by activation of the thrombin receptor. In this report we studied the effects of SFLLR, an agonist of the activated thrombin receptor and thrombin receptor peptide and non peptide antagonists on angiogenesis in the chick chorioallantoic membrane (CAM) system. As antagonists were used the tripeptide FPR and non-peptide 1,4-disubstituted piperazine derivatives. The pentapeptide SFLLR, like thrombin, caused a marked stimulation of angiogenesis in the CAM. FPR and the piperazine derivatives caused suppression of angiogenesis and in combination with thrombin antagonized its angiogenic effect. Thrombin and SFLLR activated progelatinase A (MMP-2) in the culture medium of human umbilical cord endothelial cells (HUVECs). MMP-2 is involved in the early steps of angiogenesis leading to local dissolution of basement membrane collagen and migration of the activated endothelial cells. FPR and the piperazine derivatives inhibited the activation of this enzyme. They also antagonised the effects of both thrombin and SFLLR on MMP-2 activation. These results suggest that non-thrombogenic agonists or antagonists of the activated thrombin receptor can be used as modulators of angiogenesis.

angiogenesis

angiogenic

angiogenesis

chorioallantoic membrane

angiogenesis

CAM

angiogenesis

angiogenic

angiogenesis

angiogenesis

dissolution

basement membrane collagen

migration

endothelial cells

suppression

FPR

angiogenesis

suppression

piperazine derivatives

angiogenesis

antagonized

thrombin

angiogenic

inhibited

FPR

activation

inhibited

piperazine derivatives

activation

antagonised

FPR

effects

antagonised

piperazine derivatives

effects

activation

thrombin receptor

activated

thrombin receptor

stimulation

pentapeptide SFLLR

angiogenesis

stimulation

thrombin

angiogenesis

activated

Thrombin

progelatinase A

activated

SFLLR

progelatinase A

leading

dissolution

leading

migration

activated

endothelial cells

activation

activation

activated

thrombin receptor

Modulation

angiogenesis

thrombin receptor

Modulation

progelatinase a

thrombin receptor

mediated

thrombin

activation

effects

SFLLR

effects

thrombin

activation

effects

SFLLR

activation

modulators

angiogenesis


Input:
VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding.

Co-expression of NRP1 and (VEGFR-2) KDR on the surface of endothelial cells (EC) enhances VEGF165 binding to KDR and EC chemotaxis in response to VEGF165. Overexpression of NRP1 by prostate tumor cells in vivo results in increased tumor angiogenesis and growth. We investigated the molecular mechanisms underlying NRP1-mediated angiogenesis by analyzing the association of NRP1 and KDR. An intracellular complex containing NRP1 and KDR was immunoprecipitated from EC by anti-NRP1 antibodies only in the presence of VEGF165. In contrast, VEGF121, which does not bind to NRP1, did not support complex formation. Complexes containing VEGF165, NRP1, and KDR were also formed in an intercellular fashion by co-culture of EC expressing KDR only, with cells expressing NRP1 only, for example, breast carcinoma cells. VEGF165 also mediated the binding of a soluble NRP1 dimer to cells expressing KDR only, confirming the formation of such complexes. Furthermore, the formation of complexes containing KDR and NRP1 markedly increased 125I-VEGF165 binding to KDR. Our results suggest that formation of a ternary complex of VEGF165, KDR, and NRP1 potentiates VEGF165 binding to KDR. These complexes are formed on the surface of EC and in a juxtacrine manner via association of tumor cell NRP1 and EC KDR.

formation

binding

binding

KDR

association

KDR

bind

complex formation

KDR

formed

KDR

binding

cells

formation

KDR

binding

KDR

formation

KDR

binding

KDR

formed

KDR

formed

KDR

association

KDR

angiogenesis

tumor

angiogenesis

Co-expression

KDR

Overexpression

expressing

KDR

expressing

expressing

KDR

growth

tumor

chemotaxis

EC

co-culture

EC

cells

enhance

formation

binding

enhances

Co-expression

binding

enhances

Co-expression

chemotaxis

response

enhances

increased

Overexpression

angiogenesis

increased

Overexpression

growth

mediated

angiogenesis

support

complex formation

increased

formation

binding

potentiates

formation

binding

mediates

formation

mediated

binding


Input:
Hypoxic induction of HIF-1alpha and VEGF expression in head and neck squamous cell carcinoma lines is mediated by stress activated protein kinases.

Solid tumors must establish a blood supply in order to proliferate and grow. Cancer cells secrete soluble factors which can induce proliferation and migration of capillary endothelial cells. Among the most potent of the angiogenic factors is vascular endothelial growth factor (VEGF). Increased VEGF expression by malignant tumors has been associated with high vascularity, increased cancer cell growth, and lymph node metastasis. Reduced oxygen tension has been shown to increase VEGF production by induction of the transcription factor hypoxia inducible factor 1 alpha (HIF-1alpha). The mechanisms by which hypoxic tumor environments induce HIF-1alpha and VEGF expression are largely unknown. Jun N terminal kinase (JNK1) and p38 kinase are activated by a variety of stress stimuli. To determine if hypoxic activation of these stress activated protein kinases regulated HIF-1alpha and VEGF expression, we assayed JNK1 and p38 activity in squamous cell carcinoma (SCC) lines grown under normoxic or hypoxic conditions. Hypoxia rapidly induced both JNK1 and p38 activity in these cells. This activation correlated with induction of HIF-1alpha expression and DNA binding activity which was blocked by the p38 inhibitor SB203580. Hypoxia also increased VEGF production by SCC lines, which was inhibited by treatment with SB203580. Overexpression of JNK1 or p38 was sufficient to induce HIF-1alpha and VEGF expression. These results indicate that induction of SAPKs by hypoxia regulates HIF-1alpha and VEGF expression in head and neck carcinoma cell lines.

binding

angiogenic

proliferation

capillary endothelial cells

growth

cancer cell

expression

expression

VEGF

expression

VEGF

production

VEGF

expression

expression

VEGF

expression

expression

VEGF

expression

production

VEGF

Overexpression

Overexpression

expression

expression

VEGF

expression

expression

VEGF

proliferate

Solid tumors

grow

Solid tumors

migration

capillary endothelial cells

metastasis

tumors

lymph node

Reduced

oxygen

blocked

expression

blocked

binding

treatment

induction

expression

induce

proliferation

induce

migration

Increased

expression

increased

growth

increased

metastasis

increase

production

induction

induction

hypoxia inducible factor 1 alpha

induce

expression

activated

Jun N terminal kinase

activated

p38 kinase

induced

induced

activation

activation

induction

expression

induction

binding

increased

production

induce

expression

induction

SAPKs

mediated

induction

associated

expression

increased

regulated

expression

regulates

induction

expression


Input:
[Radiologic-pathologic correlations in breast diseases]

The objective of this article is to explain radiologic patterns of benign and malignant breast lesions (masses, microcalcifications) based on histological correlations. The stromal fibrous reaction associated to infiltrating carcinomas is responsible of focal increased density, and architectural distorsion, ultrasound acoustic shadowing; abnormal neoangiogenesis can be detected by Doppler, CT or MR imaging. Invasive carcinomas without spiculated margins are poorly differentiated tumors. Mammographic patterns of microcalcifications depend on their physiopathological process (necrosis, secretion), and the shape of clusters (round, triangular) typifies their anatomical site of origin (lobular, ductal). Less frequent lesions (invasive lobular, mucinous, and medullary carcinomas, radial scar) will be also explained based on radiopathological correlations. Knowledge of radiopathological correlations in breast diseases helps the radiologists to analyze and characterize breast lesions.

neoangiogenesis

differentiated

tumors

infiltrating

carcinomas

Invasive

carcinomas


Input:
Pten signaling in gliomas.

In 1997, the PTEN gene (phosphatase and tensin homolog deleted on chromosome 10) was identified as a tumor suppressor gene on the long arm of chromosome 10. Since then, important progress has been made with respect to the understanding of the role of the Pten protein in the normal development of the brain as well as in the molecular pathogenesis of human gliomas. This review summarizes the current state of the art concerning the involvement of aberrant Pten function in the development of different biologic features of malignant gliomas, such as loss of cell-cycle control and uncontrolled cell proliferation, escape from apoptosis, brain invasion, and aberrant neoangiogenesis. Most of the tumor-suppressive properties of Pten are dependent on its lipid phosphatase activity, which inhibits the phosphatidylinositol-3'-kinase (PI3K)/Akt signaling pathway through dephosphorylation of phosphatidylinositol-(3,4,5)-triphosphate. The additional function of Pten as a dual-specificity protein phosphatase may also play a role in glioma pathogenesis. Besides the wealth of data elucidating the functional roles of Pten, recent studies suggest a diagnostic significance of PTEN gene alterations as a molecular marker for poor prognosis in anaplastic astrocytomas and anaplastic oligodendrogliomas. Furthermore, the possibility of selective targeting of PTEN mutant tumor cells by specific pharmacologic inhibitors of members of the Pten/PI3K/Akt pathway opens up new perspectives for a targeted molecular therapy of malignant gliomas.

neoangiogenesis

malignant gliomas

proliferation

cell

apoptosis

cell

dephosphorylation

phosphatidylinositol-(3,4,5)-triphosphate

development

brain

development

malignant gliomas

invasion

malignant gliomas

brain

suppressor

PTEN

tumor

escape

malignant gliomas

apoptosis

inhibits

inhibits

signaling pathway

signaling

Pten

signaling pathway

Akt

pathway

Pten

Akt

selective targeting

PTEN mutant tumor cells

therapy

gliomas

role

Pten

development

role

Pten

gliomas

aberrant

Pten

uncontrolled

proliferation

aberrant

malignant gliomas

neoangiogenesis

dependent

Pten

inhibits

Pten

dephosphorylation

play a role

Pten

glioma

alterations

PTEN


Input:
Systemic regulation of distraction osteogenesis: a cascade of biochemical factors.

