Input:
Functional significance of VEGF-a in human ovarian carcinoma: role in vasculogenic mimicry.

Ovarian cancer is a silent killer, and shows early extensive tumor invasion and peritoneal metastasis. The microcirculation of most tumors includes cooperation of pre-existing vessels, intussusceptive microvascular growth, postnatal vasculogenesis, glomeruloid angiogenesis and vasculogenic mimicry (VM). VM is critical for a tumor blood supply and is asscociated with aggressive features and metastasis. Our studies highlight the plasticity of aggressive human ovarian carcinoma cells and call into question the underlying significance of their ability to form VM in vitro induced by VEGF-a. These studies also show their clinicalpathological features of the cancers with human Paraffin-embedded tumor tissue samples. Results show that the process: VEGF-a-- greater than EphA2-- greater than MMPs-- greater than VM is the main pathway for VM formation and VEGF-a appears to play an important role in the formation of VM based on our in vitro assays and clinical immunohistochemical analyses. VM-targeting strategies for ovarian cancer include anti-VEGF-a treatment, knocking down the EphA2 gene and using antibodies against human MMPs if the tumor is VM positive. This strategy may be of significant value in laying the foundation for a more explicit anti-tumor angiogenesis therapy.

vasculogenic mimicry

vasculogenesis

angiogenesis

vasculogenic mimicry

VM

VM

VM

VM

VM formation

formation of VM

VM

VM

tumor

angiogenesis

tumor

growth

microvascular

invasion

tumor

metastasis

tumor

peritoneal

therapy

tumor

pathway

VEGF-a

MMPs

treatment

anti-VEGF-a

knocking down

using

antibodies against human MMPs

induced

VM

VEGF-a

role

vasculogenic mimicry

play an important role

VEGF-a

formation of VM

targeting

VM


Input:
A novel role of thrombospondin-1 in cervical carcinogenesis: inhibit stroma reaction by inhibiting activated fibroblasts from invading cancer.

Thrombospondin (TSP)-1, a potent angiogenesis inhibitor, has been shown to exert different biological functions on various cell types. Here, we investigate the role of TSP-1 in tumor-stroma reaction, which is mainly characterized by fibroblast activation to create a permissive microenvironment for tumor progression. Immunohistochemistry examinations in the human surgical specimens have shown that a downregulation of TSP-1 during the progression of cervical carcinogenesis was accompanied by an emergence in the upregulation of stroma markers, alpha-smooth muscle actin (alpha-SMA) and desmin. Transfection of SiHa cervical cancer cells with a plasmid expressing the TSP-1 protein exhibited antiangiogenic activity in vitro and resulted in reduced tumor growth in severe combined immunodeficiency (SCID) mice, which was accompanied by a decrease in tumor vascularization and lower expressions of alpha-SMA and desmin than those in the vector controls. Transfection with TSP-1 and purified TSP-1 added to NIH3T3 cells did not alter the protein levels of alpha-SMA and desmin but significantly inhibited matrix metalloprotease-2 activity. Transforming growth factor-beta (TGF-beta), a major factor in the activation of fibroblasts, increased alpha-SMA and desmin expression and the ability of cell migration and invasion in NIH3T3 cells. The increased migration ability and the invasive ability into tumor cluster of TGF-beta-treated NIH3T3 cells were dose dependently inhibited by TSP-1. In contrast, ectopic TSP-1 expression in SiHa cells has little effect on the invasive ability of the NIH3T3 cells. Together, our findings demonstrate a novel role of TSP-1 to inhibit tumor-stroma reaction that could be attributed to the blockage of activated fibroblasts from invading cancer cells.

reaction

tumor

stroma

reaction

tumor

stroma

angiogenesis

angiogenic

vascularization

tumor

progression

tumor

expressing

expressions

alpha-SMA

expressions

desmin

expression

alpha-SMA

expression

desmin

expression

growth

tumor

invading

cancer

migration

NIH3T3 cells

invasion

NIH3T3 cells

migration

NIH3T3 cells

invasive

tumor

NIH3T3 cells

invasive

NIH3T3 cells

invading

fibroblasts

cancer cells

inhibit

stroma

inhibiting

inhibiting

activated

downregulation

activity

Transfection

angiogenic

reduced

growth

decrease

vascularization

inhibited

Transfection

matrix metalloprotease-2

inhibited

added

matrix metalloprotease-2

inhibited

migration

inhibited

invasive

inhibit

reaction

blockage

invading

Transfection

SiHa cervical cancer cells

Transfection

NIH3T3 cells

added

NIH3T3 cells

treated

TGF-beta

NIH3T3 cells

activated

fibroblasts

activation

fibroblast

upregulation

stroma markers

upregulation

alpha-smooth muscle actin

upregulation

desmin

resulted

Transfection

reduced

activation

Transforming growth factor-beta

fibroblasts

increased

Transforming growth factor-beta

expression

increased

Transforming growth factor-beta

migration

increased

Transforming growth factor-beta

invasion

increased

migration

activated

fibroblasts

role

reaction

alter

Transfection

alpha-SMA

alter

Transfection

desmin

alter

added

alpha-SMA

alter

added

desmin

effect

expression

invasive

role

inhibit


Input:
Management of early and advanced colorectal cancer: therapeutic issues.

PURPOSE: The staging of colorectal cancer, therapeutic decision making in the management of early and advanced colorectal cancer, and dilemmas posed by drug-related toxicity are discussed. SUMMARY: Staging of colorectal cancer occurs after surgery and is based on the extent of disease invasiveness and dissemination. Surgery is the primary treatment for stage I disease. Adjuvant chemotherapy is recommended after resection in selected high-risk patients with stage II disease and in all patients with stage III disease. Convenience of administration, tolerability, and patient factors not necessarily age may be considerations in decisions about adjuvant therapy after resection. Treatment of stage IV colorectal cancer is based on the type of prior therapy and patient-specific factors. Recently, significant improvements in survival have been achieved through the use of combination chemotherapy and monoclonal antibody regimens. Bevacizumab in combination with chemotherapy is first-line therapy for stage IV disease. Age alone should not preclude the use of chemotherapy in stage IV colorectal cancer, although the ability to tolerate drug-related toxicity may be a consideration. The optimal duration of chemotherapy in patients with early and metastatic colorectal cancer is unclear. CONCLUSION: The optimal approach to the treatment of colorectal cancer depends on several considerations, including patient-specific factors.

chemotherapy

patients

chemotherapy

patients

Treatment

colorectal cancer

chemotherapy

Bevacizumab

chemotherapy

colorectal cancer

chemotherapy

colorectal cancer

treatment

colorectal cancer

management

colorectal cancer


Input:
Serum and urine levels of interleukin-8 in patients with non-Hodgkin's lymphoma.

Angiogenesis plays an important role in many types of cancer. Interleukin-8 (IL-8) is known to be a pro-inflammatory and pro-angiogenic cytokine, and IL-8 has been reported to be associated with tumor progression, prognosis and survival in several types of cancers. However, the role of IL-8 in non-Hodgkin's lymphoma (NHL) has not been fully determined. Here, we evaluated the usefulness of measuring serum and urine IL-8 levels in patients with NHL. We developed reference intervals for serum and urine IL-8 level in 131 control individuals. We measured serum IL-8 and urine IL-8 levels in patients with NHL, and we compared the concentrations with those of control individuals. The reference intervals for serum IL-8 and urine IL-8 corrected by creatinine (Cr) were 15.9-430.3 pg/mL and 0.0-28.4 pg/mg Cr, respectively. The concentrations of urine IL-8/Cr were significantly higher in patients than in controls (48.9+/-194.4 vs. 5.2+/-13.8 pg/mg Cr, P less than 0.001). However, there were no significant differences in serum IL-8 concentrations between NHL patients and controls (159.2+/-40.4 vs. 99.6+/-107.1 pg/mL; P=0.099). Receiver operating characteristic (ROC) analysis gave 0.83 and 0.43 ROC area values for urine IL-8/Cr and serum IL-8, respectively. There was no correlation between the serum and urine concentrations of IL-8 and clinical variables, the only exception being the international prognostic index (IPI), which showed a marginal correlation with urine IL-8/Cr levels (P=0.07). This study indicated that urine IL-8/Cr levels might be useful as a diagnostic marker of NHL.

Angiogenesis

angiogenic

progression

tumor

plays an important role

Angiogenesis

cancer

associated

progression

role

non-Hodgkin's lymphoma


Input:
Microscopic technique for the detection of nitric oxide-dependent angiogenesis in an animal model.

Nitric oxide (NO) plays an important role in maintaining vascular homeostasis. The importance of NO in the vasculature is demonstrated by several experimental conditions, such as vascular endothelial growth factor (VEGF)-induced angiogenesis. Thus, the NO metabolic pathway in endothelial cells could be one of the main contributing factors for angiogenesis. Although several methods have been used for measuring in vitro angiogenesis, a proper technique has not been developed for identifying in vivo NO-dependent angiogenesis. This chapter provides a new intravital microscopic method for detecting and measuring NO-dependent angiogenesis in a mouse model. This technique showed strong abdominal neovascularization in wild-type mice, but not eNOS knockout mice, locally injected with VEGF, as well as stimulation of angiogenesis in NO donor-injected mice. This technique also revealed the inhibitory effect of the NOS inhibitor N(G)-iminoethyl-L-ornithine in VEGF-mediated in vivo angiogenesis. This chapter describes intravital microscopy as a new imaging technique for detecting NO-dependent angiogenesis in an animal model.

angiogenesis

angiogenesis

angiogenesis

angiogenesis

angiogenesis

angiogenesis

neovascularization

mice

neovascularization

eNOS knockout mice

angiogenesis

mice

angiogenesis

angiogenesis

inhibitory effect

N(G)-iminoethyl-L-ornithine

angiogenesis

metabolic pathway

NO

knockout

eNOS

injected

eNOS knockout mice

VEGF

injected

mice

dependent

nitric oxide

angiogenesis

induced

vascular endothelial growth factor

angiogenesis

dependent

NO

angiogenesis

dependent

NO

angiogenesis

stimulation

angiogenesis

mediated

VEGF

angiogenesis

dependent

NO

angiogenesis


Input:
Neurotrophin p75 receptor (p75NTR) promotes endothelial cell apoptosis and inhibits angiogenesis: implications for diabetes-induced impaired neovascularization in ischemic limb muscles.

Diabetes impairs endothelial function and reparative neovascularization. The p75 receptor of neurotrophins (p75(NTR)), which is scarcely present in healthy endothelial cells (ECs), becomes strongly expressed by capillary ECs after induction of peripheral ischemia in type-1 diabetic mice. Here, we show that gene transfer-induced p75(NTR) expression impairs the survival, proliferation, migration, and adhesion capacities of cultured ECs and endothelial progenitor cells (EPCs) and inhibits angiogenesis in vitro. Moreover, intramuscular p75(NTR) gene delivery impairs neovascularization and blood flow recovery in a mouse model of limb ischemia. These disturbed functions are associated with suppression of signaling mechanisms implicated in EC survival and angiogenesis. In fact, p75(NTR) depresses the VEGF-A/Akt/eNOS/NO pathway and additionally reduces the mRNA levels of ITGB1 [beta (1) integrin], BIRC5 (survivin), PTTG1 (securin) and VEZF1. Diabetic mice, which typically show impaired postischemic muscular neovascularization and blood perfusion recovery, have these defects corrected by intramuscular gene transfer of a dominant negative mutant form of p75(NTR). Collectively, our data newly demonstrate the antiangiogenic action of p75(NTR) and open new avenues for the therapeutic use of p75(NTR) inhibition to combat diabetes-induced microvascular liabilities.

adhesion

ECs

adhesion

endothelial progenitor cells

angiogenesis

neovascularization

limb muscles

neovascularization

angiogenesis

neovascularization

angiogenesis

neovascularization

angiogenic

proliferation

ECs

proliferation

endothelial progenitor cells

apoptosis

endothelial cell

survival

ECs

survival

endothelial progenitor cells

survival

EC

expressed

p75 receptor of neurotrophins

expression

migration

ECs

migration

endothelial progenitor cells

delivery

inhibits

Neurotrophin p75 receptor

angiogenesis

impaired

neovascularization

impairs

endothelial

impairs

expression

survival

impairs

expression

proliferation

impairs

expression

migration

impairs

expression

adhesion

inhibits

expression

angiogenesis

impairs

delivery

neovascularization

depresses

pathway

reduces

reduces

reduces

reduces

action

angiogenic

inhibition

pathway

VEGF-A

Akt

eNOS

NO

cultured

ECs

cultured

endothelial progenitor cells

promotes

Neurotrophin p75 receptor

apoptosis

induced

expression

induced

microvascular


Input:
Tumor endothelial cell targeted cyclic RGD-modified heparin derivative: inhibition of angiogenesis and tumor growth.