This study investigates the systemic biochemical regulation of fracture healing in distraction osteogenesis compared with rigid osteotomy in a prospective in vivo study in humans. To further clarify the influence of mechanical strain on the regulation of bone formation, bone growth factors (insulin-like growth factor [IGF] I, IGF binding protein [IGFBP] 3, transforming growth factor [TGF] beta1, and basic FGF [bFGF]), bone matrix degrading enzymes (matrix-metalloproteinases [MMPs] 1, 2, and 3), human growth hormone (hGH), and bone formation markers (ALP, bone-specific ALP [BAP], and osteocalcin [OC]) have been analyzed in serum samples from 10 patients in each group pre- and postoperatively. In the distraction group, a significant postoperative increase in MMP-1, bFGF, ALP, and BAP could be observed during the lengthening and the consolidation period when compared with the baseline levels. Osteotomy fracture healing without the traction stimulus failed to induce a corresponding increase in these factors. In addition, comparison of both groups revealed a significantly higher increase in TGF-beta1, IGF-I, IGFBP-3, and hGH in the lengthening group during the distraction period, indicating key regulatory functions in mechanotransduction. The time courses of changes in MMP-1, bone growth factors (TGF-beta1 and bFGF), and hGH, respectively, correlated significantly during the lengthening phase, indicating common regulatory pathways for these factors in distraction osteogenesis. Significant correlation between the osteoblastic marker BAP, TGF-beta1, and bFGF suggests strain-activated osteoblastic cells as a major source of systemically increased bone growth factors during callus distraction. The systemic increase in bFGF and MMP-1 might reflect an increased local stimulation of angiogenesis during distraction osteogenesis.

angiogenesis

formation

bone

increase

increase

bFGF

increase

ALP

increase

BAP

increase

increase

IGF-I

increase

increase

hGH

activated

osteoblastic cells

increase

bFGF

increase

increased

increase

stimulation

stimulation

angiogenesis

regulation

formation

changes

changes

changes

bFGF

changes

hGH


Input:
Antiangiogenic and antitumor effects of a protein kinase Cbeta inhibitor in human breast cancer and ovarian cancer xenografts.

In cell culture, the compound 317615 2HCl, a potent inhibitor of VEGF-stimulated HUVEC proliferation, was not very effective against MX-1 breast cancer cells (IC50= 8.1 microM) or SKOV-3 ovarian carcinoma cells (IC50 = 9.5 microM). Exposure to combinations of paclitaxel or carboplatin and 317615 x 2HCl with MX-1 cells in culture resulted in cell survival that reflected primarily additivity of the two agents. Exposure of SKOV-3 cells to paclitaxel or carboplatin along with 317615 2HCl resulted in cell survivals that reflected additivity of 317615 x 2HCl with paclitaxel and greater-than-additive cytotoxicity with carboplatin. Administration of 317615 x 2HCI orally twice daily to nude mice bearing subcutaneous MX-1 tumors or SKOV-3 tumors resulted in a decreased number of intratumoral vessels as determined by CD31 and CD105 staining with decreases of 35% and 43% in MX-1 tumors and 60% and 75% in SKOV-3 tumors, respectively. 317615 x 2HCl was an active antitumor agent against the MX-1 xenograft and increased the tumor growth delay produced by paclitaxel by 1.7-fold and the tumor growth delay produced by carboplatin by 3.8-fold. Administration of 317615 x 2HCl also increased the tumor growth delay produced by fractionated radiation therapy in the MX-1 tumor. Treatment with 317615 x 2HCl alone increased the lifespan of animals bearing intraperitoneal SKOV-3 xenografts by 1.9 fold compared with untreated control animals. The combination of paclitaxel and 317615 x 2HCl resulted in 100% 120-day survival of SKOV-3 bearing animals. Administration of 317615 x 2HCl along with carboplatin to animals bearing the SKOV-3 tumor produced a 1.8-fold increase in lifespan compared with carboplatin alone. 317615 x 2HCl is a promising new antiangiogenic agent that is in early phase clinical testing.

angiogenic

ovarian cancer xenografts

angiogenic

breast cancer

angiogenic

proliferation

HUVEC

survival

MX-1 cells

survivals

SKOV-3 cells

growth

tumor

growth

tumor

growth

tumor

effects

tumor

effects

angiogenic

inhibitor

317615 2HCl

proliferation

effective against

317615 2HCl

MX-1 breast cancer cells

effective against

317615 2HCl

SKOV-3 ovarian carcinoma cells

decreased

intratumoral vessels

against

317615 x 2HCl

MX-1 xenograft

delay

growth

paclitaxel

delay

growth

carboplatin

delay

growth

culture

cell

Exposure

paclitaxel

317615 x 2HCl

MX-1 cells

Exposure

carboplatin

317615 x 2HCl

MX-1 cells

Exposure

SKOV-3 cells

paclitaxel

317615 2HCl

Exposure

SKOV-3 cells

carboplatin

317615 2HCl

Administration

317615 x 2HCI

nude mice

Administration

317615 x 2HCl

Treatment

317615 x 2HCl

Administration

317615 x 2HCl

carboplatin

stimulated

VEGF

proliferation

resulted

Exposure

survival

resulted

Exposure

survivals

resulted

Administration

decreased

increased

317615 x 2HCl

delay

increased

317615 x 2HCl

delay

increased

Administration

delay


Input:
Fibroblast growth factor 2 promotes microvessel formation from mouse embryonic aorta.

To delineate the roles that oxygen and fibroblast growth factors (FGFs) play in the process of angiogenesis from the embryonic aorta, we cultured mouse embryonic aorta explants (thoracic level to lateral vessels supplying the mesonephros and metanephros) in a three-dimensional type I collagen gel matrix. During 8 days of culture under 5% O(2), but not room air, the addition of FGF2 to explants stimulated the formation of Gs-IB(4-)positive, CD31-positive, and Flk-1-positive microvessels in a concentration-dependent manner. FGF2-stimulated microvessel formation was inhibited by sequestration of FGF2 via addition of soluble FGF receptor (FGFR) chimera protein or anti-FGF2 antibodies. FGFR1 and FGFR2 were present on explants. Levels of FGFR1, but not FGFR2, were increased in embryonic aorta cultured under 5% O(2) relative to room air. Our data suggest that low oxygen upregulates FGFR1 expression in embryonic aorta in vitro and renders it more responsive to FGF2.

angiogenesis

embryonic aorta

formation

microvessel

formation

formation

formation

Flk-1-positive microvessels

formation

microvessel

expression

inhibited

formation

sequestration

sequestration

cultured

embryonic aorta

addition

addition

FGF receptor

addition

anti-FGF2 antibodies

cultured

embryonic aorta

promotes

Fibroblast growth factor 2

formation

stimulated

addition

formation

stimulated

formation

increased

increased

upregulates

oxygen

expression

play

oxygen

angiogenesis

play

fibroblast growth factors

angiogenesis

responsive

expression


Input:
Insulin-like growth factor-I receptor-mediated vasculogenesis/angiogenesis in human lung development.

The structural and functional development of the pulmonary system is dependent upon appropriate early vascularization of the embryonic lung. Our previous in vitro studies in a rat model indicated that insulin-like growth factor-I (IGF-I) is a potent angiogenic agent for fetal lung endothelial cells. To assess its role on human vascular lung development, we first examined the expression of IGF-I/II and IGF receptor type I (IGF-IR) in human embryonic and fetal lung tissues at 4-12 wk of gestation. Immunohistochemical and in situ hybridization studies revealed the presence of IGF-I/II-IGF-IR ligands and mRNA transcripts in embryonic lungs as early as 4 wk gestation. Immunotargeting using an anti-IGF-IR neutralizing antibody on human fetal lung explants demonstrated a significant blockade of IGF-IR signaling. Inactivation of IGF-IR resulted in a loss of endothelial cells, accompanied by dramatic changes in fetal lung explant morphology. Terminal transferase dUTP end-labeling assay and TEM studies of anti-IGF-IR-treated lungs demonstrated numerous apoptotic mesenchymal cells. Rat embryonic lung explant studies further validated the importance of the IGF-IGF-IR system for lung vascular development. These data provide the first demonstration of IGF-I/II expression in the human lung in early gestation and indicate that the IGF family of growth factors, acting through the IGF-IR, is required as a survival factor during normal human lung vascularization.

vasculogenesis

lung

angiogenesis

lung

vascularization

embryonic lung

angiogenic

vascularization

lung

apoptotic

mesenchymal cells

development

lung

development

pulmonary system

development

lung

development

lung vascular

expression

IGF-I

expression

II

expression

IGF receptor type I

presence

IGF-I

presence

II

presence

IGF-IR

expression

IGF-I

expression

II

blockade

signaling

Inactivation

IGF-IR

loss

endothelial cells

signaling

IGF-IR

system

IGF

IGF-IR

Immunotargeting

anti-IGF-IR neutralizing antibody

fetal lung explants

treated

anti-IGF-IR

lungs

dependent

development

vascularization

resulted

Inactivation

loss

importance

system

development

required

acting

vascularization

mediated

Insulin-like growth factor-I receptor

vasculogenesis

mediated

Insulin-like growth factor-I receptor

angiogenesis

changes

Inactivation

fetal lung

acting

IGF

IGF-IR

presence

IGF-I

presence

II

presence

IGF-IR


Input:
Enhanced expression of vascular endothelial growth factor by periodontal pathogens in gingival fibroblasts.