PURPOSE: We prepared tumor endothelium targeted cRGD-modified heparin derivative (cRGD-HL) by coupling heparin-lithocholic acid (HL) with cRGDyK, and evaluated inhibition effects of cRGD-HL on angiogenesis and tumor growth. METHODS: To evaluate antiangiogenic activity of cRGD-HL, we performed tests on endothelial cell adhesion and migration to vitronectin, tube formation, binding affinity to purified alpha(v)beta(3) integrin, and in vivo Matrigel plug assay. The antitumor activity of cRGD-HL was also evaluated by monitoring tumor growth and microvessel formation in squamous cell carcinoma (SCC7) tumor. RESULTS: The cRGD-HL significantly inhibited adhesion and migration of endothelial cells to vitronectin, and tubular structures of endothelial cells. Compared to cRGDyK and HL, cRGD-HL has high binding affinity to purified alpha(v)beta(3) integrin. The enhanced antiangiogenic effect of cRGD-HL was confirmed in Matrigel assay by showing the significant inhibition of bFGF-driven angiogenesis and blood vessel formation. It was thought that potent antiangiogenic effect of cRGD-HL was probably due to the interference of alpha(v)beta(3)-mediated interaction, resulting in the enhanced antitumoral activity against SCC7 tumor. CONCLUSION: These results demonstrated that cRGD-modified heparin derivative enhanced anti-angiotherapeutic effects against solid tumor, and therefore, it could be applied to treat various cancers and angiogenic diseases as a potent angiogenesis inhibitor.

adhesion

endothelial cell

vitronectin

binding

endothelial cell

alpha(v)beta(3) integrin

adhesion

endothelial cells

vitronectin

binding

cRGDyK

alpha(v)beta(3) integrin

binding

HL

alpha(v)beta(3) integrin

binding

cRGD-HL

alpha(v)beta(3) integrin

interaction

angiogenesis

angiogenesis

angiogenic

angiogenic

angiogenesis

angiogenic

angiotherapeutic

solid tumor

angiogenic

angiogenesis

formation

tube

formation

microvessel

formation

blood vessel

growth

tumor

growth

tumor

growth

tumor

migration

endothelial cell

migration

endothelial cells

inhibition

growth

inhibition

angiogenesis

inhibition

cRGD-HL

angiogenesis

inhibition

cRGD-HL

growth

activity

angiogenic

cRGD-HL

activity

tumor

cRGD-HL

inhibited

cRGD-HL

adhesion

inhibited

cRGD-HL

migration

inhibited

cRGD-HL

tubular structures

effect

angiogenic

cRGD-HL

inhibition

angiogenesis

inhibition

formation

effect

angiogenic

cRGD-HL

interference

interaction

enhanced

against

SCC7 tumor

effects

angiotherapeutic

targeted

Tumor endothelial cell

cyclic RGD-modified heparin derivative

targeted

tumor endothelium

cRGD-modified heparin derivative

heparin-lithocholic acid

cRGDyK

treat

cRGD-modified heparin derivative

cancers

enhanced

effect

driven

bFGF

angiogenesis

enhanced

cRGD-HL

against

enhanced

cRGD-modified heparin derivative

effects


Input:
[Inhibitory effect of adenovirus-mediated endostatin gene transfer on transplanted lung carcinoma in mice]

OBJECTIVE: To investigate the effect of adenovirus-mediated endostatin gene transfer on transplanted lung cancer in mice and its mechanism of action. METHODS: Transplant tumor model was induced by subcutaneous inoculation of 2 x 10(6) Lewis lung cancer (LLC) cells into the back of C57BL/6 mice. The mice were treated by intratumoral injection of 2 x 10(9) pfu Ad-mEndostatin. The expression of endostatin in situ and its maintaining time were detected by immunohistochemistry and Western Blot, respectively. The endostatin level in serum was determined by ELISA . The inhibition of tumor growth and changes of survival were recorded and the microvessel density (MVD) was determined by histochemical stainingwith CD31 and CD105 antibodies. The tumor apoptosis was observed by electron microscopy. RESULTS: In comparison with controls, intratumoral injection of Ad-mEndostatin significantly inhibited the tumor growth and metastasis, and prolonged the survival rate of mice (P  less than  0.05). Strong positive expression of mEndostatin was seen in the tumor tissue after injection of Ad-mEndostatin, immunhistochemically ostained by mouse endostatin monoclonal antibody, while the control groups showed only very low expression or absence. Serum endostatin concentration was 1540 +/- 560 ng/ml at the second week of administration, the expression of endostatin diminished a month later. The microvessel density (MVD)) decreased from 42.4 +/- 4.8 to 10.5 +/- 3.2 per x 200 magnificetion microscopic field by CD10 staining and from 68.5 +/- 4.5 to 37.5 +/- 4.6 by CD31 staining, respectively (P  less than  0.05). More apoptotic tumor cells were seen under the transmission electron microscope. CONCLUSION: Endostatin gene therapy mediated by adenoviral vector efficiently induces expression of endostatin in vivo, and inhibits the growth and metastasis of tumor. It is concluded that its action is targeted to tumor neovasculature and the mechanism is inhibition of tumor angiogenesis.