Vascular endothelial growth factor (VEGF) has recently attracted attention as a potent inducer of vascular permeability and angiogenesis. Aberrant angiogenesis is often associated with lesion formation in chronic periodontitis. The aim of the present study was to investigate the properties of VEGF expression in human gingival fibroblasts (HGF) culture. HGF were stimulated with lipopolysaccharide (LPS), vesicle (Ve) and outer membrane protein (OMP) from Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. HGF constitutively produced VEGF and levels were significantly enhanced (P  less than  0.01) by stimulation with Ve and OMP from A. actinomycetemcomitans and P. gingivalis at concentrations of 10 microg/ml or higher. On the other hand, VEGF levels were not increased by LPS stimulation. VEGF mRNA expression was also observed in Ve- and OMP-stimulated HGF. A vascular permeability enhancement (VPE) assay was performed using guinea pigs to ascertain whether supernatant from cultures of Ve- and OMP-stimulated HGF enhance vascular permeability in vivo. Supernatant from cultures of Ve- and OMP-stimulated HGF strongly induced VPE. This was markedly suppressed upon simultaneous injection of anti-VEGF polyclonal antibodies with the supernatant. Heating and protease treatment of the stimulants reduced the VEGF enhancing levels in Ve and OMP in vitro. These results suggest that Ve and OMP may be crucial heat-labile and protease-sensitive components of periodontal pathogens that enhance VEGF expression. In addition, VEGF might be associated with the etiology of periodontitis in its early stages according to neovascularization stimulated by periodontal pathogens causing swelling and edema.

angiogenesis

angiogenesis

neovascularization

formation

lesion

expression

vascular endothelial growth factor

expression

VEGF

produced

VEGF

expression

VEGF

reduced

enhancing

reduced

OMP

injection

anti-VEGF polyclonal antibodies

Enhanced

expression

inducer

Vascular endothelial growth factor

angiogenesis

stimulated

HGF

lipopolysaccharide

enhanced

produced

stimulation

stimulation

HGF

Ve

stimulation

HGF

OMP

increased

VEGF

stimulated

Ve

HGF

stimulated

OMP

HGF

enhancement

vascular

stimulated

Ve

HGF

stimulated

OMP

HGF

enhance

HGF

vascular

stimulated

Ve

HGF

stimulated

OMP

HGF

enhancing

VEGF

enhance

Ve

expression

enhance

OMP

expression

stimulated

neovascularization

Aberrant

angiogenesis

associated

Aberrant

formation

expression

VEGF


Input:
Combined topical fluconazole and corticosteroid treatment for experimental Candida albicans keratomycosis.

PURPOSE: To determine the most efficient time point and concentration of topical corticosteroids in Candida albicans keratitis treated with fluconazole. METHODS: Corneas of 105 rabbits were infected with viable yeast cells of C. albicans (2.5 x 10(5)). After a 48-hour incubation period, seven groups of animals were treated for 21 days with fluconazole, with group I acting as a control, and groups II to VII receiving adjunct therapy with the corticosteroid prednisolone (5 or 10 times daily; 3, 9, or 15 days after infection). The degree of corneal infiltration, ulceration, corneal clouding, hypopyon, conjunctivitis, neovascularization, and corneal perforation was monitored over a 24-day period, as well as recultivation and resistance to fluconazole of the C. albicans pathogen. RESULTS: The control group showed the highest level of corneal clouding and neovascularization. In comparison, by day 24, the majority of groups also treated with prednisolone displayed significantly less corneal clouding and neovascularization. An immediate decrease in corneal clouding was observed in groups treated with additional low- or high-dose prednisolone from day 9 after inoculation. After additional prednisolone treatment from day 9 or 15 after inoculation, no significant difference was detected in the recultivation rate of C. albicans compared with the control. Early administration of prednisolone (day 3, low and high dose) resulted in the recultivation of significantly more C. albicans. CONCLUSIONS: Fluconazole plus adjunct high-dose prednisolone treatment was most effective when administered 9 days after infection. The delayed application of corticosteroids after treatment with antimycotic drugs in cases of fungal keratitis is therefore not contraindicated and may be beneficial in patients.

neovascularization

neovascularization

neovascularization

infiltration

corneal

treatment

fluconazole

corticosteroid

treated

fluconazole

treated

fluconazole

therapy

prednisolone

treated

prednisolone

treated

prednisolone

treatment

prednisolone

administration

prednisolone

treatment

Fluconazole

prednisolone

application

corticosteroids

patients

treatment

antimycotic drugs

patients

recultivation

C. albicans

recultivation

C. albicans


Input:
Solid tumor therapy: manipulation of the vasculature with TNF.

Drug delivery to solid tumors is one of the most challenging aspects in cancer therapy. Whereas agents seem promising in the test tube, clinical trials often fail due to unfavorable pharmacokinetics, poor delivery, low local concentrations, and limited accumulation in the target cell. A major step forwards in the treatment of solid tumors is the recognition of the tumor-associated vasculature as an important target for therapy. Inhibition of tumor vascular development has a direct effect on the growth and progression of the tumor. Destruction of an existing vasculature also directly inflicts serious damage to the tumor cell. Moreover, the tumor vascular bed can be manipulated facilitating enhanced permissiveness of the tumor for administered chemotherapeutics. In this review, we focus on the use of tumor necrosis factor alpha (TNF) in local and systemic therapy in conjunction with chemotherapy. In these settings TNF demonstrates potent and selective activity on the tumor vascular bed, which strongly improves tumor response.

Destruction

vasculature

damage

tumor cell

development

tumor vascular

progression

tumor

growth

tumor

Inhibition

development

therapy

Solid tumor

treatment

solid tumors

administered

tumor

therapy

tumor necrosis factor alpha

inflicts

Destruction

damage

improves

TNF

tumor

manipulation

vasculature

TNF

effect

Inhibition

growth

effect

Inhibition

progression

manipulated

tumor vascular bed


Input:
Comparison of tissue integration between polyester and polypropylene prostheses in the preperitoneal space.

Tissue integration and implant characteristics of various biomaterials commonly used for inguinal hernia repair have not been studied extensively. The aim of this study is to compare behavior and tissue response between two new polyester prostheses and a commonly used polypropylene (PP) mesh. The polyester prostheses utilized were polyester flat (PF) and polyester soft three-dimensional (PS); the PP mesh utilized was Marlex. Eight randomly assigned 4 x 4-cm2 pieces of two different meshes were fixed in the preperitoneal space with a centrally placed single suture. Gross evaluation included shrinkage and stiffness. Histological evaluation included amount of fibrous and fat encapsulation, connective tissue, foreign-body reaction, neovascularization, hemorrhage, necrosis, and exudate. Evaluations were graded on a zero to four scale. The area and the area ratio were measured using a calibrated micrometer. PP mesh resulted in more fibrous encapsulation and stiffness than PF and PS prostheses. PP also resulted in less connective tissue formation and foreign-body reaction than PF and PS prostheses. There was no difference in fat encapsulation, necrosis, hemorrhage, or exudate between prostheses. Both polyester prostheses (PF and PS) have better tissue integration than the PP mesh, as evidenced by the higher amount of connective tissue and lower extent of fibrous encapsulation.

neovascularization

necrosis

connective tissue

necrosis

fat

formation

connective tissue

encapsulation

fibrous

encapsulation

fat

encapsulation

fibrous

encapsulation

fat

encapsulation

fibrous

resulted

encapsulation

resulted

formation


Input:
Therapeutic targeting of the survivin pathway in cancer: initiation of mitochondrial apoptosis and suppression of tumor-associated angiogenesis.

PURPOSE: Molecular antagonists of the inhibitor of apoptosis protein survivin have shown promise as novel anticancer strategies for triggering tumor cell apoptosis, dysregulating mitotic progression, and inhibiting tumor growth in preclinical models. However, how survivin couples to the cell death machinery has remained elusive, and the relevant cellular targets of survivin antagonists have not been completely elucidated. Experimental Design: Human umbilical vein and dermal microvascular endothelial cells were infected with replication-deficient adenoviruses encoding survivin (pAd-Survivin), green fluorescent protein (pAd-GFP), or a phosphorylation-defective survivin Thr(34)-->Ala (pAd-T34A) dominant negative mutant. The effect of wild-type or mutant survivin was investigated on capillary network stability, endothelial cell viability, and caspase activation in vitro and on kinetics of tumor growth and development of angiogenesis in a breast cancer xenograft model in vivo. The cell death pathway initiated by survivin targeting was mapped with respect to cytochrome c release, changes in mitochondrial transmembrane potential, and apoptosome requirements using mouse embryonic fibroblasts deficient in Apaf-1 or caspase-9. RESULTS: Adenoviral transduction of endothelial cells with pAd-Survivin inhibited growth factor deprivation- or ceramide-induced apoptosis, reduced caspase-3 and -7 generation, and stabilized three-dimensional capillary networks in vitro. Conversely, expression of pAd-T34A caused apoptosis in umbilical vein and dermal microvascular endothelial cells and resulted in caspase-3 activity. Cell death induced by survivin targeting exhibited the hallmarks of mitochondrial-dependent apoptosis with release of cytochrome c and loss of mitochondrial transmembrane potential and was suppressed in Apaf-1 or caspase-9 knockout mouse embryonic fibroblasts. When injected in human breast cancer xenografts, pAd-T34A inhibited growth of established tumors and triggered tumor cell apoptosis in vivo. This was associated with a approximately 60% reduction in tumor-derived blood vessels by quantitative morphometry of CD31-stained tumor areas, and appearance of endothelial cell apoptosis by internucleosomal DNA fragmentation in vivo. CONCLUSIONS: Survivin functions as a novel upstream regulator of mitochondrial-dependent apoptosis, and molecular targeting of this pathway results in anticancer activity via a dual mechanism of induction of tumor cell apoptosis and suppression of angiogenesis.

angiogenesis

tumor

angiogenesis

breast cancer xenograft

angiogenesis

apoptosis

tumor cell

death

cell

death

cell

apoptosis

umbilical vein

apoptosis

dermal microvascular endothelial cells

death

Cell

apoptosis

tumor cell

apoptosis

endothelial cell

apoptosis

tumor cell

deficient

deficient

generation

generation

expression

growth

tumor

growth

tumor

growth

tumors

release

cytochrome c

release

cytochrome c

suppression

angiogenesis

inhibiting

growth

reduced

transduction

generation

inhibited

growth

reduction

blood vessels

suppression

angiogenesis

pathway

survivin

infected

umbilical vein

adenoviruses

infected

dermal microvascular endothelial cells

adenoviruses

targeting

survivin

transduction

Adenoviral

endothelial cells

targeting

survivin

knockout

knockout

injected

breast cancer xenografts

triggering

apoptosis

activation

caspase

initiated

death

targeting

caused

expression

apoptosis

resulted

expression

induced

death

targeting

triggered

apoptosis

induction

apoptosis

targeting

pathway

effect

survivin

activation

effect

survivin

growth

effect

survivin

angiogenesis

effect

survivin

capillary network

effect

survivin

endothelial cell


Input:
CCL16 activates an angiogenic program in vascular endothelial cells.