angiogenesis

tumor

apoptosis

tumor

survival

mice

apoptotic

tumor cells

expression

endostatin

expression

mEndostatin

expression

mEndostatin

absence

mEndostatin

expression

endostatin

expression

endostatin

growth

tumor

growth

tumor

growth

tumor

metastasis

tumor

metastasis

tumor

inhibition

growth

inhibited

intratumoral injection

growth

inhibited

intratumoral injection

metastasis

diminished

expression

decreased

microvessel

inhibits

gene therapy

growth

inhibits

gene therapy

metastasis

inhibition

Endostatin

angiogenesis

gene transfer

endostatin

lung carcinoma

transplanted

lung carcinoma

mice

gene transfer

endostatin

transplanted

lung cancer

mice

Transplant

tumor

subcutaneous inoculation

Lewis lung cancer (LLC) cells

mice

intratumoral injection

mice

Ad-mEndostatin

intratumoral injection

Ad-mEndostatin

injection

tumor tissue

Ad-mEndostatin

administration

endostatin

gene therapy

Endostatin

mediated

adenovirus

gene transfer

mediated

adenovirus

gene transfer

prolonged

intratumoral injection

survival

mediated

gene therapy

induces

gene therapy

expression

effect

gene transfer

lung cancer

action

Endostatin

tumor neovasculature


Input:
Diverse cell signaling events modulated by perlecan.

Perlecan is a ubiquitous pericellular proteoglycan ideally placed to mediate cell signaling events controlling migration, proliferation, and differentiation. Its control of growth factor signaling usually involves interactions with the heparan sulfate chains covalently coupled to the protein core's N-terminus. However, this modular protein core also binds with relatively high affinity to a number of growth factors and surface receptors, thereby stabilizing cell-matrix links. This review will focus on perlecan-growth factor interactions and describe recent advances in our understanding of this highly conserved proteoglycan during development, cancer growth, and angiogenesis. The pro-angiogenic capacities of perlecan that involve proliferative and migratory signals in response to bound growth factors will be explored, as well as the anti-angiogenic signals resulting from interactions between the C-terminal domain known as endorepellin and integrins that control adhesion of cells to the extracellular matrix. These two somewhat diametrically opposed roles will be discussed in light of new data emerging from various fields which converge on perlecan as a key regulator of cell growth and angiogenesis.

interactions

perlecan

bound

perlecan

interactions

endorepellin

integrins

adhesion

cells

extracellular matrix

angiogenesis

angiogenic

angiogenic

angiogenesis

growth

cell

growth

cancer

signals

angiogenic

resulting

signals

interactions

control

integrins

adhesion


Input:
[Retinochoroidopathy after intravitreal anti-VEGF treatment]

A 74-year-old man presented with persistent metamorphopsias of the right eye 2 weeks after intravitreal injection of bevacizumab to treat choroidal neovascularization due to exudative age-related macular degeneration. The diagnosis reached was retinochoroiditis as an occult manifestation of sarcoidosis, possibly resulting from an intravitreal injection of bevacizumab. The patient received a prescription for 100 mg Ultralan to be taken daily for 3 days and then tapered in 3 day steps. During the further course no deterioration of the condition was observed.

neovascularization

degeneration

macular

intravitreal injection

man

bevacizumab

treat

bevacizumab

neovascularization

intravitreal injection

bevacizumab

received

patient

Ultralan

due to

neovascularization

degeneration


Input:
Silencing of directional migration in roundabout4 knockdown endothelial cells.

BACKGROUND: Roundabouts are axon guidance molecules that have recently been identified to play a role in vascular guidance as well. In this study, we have investigated gene knockdown analysis of endothelial Robos, in particular roundabout 4 (robo4), the predominant Robo in endothelial cells using small interfering RNA technology in vitro. RESULTS: Robo1 and Robo4 knockdown cells display distinct activity in endothelial cell migration assay. The knockdown of robo4 abrogated the chemotactic response of endothelial cells to serum but enhanced a chemokinetic response to Slit2, while robo1 knockdown cells do not display chemotactic response to serum or VEGF. Robo4 knockdown endothelial cells unexpectedly show up regulation of Rho GTPases. Zebrafish Robo4 rescues both Rho GTPase homeostasis and serum reduced chemotaxis in robo4 knockdown cells. Robo1 and Robo4 interact and share molecules such as Slit2, Mena and Vilse, a Cdc42-GAP. In addition, this study mechanistically implicates IRSp53 in the signaling nexus between activated Cdc42 and Mena, both of which have previously been shown to be involved with Robo4 signaling in endothelial cells. CONCLUSION: This study identifies specific components of the Robo signaling apparatus that work together to guide directional migration of endothelial cells.

interact

guidance

vascular

migration

roundabout4 knockdown endothelial cells

migration

endothelial cell

chemotaxis

robo4 knockdown cells

migration

endothelial cells

abrogated

knockdown

response

reduced

serum

chemotaxis

signaling

signaling apparatus

Robo

knockdown

roundabout 4

small interfering RNA

Robo

endothelial cells

knockdown

enhanced

knockdown

response

up regulation

Rho GTPases

rescues

chemotaxis

activated

activated

Mena

play a role

Roundabouts

guidance

response

endothelial cells

serum

response

endothelial cells

response

robo1 knockdown cells

serum

response

robo1 knockdown cells

VEGF


Input:
p53 hot-spot mutants increase tumor vascularization via ROS-mediated activation of the HIF1/VEGF-A pathway.

The function of p53 tumor suppressor is often altered in various human tumors predominantly through missense-mutations resulting in accumulation of mutant proteins. We revealed that expression of p53 proteins with amino-acid substitutions at codons 175 (R175H), 248 (R248W), and 273 (R273H), representing the hot-spots of mutations in various human tumors, increased the number of vessels in HCT116 human colon carcinoma xenografts and, as a result, accelerated their growth. Stimulation of tumor angiogenesis was connected with about 2-fold increase in intracellular level of reactive oxygen species (ROS). Antioxidant N-acetyl-l-aspartate (NAC) decreased vessels number in tumors formed by cells with inactivated p53 and inhibited their growth. Effect of ROS on angiogenesis in tumors expressing hot-spot p53 mutants was correlated with their ability to increase a content of HIF1 transcriptional factor responsible for up-regulation of VEGF-A mRNAs.

vascularization

tumor

angiogenesis

tumor

angiogenesis

tumors

formed

tumors

expression

expressing

growth

HCT116 human colon carcinoma xenografts

growth

tumors

decreased

N-acetyl-l-aspartate

vessels

inactivated

N-acetyl-l-aspartate

inhibited

N-acetyl-l-aspartate

growth

pathway

VEGF-A

increase

vascularization

activation

mediated

ROS

activation

activation

pathway

increased

vessels

accelerated

increased

growth

Stimulation

angiogenesis

increase

reactive oxygen species

increase

up-regulation

VEGF-A

Effect

ROS

angiogenesis

responsible

up-regulation


Input:
Estradiol increases IL-8 secretion of normal human breast tissue and breast cancer in vivo.

IL-8 or CXCL8 has been associated with tumor angiogenesis, metastasis, and poor prognosis in breast cancer. Estrogen is crucial in breast carcinogenesis and tumor progression. Whether sex steroids affect IL-8 secretion of normal breast tissue or breast cancer is not known. Several cell types in a tissue secrete IL-8. Hence, regulatory mechanisms of IL-8 need to be investigated in whole tissue. We used microdialysis to sample IL-8 in normal human breast tissue in situ in pre- and postmenopausal women, preoperatively in breast cancers of women, and in experimental breast cancer in mice. We found a significant positive correlation between IL-8 and estradiol in normal breast tissue and hormone-dependent breast cancer in vivo. Ex vivo, estradiol exposure increased the IL-8 secretion of normal whole breast tissue in culture. In experimental breast cancer, estradiol increased IL-8 whereas the anti-estrogen tamoxifen inhibited the secretion of IL-8 both in vitro and extracellularly in vivo in tumors of nude mice. An anti-IL-8 Ab inhibited endothelial cell proliferation induced by cancer cell produced IL-8 and tumors with low IL-8 levels exhibited decreased angiogenesis. Our results strongly suggest that estradiol has a critical role in the regulation of IL-8 in normal human breast tissue and human breast cancer. IL-8 may present a novel therapeutic target for estrogen driven breast carcinogenesis and tumor progression.

angiogenesis

tumor

angiogenesis

proliferation

endothelial cell

progression

tumor

progression

tumor

produced

secretion

metastasis

tumor

secretion

secrete

secretion

secretion

inhibited

tamoxifen

secretion

inhibited

anti-IL-8 Ab

proliferation

decreased

angiogenesis

exposure

estradiol

culture

breast tissue

increases

Estradiol

secretion

crucial

Estrogen

progression

increased

exposure

secretion

increased

estradiol

secretion

induced

proliferation

associated

angiogenesis

associated

metastasis

associated

angiogenesis

associated

metastasis

affect

secretion

regulatory

critical role

estradiol

regulation

regulation

driven

estrogen

progression


Input:
Effect of estrogen and progesterone on macrophage activation during wound healing.

Age-related impaired wound healing leads to substantial morbidity and mortality along with a large financial burden to health services. There is accumulating evidence that the tissue damage associated with chronic wounds is initiated and propagated by an inappropriately excessive inflammatory response. Research on age-related impaired wound healing suggests that the decline in sex steroid hormones with age may have a substantial influence on the inflammatory response in vivo. Topical and systemic estrogen treatments have shown an increased rate of healing by reducing inflammation, however the underlying mechanisms are little understood. In vitro studies also suggest progesterone may play a role in modulating inflammation. Macrophages are essential mediators of inflammation and wound healing. Macrophages can be activated in a classical or alternative manner in parallel with the T(H)1/T(H)2 dichotomy, respectively. Using a murine incisional wound healing model this study was carried out to investigate the roles of estrogen and progesterone on macrophage activation during the wound healing response. Our findings suggest with a reduction of steroid hormones following ovariectomy, alternatively activated macrophage markers (Fizz1 and Ym1) were reduced, with this effect being reversed with the administration of estrogen or progesterone; suggesting that with the reduction of steroid hormones macrophages are activated in a classical manner, promoting inflammation, whereas estrogen or progesterone are contributing toward macrophage activation in an alternative manner, driving wound repair, angiogenesis, and remodeling.

angiogenesis

damage

tissue

reduction

steroid hormones

reduced

reduced

reversed

activated

administration

reduction

steroid hormones

treatments

estrogen

administration

estrogen

administration

progesterone

activation

macrophage

initiated

damage

activated

Macrophages

activation

macrophage

activated

activated

activated

reduction

macrophages

activation

macrophage

driving

estrogen

angiogenesis

driving

progesterone

angiogenesis

Effect

estrogen

activation

Effect

progesterone

activation

the roles of

estrogen

activation

the roles of

progesterone

activation

contributing

estrogen

activation

contributing

progesterone

activation


Input:
Effect of platelet-rich plasma and fibrin glue on healing of critical-size calvarial bone defects.

Despite the insufficient number of experimental studies, platelet-rich plasma (PRP) including high amounts of growth factors is introduced to clinical use rapidly. The aim of this study was to compare the effects of PRP and platelet-poor plasma (PPP) on healing of critical-size bone defects.Bilateral full-thickness, critical-size bone defects were created in the parietal bones of 32 rabbits, which had been studied in 4 groups. Saline, thrombin solution, PPP, and PRP were applied to the created defects before closure. Radiologic defect area measurement results at 0, 4, and 16 weeks were compared between the groups. In addition, densities of the newly formed bones at 16th week were studied. Histologic parameters (primary and secondary bone trabecula, neovascularization, and bone marrow and connective tissue formation) were compared between 4- and 16-week groups.More rapid decrease in defect size was observed in groups 3 and 4 than in groups 1 and 2, both in the 4th and 16th weeks. Newly formed bone densities were also found to be higher in these 2 groups. New bone formation was detected to be more rapid considering histologic parameters, in groups 3 and 4 at 4th and 16th weeks.Study demonstrates that PRP and PPP might have favorable effects on bone healing. Although we cannot reveal any statistical difference between these 2 substances considering osteoinductive potential, PRP group has demonstrated superior results compared with fibrin glue group. Higher platelet concentrations may expose beneficial effects of PRP.

neovascularization

formed

bones

formation

bone marrow

formation

connective tissue

formed

bone

formation

bone

applied

Saline

applied

thrombin

applied

PPP

applied

PRP

effects

PRP

bone

effects

platelet-poor plasma

bone

effects

PRP

bone

effects

PPP

bone


Input:
Host-derived angiopoietin-2 affects early stages of tumor development and vessel maturation but is dispensable for later stages of tumor growth.