Besides regulating leukocyte trafficking in normal and injured tissues, several chemokines may positively or negatively regulate angiogenesis. Here we report that CCL16 activates an angiogenic program in vascular endothelial cells by activating CCR1. CCL16 induces dose-dependent random and directional migration of endothelial cells isolated from large vessels and liver capillaries without inducing their proliferation. It also promotes endothelial differentiation into capillary-like structures in an in vitro assay and is angiogenic in the chick chorionallantoic membrane. These angiogenic activities are neutralized by a specific antibody against CCL16. The direct angiogenic activity of CCL16 is further amplified by its ability to prime endothelium to a mitogen signal induced by vascular endothelial growth factor A and to raise their basal production of CXCL8 and CCL2, 2 other angiogenic chemokines. BX471 (R-N-[5-chloro-2-[2-[4(4-fluorophenyl) methyl]-2-methyl-1-piperazinyl]-2-oxoethoxy]phenyl] urea hydrochloric acid salt), a CCR1 antagonist, inhibits angiogenic properties of CCL16, whereas blocking of CCR8 or desensitizing CCR2, which are both well known receptors for CCL16, did not abolish endothelial activation. CCL16 may be specifically cross-linked to CCR1 expressed on endothelial cells. The largely restricted CCL16 expression in the liver suggests that this chemokine may play a role in hepatic vascular formation during development and in angiogenesis associated to hepatic diseases.

angiogenic

angiogenesis

angiogenic

angiogenic

chorionallantoic membrane

angiogenic

angiogenic

angiogenic

angiogenic

angiogenesis

injured

tissues

proliferation

endothelial cells

differentiation

endothelial

formation

vascular

production

production

expressed

expression

trafficking

leukocyte

migration

endothelial cells

negatively regulate

angiogenesis

neutralized

angiogenic

inhibits

blocking

desensitizing

abolish

blocking

activation

abolish

desensitizing

activation

restricted

expression

activates

angiogenic

positively

angiogenesis

activates

angiogenic

activating

activating

induces

migration

inducing

proliferation

promotes

differentiation

raise

production

activation

endothelial

regulating

trafficking

may play a role

formation


Input:
Autocrine angiotensin system regulation of bovine aortic endothelial cell migration and plasminogen activator involves modulation of proto-oncogene pp60c-src expression.

Rapid endothelial cell migration and inhibition of thrombosis are critical for the resolution of denudation injuries to the vessel wall. Inhibition of the endothelial cell autocrine angiotensin system, with either the angiotensin-converting enzyme inhibitor lisinopril or the angiotensin II receptor antagonist sar1, ile8-angiotensin II, leads to increased endothelial cell migration and urokinase-like plasminogen activator (u-PA) activity (Bell, L., and J. A. Madri. 1990. Am. J. Pathol. 137:7-12). Inhibition of the autocrine angiotensin system with the converting-enzyme inhibitor or the receptor antagonist also leads to increased expression of the proto-oncogene c-src: pp60c-src mRNA increased 7-11-fold, c-src protein 3-fold, and c-src kinase activity 2-3-fold. Endothelial cell expression of c-src was constitutively elevated after stable infection with a retroviral vector containing the c-src coding sequence. Constitutively increased c-src kinase activity reconstituted the increases in migration and u-PA observed with angiotensin system interruption. Antisera to bovine u-PA blocked the increase in migration associated with increased c-src expression. These data suggest that increases in endothelial cell migration and plasminogen activator after angiotensin system inhibition are at least partially pp60c-src mediated. Elevated c-src expression with angiotensin system inhibition may act to enhance intimal wound closure and to reduce luminal thrombogenicity in vivo.

expression

expression

c-src

expression

c-src

expression

c-src

expression

c-src

migration

aortic endothelial cell

migration

endothelial cell

migration

endothelial cell

migration

endothelial cell

Inhibition

system

Inhibition

system

interruption

system

inhibition

system

inhibition

system

system

angiotensin

system

angiotensin

system

angiotensin

system

angiotensin

system

angiotensin

system

angiotensin

increased

lisinopril

migration

increased

lisinopril

urokinase-like plasminogen activator

increased

ile8-angiotensin II,

migration

increased

ile8-angiotensin II,

urokinase-like plasminogen activator

increased

expression

increased

increased

c-src

increased

c-src

elevated

expression

increased

c-src

increases

u-PA

increased

expression

increases

migration

increases

plasminogen activator

Elevated

expression

regulation

system

migration

modulation

plasminogen activator

expression

mediated

increases

mediated

inhibition


Input:
Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1.

Understanding molecular mechanisms regulating angiogenesis may lead to novel therapies for ischemic disorders. Hypoxia-inducible factor 1 (HIF-1) activates vascular endothelial growth factor (VEGF) gene expression in hypoxic/ischemic tissue. In this study we demonstrate that exposure of primary cultures of cardiac and vascular cells to hypoxia or AdCA5, an adenovirus encoding a constitutively active form of HIF-1alpha, modulates the expression of genes encoding the angiogenic factors angiopoietin-1 (ANGPT1), ANGPT2, placental growth factor, and platelet-derived growth factor-B. Loss-of-function effects were also observed in HIF-1alpha-null embryonic stem cells. Depending on the cell type, expression of ANGPT1 and ANGPT2 was either activated or repressed in response to hypoxia or AdCA5. In all cases, there was complete concordance between the effects of hypoxia and AdCA5. Injection of AdCA5 into mouse eyes induced neovascularization in multiple capillary beds, including those not responsive to VEGF alone. Analysis of gene expression revealed increased expression of ANGPT1, ANGPT2, platelet-derived growth factor-B, placental growth factor, and VEGF mRNA in AdCA5-injected eyes. These results indicate that HIF-1 functions as a master regulator of angiogenesis by controlling the expression of multiple angiogenic growth factors and that adenovirus-mediated expression of a constitutively active form of HIF-1alpha is sufficient to induce angiogenesis in nonischemic tissue of an adult animal.

angiogenic

angiogenesis

nonischemic tissue

angiogenesis

angiogenic

neovascularization

capillary beds

angiogenesis

angiogenic

angiogenesis

nonischemic tissue

expression

vascular endothelial growth factor

expression

expression

expression

placental growth factor

expression

platelet-derived growth factor-B

expression

expression

expression

repressed

expression

exposure

cardiac

exposure

vascular cells

Injection

eyes

injected

eyes

induction

angiogenesis

hypoxia-inducible factor 1

activates

Hypoxia-inducible factor 1

expression

activated

expression

induced

Injection

neovascularization

increased

expression

induce

angiogenesis

regulating

angiogenesis

modulates

exposure

expression

regulator

angiogenesis

controlling

controlling

expression

expression

expression

expression

platelet-derived growth factor-B

expression

placental growth factor

expression

VEGF


Input:
Differential regulation of in vivo angiogenesis by angiotensin II receptors.

Angiotensin II (ANG II), a key regulator of blood pressure and body fluid homeostasis, exerts mitogenic effects on endothelial cells. We therefore hypothesized that ANG II could be a mediator between homeostatic changes within the vascular perfusion bed and growth factor-driven angiogenesis. In the present study, we applied the alginate implant angiogenesis model in mice with normal ANG II levels, elevated ANG II levels by transgenic overexpression of angiotensinogen (AOGEN), or in AT2 receptor-deficient mice. We demonstrate that a decrease in the amount of circulating ANG II by the angiotensin-converting enzyme (ACE) inhibitor enalapril or the AT1 receptor antagonist losartan induced a stimulation of in vivo angiogenesis implying an inhibitory function of ANG II through the AT1 receptor. However, the strong increase of angiogenesis in AOGEN-transgenic mice compared with mice with normal ANG II levels suggests additional stimulatory activity. We showed that the ANG II-induced stimulation of angiogenesis is linked to the AT2 receptor as an impaired induction of angiogenesis was obtained in AT2 receptor knockout mice. These findings provide the first evidence that the AT2 receptor mediates a stimulation of in vivo angiogenesis and indicate that ANG II is a humoral regulator of peripheral angiogenesis involving two receptor subtypes with opposing actions.

angiogenesis

angiogenesis

angiogenesis

angiogenesis

angiogenesis

angiogenesis

angiogenesis

angiogenesis

angiogenesis

overexpression

angiotensinogen

deficient

AT2 receptor

knockout

AT2 receptor

decrease

ANG II

enalapril

impaired

induction

implant

alginate

mice

elevated

ANG II

overexpression

induced

losartan

stimulation

stimulation

angiogenesis

increase

angiogenesis

induced

ANG II

stimulation

stimulation

angiogenesis

induction

angiogenesis

stimulation

angiogenesis

regulation

angiogenesis

angiotensin II receptors

exerts mitogenic effects

Angiotensin II

endothelial cells

mediator

ANG II

changes

mediator

ANG II

angiogenesis

changes

vascular perfusion bed

mediates

AT2 receptor

stimulation


Input:
Levels of expression of CYR61 and CTGF are prognostic for tumor progression and survival of individuals with gliomas.

The biological properties of CCN proteins include stimulation of cell proliferation, migration, and adhesion, as well as angiogenesis and tumorigenesis. We quantified CYR61, CTGF, WISP-1, and NOV mRNA expression levels in samples from sixty-six primary gliomas and five normal brain samples using quantitative real-time PCR assay. Statistical analysis was performed to explore the links between expression of the CCN genes and clinical and pathological parameters. Overexpression of CYR61, CTGF, WISP-1, and NOV occurred in 48% (32 of 66), 58% (38 of 66), 36% (24 of 66), and 15% (10 of 66) of primary gliomas, respectively. Interestingly, significant associations were found between CYR61 expression versus tumor grade, pathology, gender, and age at diagnosis. Also, a significant correlation existed between CTGF mRNA levels versus tumor grade, gender, and pathology. In contrast to CYR61 and CTGF, no significant association was found between expression of either WISP-1 or NOV versus any of the pathological features. Furthermore, Cox regression analysis showed that CYR61 and CTGF expression had a significant correlation with patient survival. These results suggest that CYR61 and CTGF may play a role in the progression of gliomas; their levels at diagnosis may have prognostic significance; and these proteins might serve as valuable targets for therapeutic intervention.

adhesion

cell

angiogenesis

proliferation

cell

survival

individuals

survival

patient

progression

tumor

progression

gliomas

expression

expression

CTGF

expression

CCN

Overexpression

Overexpression

CTGF

Overexpression

Overexpression

NOV

expression

expression

expression

NOV

expression

CTGF

migration

cell

stimulation

CCN

proliferation

stimulation

CCN

migration

stimulation

CCN

adhesion

stimulation

CCN

angiogenesis

play a role

progression

play a role

CTGF

progression

expression

expression

CTGF

expression

expression

NOV


Input:
Oxidation in rheumatoid arthritis.

Oxygen metabolism has an important role in the pathogenesis of rheumatoid arthritis. Reactive oxygen species (ROS) produced in the course of cellular oxidative phosphorylation, and by activated phagocytic cells during oxidative bursts, exceed the physiological buffering capacity and result in oxidative stress. The excessive production of ROS can damage protein, lipids, nucleic acids, and matrix components. They also serve as important intracellular signaling molecules that amplify the synovial inflammatory-proliferative response. Repetitive cycles of hypoxia and reoxygenation associated with changes in synovial perfusion are postulated to activate hypoxia-inducible factor-1alpha and nuclear factor-kappaB, two key transcription factors that are regulated by changes in cellular oxygenation and cytokine stimulation, and that in turn orchestrate the expression of a spectrum of genes critical to the persistence of synovitis. An understanding of the complex interactions involved in these pathways might allow the development of novel therapeutic strategies for rheumatoid arthritis.

damage

matrix components

damage

lipids

damage

nucleic acids

metabolism

Oxygen

perfusion

synovial

activated

phagocytic cells

excessive

production

activate

hypoxia-inducible factor-1alpha

activate

nuclear factor-kappaB

regulated

hypoxia-inducible factor-1alpha

regulated

nuclear factor-kappaB

produced

Reactive oxygen species

production

ROS


Input:
Investigating the causes of low birth weight in contrasting ovine paradigms.

Intrauterine growth restriction (IUGR) still accounts for a large incidence of infant mortality and morbidity worldwide. Many of the circulatory and transport properties of the sheep placenta are similar to those of the human placenta and as such, the pregnant sheep offers an excellent model in which to study the development of IUGR. Two natural models of ovine IUGR are those of hyperthermic exposure during pregnancy, and adolescent overfeeding, also during pregnancy. Both models yield significantly reduced placental weights and an asymmetrically growth-restricted fetus, and display altered maternal hormone concentrations, indicative of an impaired trophoblast capacity. Additionally, impaired placental angiogenesis and uteroplacental blood flow appears to be an early defect in both the hyperthermic and adolescent paradigms. The effects of these alterations in placental functional development appear to be irreversible. IUGR fetuses are both hypoxic and hypoglycaemic, and have reduced insulin and insulin-like growth factor-1 (IGF-1), and elevated concentrations of lactate. However, fetal utilization of oxygen and glucose, on a weight basis, remain constant compared with control pregnancies. Maintained utilization of these substrates, in a substrate-deficient environment, suggests increased sensitivities to metabolic signals, which may play a role in the development of metabolic diseases in later adult life.

angiogenesis

placental

development

placental

growth

fetus

reduced

placental

restricted

growth

impaired

trophoblast

impaired

angiogenesis

reduced

insulin

reduced

insulin-like growth factor-1

elevated

lactate

effects

alterations

alterations

development


Input:
Randomized, open label, prospective study on the effect of zoledronic acid on the prevention of bone metastases in patients with recurrent solid tumors that did not present with bone metastases at baseline.

OBJECTIVES: Bisphosphonates have been used successfully in the treatment of hypercalcemia and to reduce skeletal-related complications of bone metastases. Recent in vitro and in vivo evidence suggest that they may also have direct antitumor effects via induction of apoptosis, inhibition of the invasive potential of tumor cell lines in vitro, inhibition of angiogenesis, and reduction in tumor growth indirectly via effects on accessory cells. This is a randomized, open label, prospective study that examined the effect of preventive zoledronic acid treatment on the development of bone metastases in patients with recurrent solid tumors, without bone metastases at the time of randomization. METHODS: Forty patients with recurrent or metastatic advanced cancer, without bone metastases, were randomized into the trial to either receive zoledronic acid or no treatment. Patients were followed up until bone metastases were established. RESULTS: The percentage of patients being bone metastases free at 12 mo was 60% in the zoledronic acid and 10% in the control group (p less than 0.0005), while the percentages at 18 mo were 20% and 5% respectively (p=0.0002). CONCLUSIONS: The results have shown that bisphosphonates as adjuvant treatment might be useful for the prevention of bone metastases; however, there is need for blinded randomized data before such an approach would be confirmed. In the meantime preventive use of bisphosphonates in patients without any bone metastases should not be used outside the scope of a clinical trial.

angiogenesis

development

bone metastases

growth

tumor

invasive

tumor cell lines

prevention

bone metastases

inhibition

invasive

inhibition

angiogenesis

reduction

growth

prevention

bone metastases

treatment

Bisphosphonates

bone metastases

treatment

zoledronic acid

receive

patients

zoledronic acid

treatment

patients

adjuvant treatment

bisphosphonates

preventive use

bisphosphonates

patients

effect

zoledronic acid

prevention

effect

treatment

development


Input:
Impaired coronary collateral vessel development in patients with proliferative diabetic retinopathy.

BACKGROUND: Diabetic patients have been reported to have impaired coronary collateral vessel growth, although they have excessive neovascularization in the retina. HYPOTHESIS: This study was designed to compare coronary collateral circulation (CCC) in patients with proliferative diabetic retinopathy (PDR) with that in patients without DR. METHODS: Ninety diabetic patients with chronic total occlusion in at least one major epicardial coronary artery were enrolled in the study. Groups 1 and 2 consisted of 48 patients without DR and 42 patients with PDR, respectively. Coronary collateral circulation (CCC) was analyzed according to the Rentrop system. Each group was also divided into two subgroups according to poor and good CCC. Serum vascular endothelial growth factor (VEGF) levels were measured using the enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: The mean Rentrop collateral score was higher in Group 1 than in Group 2 (2.39 +/- 1.07 vs. 1.76 +/- 0.76, respectively, p  less than  0.001). When the two groups were compared with respect to poor and good CCC, poor CCC was higher in patients with PDR (64 vs. 36%, respectively, p = 0.01). Serum VEGF levels were higher in patients with PDR than in those without DR (219 +/- 99 vs. 139 +/- 98 pg/ml, p  less than  0.001); however, patients with poor and good CCC had similar VEGF levels. CONCLUSIONS: We have shown that patients with PDR have a lower coronary collateral score than patients without DR. Also, serum VEGF was significantly higher in patients with PDR than in those without DR. These findings have suggested that diabetes mellitus may have a different action on retinal and coronary circulation.

neovascularization

retina

development

coronary collateral vessel

growth

coronary collateral vessel


Input:
Mechanisms of pericyte recruitment in tumour angiogenesis: a new role for metalloproteinases.

Pericytes occur in tumour blood vessels and are critical for the development of a functional vascular network. Targeting tumour pericytes is a promising anti-angiogenic therapy but requires identifying the mechanisms of their recruitment in tumour and addressing whether these mechanisms can be selectively harnessed. Among the pathways involved in pericyte recruitment during embryonic development, the contribution of platelet-derived growth factor B and sphingosine 1-phosphate is confirmed in tumour angiogenesis. The effect of angiopoietin 1 depends on the tumour model. Transforming growth factor-beta1 enhances tumour vascularization and microvessel maturation. Recent reports suggest a participation of matrix metalloproteinases (MMP) in tumour pericyte recruitment that is consistent with the effect of certain MMPs in the development of microvasculature in embryonic development and in in vitro models of vascular remodelling. Here, we discuss the possibility for MMPs to contribute to pericyte recruitment at six levels: (1) direct promotion of pericyte invasion by extracellular matrix degradation; (2) stimulation of pericyte proliferation and protection against apoptosis by modification of the ECM; (3) activation of pericytes through the release of growth factor bound to the ECM; (4) transactivation of angiogenic cell surface receptor; (5) propagation of angiogenic signalling as cofactor; and (6) recruitment of bone marrow-derived stem cells.

bound

ECM

angiogenesis

tumour

angiogenic

angiogenesis

tumour

vascularization

tumour

angiogenic

angiogenic

degradation

extracellular matrix

proliferation

pericyte

development

vascular network

maturation

microvessel

development

microvasculature

recruitment

pericyte

tumour

recruitment

tumour pericytes

tumour

recruitment

pericyte

recruitment

tumour pericyte

recruitment

pericyte

invasion

pericyte

recruitment

bone marrow-derived stem cells

therapy

angiogenic

Targeting

tumour pericytes

critical

Pericytes

development

enhances

Transforming growth factor-beta1

vascularization

enhances

Transforming growth factor-beta1

maturation

contribute

MMPs

recruitment

promotion

invasion

degradation

stimulation

proliferation

activation

pericytes

contribution

platelet-derived growth factor B

angiogenesis

contribution

sphingosine 1-phosphate

angiogenesis

participation

matrix metalloproteinases

recruitment

effect

MMPs

development

remodelling

vascular


Input:
Ectopic localization of mitochondrial ATP synthase: a target for anti-angiogenesis intervention?