The angiopoietin/Tie2 system has been identified as the second vascular-specific receptor tyrosine kinase system controlling vessel assembly, maturation, and quiescence. Angiopoietin-2 (Ang-2) is prominently up-regulated in the host-derived vasculature of most tumors, making it an attractive candidate for antiangiogenic intervention. Yet, the net outcome of Ang-2 functions on tumor angiogenesis is believed to be contextual depending on the local cytokine milieu. Correspondingly, Ang-2 manipulatory therapies have been shown to exert protumorigenic as well as antitumorigenic effects. To clarify the role of Ang-2 for angiogenesis and tumor growth in a definite genetic experimental setting, the present study was aimed at comparatively studying the growth of different tumors in wild-type and Ang-2-deficient mice. Lewis lung carcinomas, MT-ret melanomas, and B16F10 melanomas all grew slower in Ang-2-deficient mice. Yet, tumor growth in wild-type and Ang-2-deficient mice dissociated during early stages of tumor development, whereas tumor growth rates during later stages of primary tumor progression were similar. Analysis of the intratumoral vascular architecture revealed no major differences in microvessel density and perfusion characteristics. However, diameters of intratumoral microvessels were smaller in tumors grown in Ang-2-deficient mice, and the vasculature had an altered pattern of pericyte recruitment and maturation. Ang-2-deficient tumor vessels had higher pericyte coverage indices. Recruited pericytes were desmin and NG2 positive and predominately alpha-smooth muscle actin negative, indicative of a more mature pericyte phenotype. Collectively, the experiments define the role of Ang-2 during tumor angiogenesis and establish a better rationale for combination therapies involving Ang-2 manipulatory therapies.

angiogenic

angiogenesis

tumor

angiogenesis

angiogenesis

tumor

development

tumor

maturation

vessel

assembly

vessel

maturation

vessel

quiescence

vessel

development

tumor

progression

tumor

maturation

pericyte

deficient

deficient

deficient

deficient

deficient

growth

tumor

growth

tumor

growth

tumors

grew

B16F10 melanomas

grew

Lewis lung carcinomas

grew

MT-ret melanomas

growth

tumor

growth

tumor

grown

tumors

perfusion

microvessel

recruitment

pericyte

Recruited

pericytes

intervention

angiogenic

system

angiopoietin

up-regulated

affects

development

affects

maturation

dispensable

growth

controlling

system

assembly

controlling

system

maturation

controlling

system

quiescence

depending

role

angiogenesis

role

growth

role

angiogenesis


Input:
Short pigment epithelial-derived factor-derived peptide inhibits angiogenesis and tumor growth.

PURPOSE: Pigment epithelial-derived factor (PEDF) is a potent angiogenesis inhibitor with multiple other functions, some of which enhance tumor growth. Our previous studies mapped PEDF antiangiogenic and prosurvival activities to distinct epitopes. This study was aimed to determine the minimal fragment of PEDF, which maintains antiangiogenic and antitumor efficacy. EXPERIMENTAL DESIGN: We analyzed antigenicity, hydrophilicity, and charge distribution of the angioinhibitory epitope (the 34-mer) and designed three peptides covering its COOH terminus, P14, P18, and P23. We analyzed their ability to block endothelial cell chemotaxis and induce apoptosis in vitro and their antiangiogenic activity in vivo. The selected peptide was tested for the antitumor activity against mildly aggressive xenografted prostate carcinoma and highly aggressive renal cell carcinoma. To verify that P18 acts in the same manner as PEDF, we used immunohistochemistry to measure PEDF targets, vascular endothelial growth factor receptor 2, and CD95 ligand expression in P18-treated vasculature. RESULTS: P14 and P18 blocked endothelial cell chemotaxis; P18 and P23 induced apoptosis. P18 showed the highest IC50 and blocked angiogenesis in vivo: P23 was inactive and P14 was proangiogenic. P18 increased the production of CD95 ligand and reduced the expression of vascular endothelial growth factor receptor 2 by the endothelial cells in vivo. In tumor studies, P18 was more effective in blocking the angiogenesis and growth of the prostate cancer than parental 34-mer; in the renal cell carcinoma, P18 strongly decreased angiogenesis and halted the progression of established tumors. CONCLUSIONS: P18 is a novel and potent antiangiogenic biotherapeutic agent that has potential to be developed for the treatment of prostate and renal cancer.

angiogenesis

angiogenesis

angiogenic

angiogenic

angioinhibitory

angiogenic

angiogenesis

angiogenic

angiogenesis

prostate cancer

angiogenesis

renal cell carcinoma

angiogenesis

tumors

angiogenic

apoptosis

endothelial cell

apoptosis

endothelial cell

expression

PEDF targets

expression

vascular endothelial growth factor receptor 2

expression

CD95 ligand

production

CD95 ligand

expression

vascular endothelial growth factor receptor 2

growth

tumor

growth

tumor

growth

prostate cancer

growth

renal cell carcinoma

chemotaxis

endothelial cell

chemotaxis

endothelial cell

inhibits

Short pigment epithelial-derived factor-derived peptide

angiogenesis

inhibits

Short pigment epithelial-derived factor-derived peptide

growth

activities

PEDF

angiogenic

efficacy

PEDF

angiogenic

efficacy

PEDF

tumor

block

chemotaxis

block

chemotaxis

block

chemotaxis

activity

angiogenic

activity

angiogenic

activity

angiogenic

activity

prostate carcinoma

activity

renal cell carcinoma

blocked

chemotaxis

blocked

chemotaxis

blocked

angiogenesis

inactive

reduced

expression

blocking

angiogenesis

blocking

growth

decreased

angiogenesis

halted

progression

xenografted

prostate carcinoma

treated

vasculature

treatment

prostate

treatment

renal cancer

enhance

growth

induce

apoptosis

induce

apoptosis

induce

apoptosis

induced

apoptosis

induced

apoptosis

increased

production

progression

tumors


Input:
Distinct role of PLCbeta3 in VEGF-mediated directional migration and vascular sprouting.