A receptor for angiostatin was identified on the surface of endothelial cells as F(1)-F(0) ATP synthase (Moser et al., 1999). Proc. Natl. Acad. Sci. U.S.A. 96, 2811-2816. This ectopic ATP synthase catalyzes ATP synthesis and is inhibited by angiostatin over a wide pH range. Endothelial cells grown at normal pH suffer no ill effects from this angiostatin-mediated inhibition of ATP synthase, whereas endothelial cells grown at low, tumor-like extracellular pH cannot maintain a normal intracellular pH and die. Angiostatin inhibits both ATP synthesis and ATP hydrolysis (Moser et al., 2001) and interferes with intracellular pH regulation (Wahl and Grant, 2002; Wahl et al., 2002). Although angiostatin administered intravenously is cleared from the circulation in a matter of minutes, angiostatin-mimetics that are more stable have potential for clinical application. An angiostatin-mimetic activity has recently been observed using a polyclonal antibody against the beta catalytic subunit of ATP synthase. In order to explore the mechanism of action of angiostatin and its mimetics, further work needs to be done to evaluate clinical applicability, specificity, and contraindications for this class of therapeutics.

angiogenesis

hydrolysis

ATP

grown

Endothelial cells

grown

endothelial cells

localization

mitochondrial ATP synthase

identified

endothelial cells

F(1)-F(0) ATP synthase

intervention

angiogenesis

inhibited

catalyzes

angiostatin

inhibition

angiostatin

ATP synthase

inhibits

Angiostatin

synthesis

inhibits

Angiostatin

hydrolysis

administered

angiostatin

catalyzes

ATP synthase

synthesis

target

mitochondrial ATP synthase

intervention

synthesis

ATP

synthesis

ATP


Input:
Prostate-specific membrane antigen regulates angiogenesis by modulating integrin signal transduction.

The transmembrane peptidase prostate-specific membrane antigen (PSMA) is universally upregulated in the vasculature of solid tumors, but its functional role in tumor angiogenesis has not been investigated. Here we show that angiogenesis is severely impaired in PSMA-null animals and that this angiogenic defect occurs at the level of endothelial cell invasion through the extracellular matrix barrier. Because proteolytic degradation of the extracellular matrix is a critical component of endothelial invasion in angiogenesis, it is logical to assume that PSMA participates in matrix degradation. However, we demonstrate a novel and more complex role for PSMA in angiogenesis, where it is a principal component of a regulatory loop that is tightly modulating laminin-specific integrin signaling and GTPase-dependent, p21-activated kinase 1 (PAK-1) activity. We show that PSMA inhibition, knockdown, or deficiency decreases endothelial cell invasion in vitro via integrin and PAK, thus abrogating angiogenesis. Interestingly, the neutralization of beta(1) or the inactivation of PAK increases PSMA activity, suggesting that they negatively regulate PSMA. This negative regulation is mediated by the cytoskeleton as the disruption of interactions between the PSMA cytoplasmic tail and the anchor protein filamin A decreases PSMA activity, integrin function, and PAK activation. Finally, the inhibition of PAK activation enhances the PSMA/filamin A interaction and, thus, boosts PSMA activity. These data imply that PSMA participates in an autoregulatory loop, wherein active PSMA facilitates integrin signaling and PAK activation, leading to both productive invasion and downregulation of integrin beta(1) signaling via reduced PSMA activity. Therefore, we have identified a novel role for PSMA as a true molecular interface, integrating both extracellular and intracellular signals during angiogenesis.

interactions

PSMA

filamin A

interaction

PSMA

filamin A

angiogenesis

angiogenesis

tumor

angiogenesis

angiogenic

angiogenesis

angiogenesis

angiogenesis

angiogenesis

degradation

extracellular matrix

degradation

matrix

deficiency

PSMA

invasion

endothelial cell

invasion

endothelial

invasion

endothelial cell

impaired

angiogenesis

defect

angiogenic

inhibition

PSMA

decreases

decreases

invasion

abrogating

angiogenesis

neutralization

inactivation

PAK

negatively regulate

PSMA

negatively regulate

PAK

PSMA

negative regulation

PSMA

disruption

interactions

decreases

disruption

PSMA

decreases

disruption

integrin

decreases

disruption

activation

inhibition

activation

downregulation

signaling

reduced

PSMA

PSMA

signaling

integrin

signaling

integrin

signaling

integrin beta(1)

knockdown

PSMA

upregulated

prostate-specific membrane antigen

increases

neutralization

PSMA

increases

inactivation

PSMA

activation

PAK

activation

PAK

enhances

inhibition

interaction

enhances

inhibition

boosts

boosts

PSMA

facilitates

PSMA

signaling

facilitates

PSMA

activation

activation

PAK

leading

downregulation

reduced

regulates

angiogenesis

modulating

modulating

Prostate-specific membrane antigen

integrin

role

angiogenesis

participates

PSMA

degradation

role

PSMA

angiogenesis

modulating

PSMA

signaling

modulating

PSMA

p21-activated kinase 1

decreases

deficiency

integrin

decreases

deficiency

PAK

decreases

deficiency

abrogating

decreases

inhibition

integrin

decreases

inhibition

PAK

decreases

inhibition

abrogating

decreases

knockdown

integrin

decreases

knockdown

PAK

decreases

knockdown

abrogating

mediated

negative regulation

disruption

participates

PSMA

PSMA


Input:
Heparin immobilized porous PLGA microspheres for angiogenic growth factor delivery.

PURPOSE: Heparin immobilized porous poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres were prepared for sustained release of basic fibroblast growth factor (bFGF) to induce angiogenesis. MATERIALS AND METHODS: Porous PLGA microspheres having primary amine groups on the surface were prepared using an oil-in-water (O/W) single emulsion method using Pluronic F-127 as an extractable porogen. Heparin was surface immobilized via covalent conjugation. bFGF was loaded into the heparin functionalized (PLGA-heparin) microspheres by a simple dipping method. The bFGF loaded PLGA-heparin microspheres were tested for in vitro release and in vivo angiogenic activity. RESULTS: PLGA microspheres with an open-porous structure were formed. The amount of conjugated amine group onto the microspheres was 1.93+/-0.01 nmol/mg-microspheres, while the amount of heparin was 95.8 pmol/mg-microspheres. PLGA-heparin microspheres released out bFGF in a more sustained manner with a smaller extent of initial burst than PLGA microspheres, indicating that surface immobilized heparin controlled the release rate of bFGF. Subcutaneous implantation of bFGF loaded PLGA-heparin microspheres in mice significantly induced the formation of new vascular microvessels. CONCLUSIONS: PLGA microspheres with an open porous structure allowed significant amount of heparin immobilization and bFGF loading. bFGF loaded PLGA-HP microspheres showed sustained release profiles of bFGF in vitro, demonstrating reversible and specific binding of bFGF to immobilized heparin. They also induced local angiogenesis in vivo in an animal model.

binding

bFGF

heparin

angiogenic

angiogenesis

angiogenic

angiogenesis

formation

vascular microvessels

release

basic fibroblast growth factor

release

bFGF

released

bFGF

release

bFGF

release

bFGF

loaded

bFGF

loaded

bFGF

implantation

mice

loaded

bFGF

immobilization

heparin

loading

bFGF

loaded

bFGF

induce

release

angiogenesis

induced

implantation

formation

induced

angiogenesis

controlled

heparin

release


Input:
The role of syndecans in disease and wound healing.

Syndecans are a family of transmembrane heparan sulfate proteoglycans widely expressed in both developing and adult tissues. Until recently, their role in pathogenesis was largely unexplored. In this review, we discuss the reported involvement of syndecans in human cancers, infectious diseases, obesity, wound healing and angiogenesis. In some cancers, syndecan expression has been shown to regulate tumor cell function (e.g. proliferation, adhesion, and motility) and serve as a prognostic marker for tumor progression and patient survival. The ectodomains and heparan sulfate glycosaminoglycan chains of syndecans can also act as receptors/co-receptors for some bacterial and viral pathogens, mediating infection. In addition, syndecans bind to obesity-related factors and regulate their signaling, in turn modulating food consumption and weight balance. In vivo animal models of tissue injury and in vitro data also implicate syndecans in processes necessary for wound healing, including fibroblast and endothelial proliferation, cell motility, angiogenesis, and extracellular matrix organization. These new insights into the involvement of syndecans in disease and tissue repair coupled with the emergence of syndecan-specific molecular tools may lead to novel therapies for a variety of human diseases.

adhesion

tumor cell

bind

syndecans

angiogenesis

angiogenesis

injury

tissue

proliferation

tumor cell

proliferation

fibroblast

proliferation

endothelial

survival

patient

progression

tumor

organization

extracellular matrix

expressed

Syndecans

expression

syndecan

motility

tumor cell

motility

cell

necessary

syndecans

proliferation

necessary

syndecans

motility

necessary

syndecans

angiogenesis

necessary

syndecans

organization

regulate

expression

proliferation

regulate

expression

adhesion

regulate

expression

motility

repair

tissue


Input:
Role of the fibrinolytic and matrix metalloproteinase systems in development of adipose tissue.

Obesity is a common disorder and related diseases such as diabetes, atherosclerosis, hypertension, cardiovascular disease and cancer are a major cause of mortality and morbidity in Western-type societies. Development of obesity is associated with extensive modifications in adipose tissue involving adipogenesis, angiogenesis and extracellular matrix proteolysis. The fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems cooperate in these processes. A nutritionally induced obesity model in transgenic mice has been used extensively to study the role of the fibrinolytic and MMP systems in the development of obesity. These studies support a role of both systems in adipogenesis and obesity; the role of specific members of these families, however, remains to be determined.

angiogenesis

proteolysis

extracellular matrix

development

adipose tissue

fibrinolytic

systems

matrix metalloproteinase

fibrinolytic

plasminogen

plasmin

systems

matrix metalloproteinase

fibrinolytic

systems

MMP

transgenic

mice

Role

fibrinolytic

development

Role

systems

development

modifications

adipose tissue


Input:
Recombinant human prothrombin kringle-2 inhibits B16F10 melanoma metastasis through inhibition of neovascularization and reduction of matrix metalloproteinase expression.