Endothelial cell proliferation and migration is essential to angiogenesis. Typically, proliferation and chemotaxis of endothelial cells is driven by growth factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). VEGF activates phospholipases (PLCs) - specifically PLCgamma1 - that are important for tubulogenesis, differentiation and DNA synthesis. However, we show here that VEGF, specifically through VEGFR2, induces phosphorylation of two serine residues on PLCbeta3, and this was confirmed in an ex vivo embryoid body model. Knockdown of PLCbeta3 in HUVEC cells affects IP3 production, actin reorganization, migration and proliferation; whereas migration is inhibited, proliferation is enhanced. Our data suggest that enhanced proliferation is precipitated by an accelerated cell cycle, and decreased migration by an inability to activate CDC42. Given that PLCbeta3 is typically known as an effector of heterotrimeric G-proteins, our data demonstrate a unique crosstalk between the G-protein and receptor tyrosine kinase (RTK) axes and reveal a novel molecular mechanism of VEGF signaling and, thus, angiogenesis.

angiogenesis

tubulogenesis

angiogenesis

proliferation

Endothelial cell

proliferation

endothelial cells

proliferation

HUVEC cells

proliferation

HUVEC cells

sprouting

vascular

production

migration

Endothelial cell

chemotaxis

endothelial cells

migration

HUVEC cells

migration

HUVEC cells

inhibited

Knockdown

migration

signaling

VEGF

phosphorylation

two serine residues

Knockdown

essential

proliferation

angiogenesis

essential

migration

angiogenesis

activates

VEGF

important

activates

tubulogenesis

induces

induces

phosphorylation

enhanced

Knockdown

proliferation

activate

mediated

VEGF

sprouting

driven

proliferation

vascular endothelial growth factor

driven

chemotaxis

vascular endothelial growth factor

driven

proliferation

basic fibroblast growth factor

driven

chemotaxis

basic fibroblast growth factor

induces

VEGF

affects

Knockdown

production

affects

Knockdown

reorganization

affects

Knockdown

migration

affects

Knockdown

proliferation

reorganization

actin


Input:
Antivascular actions of microtubule-binding drugs.

Microtubule-binding drugs (MBD) are widely used in cancer chemotherapy and also have clinically relevant antiangiogenic and vascular-disrupting properties. These antivascular actions are due in part to direct effects on endothelial cells, and all MBDs (both microtubule-stabilizing and microtubule-destabilizing) inhibit endothelial cell proliferation, migration, and tube formation in vitro, actions that are thought to correspond to therapeutic antiangiogenic actions. In addition, the microtubule-destabilizing agents cause prominent changes in endothelial cell morphology, an action associated with rapid vascular collapse in vivo. The effects on endothelial cells occur in vitro at low drug concentrations, which do not affect microtubule gross morphology, do not cause microtubule bundling or microtubule loss and do not induce cell cycle arrest, apoptosis, or cell death. Rather, it has been hypothesized that, at low concentrations, MBDs produce more subtle effects on microtubule dynamics, block critical cell signaling pathways, and prevent the microtubules from properly interacting with transient subcellular assemblies (focal adhesions and adherens junctions) whose subsequent stabilization and/or maturation are required for cell motility and cell-cell interactions. This review will focus on recent studies to define the molecular mechanisms for the antivascular actions of the MBDs, information that could be useful in the identification or design of agents whose actions more selectively target the tumor vasculature.

interacting

microtubules

interactions

cell

cell

angiogenic

angiogenic

disrupting

vascular

collapse

vascular

loss

microtubule

stabilization

focal adhesions

stabilization

adherens junctions

proliferation

endothelial cell

apoptosis

cell

death

cell

formation

tube

bundling

microtubule

maturation

focal adhesions

maturation

adherens junctions

migration

endothelial cell

motility

e

actions

vascular

microtubule-binding drugs

properties

Microtubule-binding drugs

angiogenic

actions

vascular

effects

inhibit

MBDs

proliferation

inhibit

MBDs

migration

inhibit

MBDs

formation

prevent

MBDs

interacting

actions

vascular

MBDs

chemotherapy

cancer

actions

MBDs

angiogenic

required

stabilization

motility

required

stabilization

interactions

required

maturation

motility

required

maturation

interactions

effects

endothelial cells

cause

microtubule-destabilizing agents

changes

changes

endothelial cell

associated

microtubule-destabilizing agents

collapse

effects

endothelial cells

affect

microtubule

cause

bundling

cause

loss

effects

MBDs

microtubule

target

MBDs

tumor vasculature


Input:
Neurovascular effects of CD47 signaling: promotion of cell death, inflammation, and suppression of angiogenesis in brain endothelial cells in vitro.

The concept of the neurovascular unit emphasizes that common signals and substrates underlie the physiology and pathophysiology of neuronal and endothelial compartments in brain. Recent data suggest that activation of the integrin-associated protein CD47 promotes neuronal cell death. Is it possible that CD47 may also negatively affect cerebral endothelial cells? Exposure of wild-type primary mouse cerebral endothelial cells to the CD47 ligand thrombospondin 1 (TSP-1) induced an increasing amount of cell death, whereas cytotoxicity was significantly decreased in cerebral endothelial cells derived from CD47 knockout mice. The specific CD47-activating peptide, 4N1K, similarly induced cell death in human brain microvascular endothelial cells. Promotion of inflammation was also involved because lower TSP-1 was able to up-regulate the adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Finally, CD47 signaling may suppress angiogenesis because 4N1K significantly inhibited endothelial cell migration and tube formation in vitro. We conclude that CD47 signaling can negatively affect the viability and function of cerebral endothelial cells, further supporting the notion that CD47 may be a potential neurovascular target for stroke and brain injury.

associated

integrin

angiogenesis

angiogenesis

injury

brain

death

cell

death

neuronal cell

death

cell

cell death

brain microvascular endothelial cells

formation

tube

migration

endothelial cell

suppression

signaling

angiogenesis

negatively affect

cerebral endothelial cells

suppress

signaling

angiogenesis

inhibited

migration

inhibited

formation

negatively affect

signaling

cerebral endothelial cells

signaling

signaling

signaling

Exposure

cerebral endothelial cells

thrombospondin 1

knockout

promotion

signaling

death

activation

promotes

activation

death

induced

Exposure

death

activating

induced

cell death

up-regulate

intercellular adhesion molecule-1

up-regulate

vascular cell adhesion molecule-1


Input:
Cisplatin reduces endothelial cell migration via regulation of type 2-matrix metalloproteinase activity.