Angiogenesis, a multi-step process which involves endothelial cell proliferation, adhesion, migration, and basement membrane (BM) degradation, is essential for tumor metastasis. Here we show that recombinant human prothrombin kringle-2 (rk-2) inhibited bovine capillary endothelial cell migration with an IC(50) (concentration for half maximal inhibition) of 38 nM and inhibited adhesion to extracellular matrix (ECM) proteins. Because tumor metastasis requires angiogenesis, we examined whether rk-2 could inhibit metastases induced by injection of B16F10 melanoma cells into mice. The results revealed that the metastatic tumors in mouse lung were markedly decreased in a dose-dependent manner and acute lung injury induced by B16F10 melanoma metastasis was diminished by systemic rk-2 treatment. In immunohistochemical analysis, rk-2 reduced expression of vascular endothelial growth factor, which is a potent angiogenic activator and neovascularization in the mouse lung. Also, rk-2 diminished the expression of matrix metalloproteinase-2 and -9 in the mouse lung which induces tumor metastasis and angiogenesis. These data suggest that inhibition of B16F10 melanoma metastasis by rk-2 was caused by inhibition of neovascularization and reduction of matrix metalloproteinase expression.

adhesion

endothelial cell

neovascularization

Angiogenesis

angiogenesis

angiogenic

neovascularization

angiogenesis

neovascularization

degradation

basement membrane

proliferation

endothelial cell

expression

matrix metalloproteinase

expression

vascular endothelial growth factor

expression

matrix metalloproteinase-2

expression

expression

matrix metalloproteinase

metastasis

B16F10 melanoma

migration

endothelial cell

metastasis

tumor

migration

capillary endothelial cell

metastasis

tumor

metastatic

tumors

lung

metastasis

B16F10 melanoma

metastasis

tumor

metastasis

B16F10 melanoma

inhibits

metastasis

inhibition

inhibition

prothrombin kringle-2

neovascularization

reduction

prothrombin kringle-2

expression

inhibited

prothrombin kringle-2

migration

inhibit

metastases

decreased

metastatic

reduced

expression

diminished

expression

inhibition

metastasis

inhibition

neovascularization

reduction

expression

injection

B16F10 melanoma cells

mice

treatment

essential

degradation

metastasis

requires

metastasis

angiogenesis

induced

metastases

injection

induces

diminished

metastasis

induces

diminished

angiogenesis

caused

inhibition

inhibition

caused

inhibition

reduction


Input:
Extracellular matrix as a bioactive material for soft tissue reconstruction.

The extracellular matrix (ECM) directs all phases of healing following trauma or disease and is therefore a natural source of prosthetic mesh material that can be used strategically to induce the repair and restoration of soft tissues following surgery. Biomaterials such as Surgisis (Cook Biotech Incorporated, West Lafayette, IN, USA), which are derived from natural ECM, provide the extracellular components necessary to direct the healing response, allow for the proliferation of new, healthy tissue and restore tissue integrity to the damaged site. The 3-D organization of these extracellular components distinguishes the Surgisis mesh from synthetic materials and is associated with constructive tissue remodelling instead of scar tissue. Common features of this ECM-assisted tissue remodelling include angiogenesis, recruitment of circulating progenitor cells and constructive remodelling of damaged tissue structures. The tissue response to this biologic mesh is discussed in the context of recent reports on clinical hernia repair.

angiogenesis

repair

soft tissues

restoration

soft tissues

proliferation

tissue

recruitment

progenitor cells

surgery

soft tissues

induce

repair

induce

restoration

assisted

ECM

remodelling

assisted

ECM

angiogenesis

assisted

ECM

recruitment

reconstruction

soft tissue

remodelling

tissue

remodelling

tissue

remodelling

tissue


Input:
[Study on the expression of angiogenesis and spontaneous apoptosis and their relevance in laryngeal squamous cell carcinoma]

OBJECTIVE: To investigate the relationship among angiogenesis, spontaneous apoptosis and clinicopathological parameters in laryngeal squamous cell carcinoma (LSCC). METHOD: The intratumor microvessel density (IMVD), apoptotic index (AI) and vascular endothelial growth factor (VEGF) expression were detected by immunohistochemistry SABC and terminal uridine deoxynucleotidyl transferase mediated nick end labeling(TUNEL) methods in34 LSCC patients. RESULT: The average IMVD was (21.50 +/- 8.87), and median of AI was 1.15%. The average IMVD in positive and negative cervical lymphatic metastasis was (26.33 +/- 9.70) and (17.68 +/- 6.06) respectively, and the IMVD with positive lymphatic metastasis tumors was statistical significantly higher than those with negative cervical lymphatic metastasis tumors (P  less than  0.01). The average IMVD had statistical difference in histological grading (P  less than  0.01), and analysis by one to one, the average IMVD had statistical difference between high and median grading. Expression of VEGF had a significantly positive correlation with IMVD (r = 0.51, P  less than  0.01). Statistical analysis revealed a significantly inverse correlation between AI and IMVD (r = -0.53, P  less than  0.01). We failed to find the statistical difference between IMVD and tumor T-stage in LSCC. CONCLUSION: IMVD may be an important indicator to predict cervical lymphatic metastasis in LSCC. VEGF might be an important angiogenic factor, and could promote tumor angiogenesis in LSCC. Tumor angiogenesis might contribute to tumor malignant progression by inhibiting spontaneous apoptosis in LSCC.

angiogenesis

laryngeal squamous cell carcinoma

angiogenesis

laryngeal squamous cell carcinoma

angiogenic

angiogenesis

LSCC

angiogenesis

Tumor

apoptosis

LSCC

progression

tumor

expression

vascular endothelial growth factor

Expression

VEGF

inhibiting

angiogenesis

apoptosis

promote

angiogenesis

contribute

progression

inhibiting


Input:
Pathological animal models in the experimental evaluation of tumour microvasculature with magnetic resonance imaging.

PURPOSE: The purpose of this study was to evaluate the applications of magnetic resonance imaging (MRI), and in particular, dynamic contrast-enhanced MRI (DCE-MRI), in the assessment of tumour microvasculature by means of animal tumour models evaluated before and after antiangiogenic treatment. MATERIALS AND METHODS: Forty-two MRI exams were performed with intravascular contrast media in 21 rats: tumours were induced by subcutaneous injection of colon carcinoma cells in 7 rats and mammary adenocarcinoma cells in 14 rats. Perfusion and permeability parameters of the implanted tumours were evaluated by using two contrast media (B22956/1 and Gd-DTPA37-albumin) to establish response to treatment with two different antiangiogenic drugs (tamoxifen and SU6668). These parameters were correlated with histology to obtain a radiological-histological map of tumour microvasculature. RESULTS: DCE-MRI revealed greater enhancement in the peripheral area than in the central area in all the examined animal models. In the mammary carcinoma experiment, vascular permeability measured by means of B22956/1 in the animals treated with the antiangiogenic drug (0.0043317+/-0.0040418 ml/min(-1)/ml(-1)) was significantly less than in untreated animals (0.0090460+/-0.0043680 ml/min(-1)/ml(-1)), whereas no significant difference was observed with Gd-DTPA-albumin (13.14+/-13.94 ml/min(-1)/ml(-1) in treated animals and 18.07+/-11.92 ml/min(-1)/ml(-1) in untreated animals). In the colon carcinoma experiment, mean permeability and perfusion decreased by 51% (from 5.2+/-1.1 to 2.5+/-0.8 ml/100 ml) and 59% (from 0.00165+/-5.1 to 0.0067+/-4.8 ml/min(-1)/ml(-1) of tissue), respectively, in all animals after antiangiogenic drug administration. CONCLUSIONS: DCE-MRI permits a noninvasive evaluation of tumour microcirculation and in particular of its dynamic characteristics and vascularity before and after antiangiogenic treatment.

angiogenic

angiogenic

angiogenic

angiogenic

angiogenic

treatment

tumour

subcutaneous injection

colon carcinoma cells

rats

subcutaneous injection

mammary adenocarcinoma cells

rats

implanted

tumours

treatment

tamoxifen

treatment

treated

Gd-DTPA-albumin

induced

tumours

subcutaneous injection


Input:
Angiogenesis in the caprine caruncles in non-pregnant and pregnant normal and swainsonine-treated does.

Microvascular corrosion casts of caruncles from non-pregnant and pregnant doe goats at 4, 7, 10, 13, 16, and 18 weeks were examined with scanning electron microscopy. The internal convex surface of the caruncles of non-pregnant does was covered with capillary meshes of regular diameter and form, without crypts. As pregnancy advanced the complexity of the vasculature increased: at 4 weeks the surface showed a pattern of ridges separated by troughs. At later stages, branches of radial arteries penetrated the periphery forming an extensive mesh of capillaries on the concave surface. Capillary diameters increased significantly during pregnancy, especially after 4 weeks, when large flattened sinusoids formed. These sinusoids had a great deal of surface area for potential contact with the fetal component. The caprine placenta is usually considered to have increased interhemal distance compared with endotheliochorial and hemochorial types: our results suggest that the very extensive development of sinusoids and crypts may compensate for any negative consequences of the placental architecture. Placental angiogenesis, which is physiologically normal, may serve as a general model of this process in other circumstances, such as tumor. The effect of swainsonine (active compound of locoweed and a potential anticancer drug) on vascular development showed no differences in sinusoidal diameters at 7 weeks, but a decrease in capillary density was noted. Swainsonine caused a great distortion to the vasculature at 18 weeks. The effects of this compound on the vascular development lend credibility to its potential as an anticancer agent.

Angiogenesis

caruncles

angiogenesis

Placental

diameters increased

Capillary

development

sinusoids

development

vascular

development

vascular

decrease

capillary

treated

swainsonine

does

effect

swainsonine

development

effects

Swainsonine

development


Input:
High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT-PCR mRNA expression profile.

Clear cell renal cell carcinoma (CC-RCC) is a highly vascularised tumour and is therefore an attractive disease to study angiogenesis and to test novel angiogenesis inhibitors in early clinical development. Endothelial cell proliferation plays a pivotal role in the process of angiogenesis. The aim of this study was to compare angiogenesis parameters in low nuclear grade (n=87) vs high nuclear grade CC-RCC (n=63). A panel of antibodies was used for immunohistochemistry: CD34/Ki-67, carbonic anhydrase IX, hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF). Vessel density (MVD - microvessel density), endothelial cell proliferation fraction (ECP%) and tumour cell proliferation fraction (TCP%) were assessed. mRNA expression levels of angiogenesis stimulators and inhibitors were determined by quantitative RT-PCR. High-grade CC-RCC showed a higher ECP% (P=0.049), a higher TCP% (P=0.009), a higher VEGF protein expression (P less than 0.001), a lower MVD (P less than  0.001) and a lower HIF-1alpha protein expression (P=0.002) than low-grade CC-RCC. Growth factor mRNA expression analyses revealed a higher expression of angiopoietin 2 in low-grade CC-RCC. Microvessel density and ECP% were inversely correlated (Rho=-0.26, P=0.001). Because of the imperfect association of nuclear grade and ECP% or MVD, CC-RCC was also grouped based on low/high MVD and ECP%. This analysis revealed a higher expression of vessel maturation and stabilisation factors (placental growth factor, PDGFB1, angiopoietin 1) in CC-RCC with high MVD, a group of CC-RCC highly enriched in low nuclear grade CC-RCC, with low ECP%. Our results suggest heterogeneity in angiogenic activity and vessel maturation of CC-RCC, to a large extent linked to nuclear grade, and, with probable therapeutic implications.

angiogenic

clear cell renal cell carcinoma

angiogenic

renal cell carcinoma

angiogenesis

angiogenesis

angiogenesis

angiogenesis

angiogenesis

angiogenic

CC-RCC

proliferation

Endothelial cell

proliferation

endothelial cell

proliferation

tumour cell

maturation

vessel

maturation

vessel

expression

VEGF

expression

expression

placental growth factor

expression

expression

angiopoietin 1

plays a pivotal role

proliferation

angiogenesis

expression

angiopoietin 2


Input:
The contribution of Harold F. Dvorak to the study of tumor angiogenesis and stroma generation mechanisms.

In 1983, Harold Dvorak and his colleagues were the first to show that tumor cells secreted vascular permeability factor (VPF) and that a blocking antibody to VPF could prevent the edema and fluid accumulation that is characteristic of human cancers. In 1986, Dvorak went on to demonstrate that VPF was secreted by a variety of human tumor cell lines and proposed that VPF was in part responsible for the abnormal vasculature seen in human tumors. As a result, he and other investigators demonstrated that VPF was capable of stimulating endothelial cell growth and angiogenesis. These fundamental discoveries led to additional research conducted by Napoleone Ferrara and his laboratory, confirming the cloning of VPF and renaming the protein vascular endothelial growth factor (VEGF). In 1986, Dvorak proposed that by secreting VPF, tumors induce angiogenesis by turning on the wound healing response. He noted that wounds, like tumors, secrete VPF, causing blood vessels to leak plasma fibrinogen, which stimulates blood vessel growth and provides a matrix on which they can spread. Unlike wounds, however, that turn off VPF production after healing, tumors did not turn off their VPF production and instead continued to make large amounts of VPF, allowing malignant cells to continue to induce new blood vessels and so to grow and spread. Thus, tumors behave like wounds that fail to heal. This work is again extremely significant for patients worldwide, as Dvorak's scientific research is leading his colleagues all over the world to examine how to treat a tumor through its blood supply.

angiogenesis

tumor

angiogenesis

angiogenesis

growth

endothelial cell

grow

malignant cells

generation

stroma

induce

blood vessels

production

VPF

production

VPF

make

VPF

growth

blood vessel

secreted

tumor cells

vascular permeability factor

secreted

VPF

tumor cell lines

secreting

VPF

tumors

secrete

VPF

leak

fibrinogen

spread

malignant cells

prevent

VPF

edema

turn off

production

turn off

tumors

production

treat

tumor

stimulating

VPF

growth

stimulating

VPF

angiogenesis

induce

tumors

angiogenesis

stimulates

leak

growth

induce

malignant cells

induce


Input:
Hedgehog signaling in the murine melanoma microenvironment.

The Hedgehog intercellular signaling pathway regulates cell proliferation and differentiation. This pathway has been implicated to play a role in the pathogenesis of cancer and in embryonic blood vessel development. In the current study, Hedgehog signaling in tumor related vasculature and microenvironment was examined using human umbilical vein endothelial cells and B16F0 (murine melanoma) tumors models. Use of exogenous Sonic hedgehog (Shh) peptide significantly increased BrdU incorporation in endothelial cells in vitro by a factor of 2 (P  less than  0.001). The Hedgehog pathway antagonist cyclopamine effectively reduced Shh-induced proliferation to control levels. To study Hedgehog signaling in vivo a hind limb tumor model with the B16F0 cell line was used. Treatment with 25 mg/kg cyclopamine significantly attenuated BrdU incorporation in tumor cells threefold (P  less than  0.001), in tumor related endothelial cells threefold (P = 0.004), and delayed tumor growth by 4 days. Immunohistochemistry revealed that the Hedgehog receptor Patched was localized to the tumor stroma and that B16F0 cells expressed Shh peptide. Furthermore, mouse embryonic fibroblasts required the presence of B16F0 cells to express Patched in a co-culture assay system. These studies indicate that Shh peptide produced by melanoma cells induces Patched expression in fibroblasts. To study tumor related angiogenesis a vascular window model was used to monitor tumor vascularity. Treatment with cyclopamine significantly attenuated vascular formation by a factor of 2.5 (P  less than  0.001) and altered vascular morphology. Furthermore, cyclopamine reduced tumor blood vessel permeability to FITC labeled dextran while having no effect on normal blood vessels. These studies suggest that Hedgehog signaling regulates melanoma related vascular formation and function.

angiogenesis

tumor

proliferation

cell

proliferation

endothelial cells

differentiation

cell

development

blood vessel

formation

vascular

formation

vascular

expressed

Shh

express

Patched

produced

Shh

expression

Patched

growth

tumor

incorporation

BrdU

endothelial cells

incorporation

BrdU

tumor cells

localized

Patched

tumor stroma

reduced

cyclopamine

proliferation

attenuated

Treatment

incorporation

delayed

growth

attenuated

Treatment

formation

signaling

Hedgehog

intercellular signaling pathway

Hedgehog

signaling

Hedgehog

pathway

Hedgehog

signaling

Hedgehog

signaling

Hedgehog

Treatment

cyclopamine

Treatment

cyclopamine

labeled

FITC

dextran

increased

Sonic hedgehog

incorporation

induced

Shh

proliferation

induces

Shh

expression

altered

Treatment

vascular

effect

cyclopamine

blood vessels

regulates

signaling

vascular

regulates

signaling

formation


Input:
CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration.

The role of retinal microglial cells (MCs) in age-related macular degeneration (AMD) is unclear. Here we demonstrated that all retinal MCs express CX3C chemokine receptor 1 (CX3CR1) and that homozygosity for the CX3CR1 M280 allele, which is associated with impaired cell migration, increases the risk of AMD. In humans with AMD, MCs accumulated in the subretinal space at sites of retinal degeneration and choroidal neovascularization (CNV). In CX3CR1-deficient mice, MCs accumulated subretinally with age and albino background and after laser impact preceding retinal degeneration. Raising the albino mice in the dark prevented both events. The appearance of lipid-bloated subretinal MCs was drusen-like on funduscopy of senescent mice, and CX3CR1-dependent MC accumulation was associated with an exacerbation of experimental CNV. These results show that CX3CR1-dependent accumulation of subretinal MCs evokes cardinal features of AMD. These findings reveal what we believe to be a novel pathogenic process with important implications for the development of new therapies for AMD.

neovascularization

CNV

CNV

degeneration

macular

degeneration

macular

degeneration

retinal

degeneration

retinal

accumulation

subretinal microglia cell

accumulated

MCs

accumulated

MCs

accumulation

MC

accumulation

subretinal MCs

express

CX3C chemokine receptor 1

migration

cell

impaired

migration

dependent

accumulation

dependent

accumulation

exacerbation

CNV

dependent

accumulation

associated

accumulation

degeneration

role

microglial cells

degeneration

associated

accumulation

exacerbation


Input:
[Clinical significance of interleukin-6 (IL-6) as a prognostic factor of cancer disease]

Interleukin-6 (IL-6) is proinflammatory cytokine that produces multifunctional effects. It is also involved in the regulation of immune reactions, hematopoiesis and inflammatory state. Interleukin-6 has been shown to be associated with tumor progression including inhibition of cancer cells apoptosis and stimulation of angiogenesis. Anti-IL-6 therapy is a new strategy in the inflammatory autoimmune diseases and cancer. Clinical studies have shown elevated serum IL-6 concentrations in patients with endometrial cancer, non-small cell lung carcinoma, colorectal cancer, renal cell carcinoma, breast and ovarian cancer. Serum IL-6 levels correlate with tumor stage, and survival of patients. In this article we have focused on a role of IL-6 as a prognostic factor in several malignancies such as colorectal cancer, breast cancer, gastric cancer and pancreatic cancer.

angiogenesis

apoptosis

cancer cells

survival

patients

progression

tumor

inhibition

apoptosis

therapy

cancer

stimulation

angiogenesis

elevated

associated

progression