AIMS: In this study we investigated the effect of cisplatin on endothelial cell migration, an essential process for vascular remodeling and regeneration in several physiological and pathological situations. MATERIAL AND METHODS: Human umbilical vein endothelial cells (HUVEC) were treated with cisplatin and endothelial cell migration analyzed by fluorescence and scratch-wound migration assay. MMP2 and MMP9 activity were determined by zymographic assay, and MAPK activation by Western blotting analysis. RESULTS: We demonstrated that cisplatin provoked a time- and dose-dependent decrease of HUVEC migration; this effect was clearly independent from its well known cytotoxic activity. In addition, cisplatin markedly reduced MMP2 activity in both conditioned media and cell lysates, increased p38 MAPK and JNK phosphorylation, but did not affect ERK phosphorylation. Endothelial cell migration was attenuated by treatment of cells with GM6001, a non-specific inhibitor of MMPs, or by a selective anti-MMP2 antibody. However, treatment of cells with SB202190 or SP600125, inhibitors of p38 MAPK and JNK respectively, did not affect HUVEC migration. CONCLUSION: These results suggested that cisplatin induced a reduction of endothelial cell migration through an inhibition of MMP2 activity by downstream signal transduction pathways independent of JNK and p38 MAPK activation.

regeneration

vascular

migration

endothelial cell

migration

endothelial cell

migration

endothelial cell

migration

HUVEC

migration

Endothelial cell

migration

HUVEC

migration

endothelial cell

reduces

migration

regulation

decrease

migration

reduced

cisplatin

attenuated

migration

treatment

attenuated

migration

selective anti-MMP2 antibody

reduction

migration

inhibition

cisplatin

phosphorylation

p38 MAPK

phosphorylation

JNK

phosphorylation

ERK

treated

Human umbilical vein endothelial cells

cisplatin

treatment

cells

treatment

treatment

essential

migration

remodeling

essential

migration

regeneration

activation

MAPK

provoked

cisplatin

decrease

increased

cisplatin

phosphorylation

induced

reduction

inhibition

activation

cisplatin

JNK

activation

cisplatin

p38 MAPK

regulation

Cisplatin

type 2-matrix metalloproteinase

effect

cisplatin

migration

affect

cisplatin

phosphorylation

affect

treatment

migration

independent

reduction

activation

remodeling

vascular


Input:
The modulation of platelet and endothelial cell adhesion to vascular graft materials by perlecan.

Controlled neo-endothelialisation is critical to the patency of small diameter vascular grafts. Endothelialisation and platelet adhesion to purified endothelial cell-derived perlecan, the major heparan sulfate (HS) proteoglycan in basement membranes, were investigated using in vivo and in vitro assays. Expanded polytetrafluoroethylene (ePTFE) vascular grafts were coated with perlecan and tested in an ovine carotid interposition model for a period of 6 weeks and assessed using light and scanning microscopy. Enhanced endothelial cell growth and reduced platelet adhesion were observed on the perlecan coated grafts when compared to uncoated controls implanted in the same sheep (n=5). Perlecan was also found to stimulate endothelial cell proliferation in vitro over a period of 6 days in the presence of plasma proteins and fibroblastic growth factor 2 (FGF-2), however in the absence of FGF-2 endothelial cell growth could not be maintained during this period. Perlecan was found to be anti-adhesive for platelets, however after removal of the HS chains attached to perlecan, platelet adhesion and aggregation were supported. These results suggest a role for HS chains of perlecan in improving graft patency by selectively promoting endothelial cell proliferation while modulating platelet adhesion.

adhesion

platelet

adhesion

endothelial cell

adhesion

platelet

adhesion

platelet

anti-adhesive

Perlecan

platelets

adhesion

platelet

aggregation

platelet

adhesion

platelet

neo-endothelialisation

Endothelialisation

growth

endothelial cell

proliferation

endothelial cell

growth

endothelial cell

proliferation

endothelial cell

presence

fibroblastic growth factor 2

absence

reduced

adhesion

coated

perlecan

coated

perlecan

uncoated

perlecan

implanted

sheep

Enhanced

growth

stimulate

Perlecan

proliferation

promoting

perlecan

proliferation

modulation

adhesion

perlecan

Controlled

neo-endothelialisation

modulating

adhesion


Input:
Tumour angiogenesis: its mechanism and therapeutic implications in malignant gliomas.

Angiogenesis is a key event in the progression of malignant gliomas. The presence of microvascular proliferation leads to the histological diagnosis of glioblastoma multiforme. Tumour angiogenesis involves multiple cellular processes including endothelial cell proliferation, migration, reorganisation of extracellular matrix and tube formation. These processes are regulated by numerous pro-angiogenic and anti-angiogenic growth factors. Angiogenesis inhibitors have been developed to interrupt the angiogenic process at the growth factor, receptor tyrosine kinase and intracellular kinase levels. Other anti-angiogenic therapies alter the immune response and endogeneous angiogenesis inhibitor levels. Most anti-angiogenic therapies for malignant gliomas are in Phase I/II trials and only modest efficacies are reported for monotherapies. The greatest potential for angiogenesis inhibitors may lie in their ability to combine safely with chemotherapy and radiotherapy.

angiogenesis

Tumour

Angiogenesis

angiogenesis

Tumour

angiogenic

angiogenic

Angiogenesis

angiogenic

angiogenic

angiogenesis

angiogenic

gliomas

angiogenesis

proliferation

endothelial cell

progression

gliomas

proliferation

microvascular

formation

tube

migration

endothelial cell

therapies

angiogenic

therapies

angiogenic

involves

angiogenesis

proliferation

involves

angiogenesis

migration

involves

angiogenesis

reorganisation

involves

angiogenesis

formation

reorganisation

extracellular matrix


Input:
Regulation of thrombospondin-1 by natural and synthetic progestins in human breast cancer cells.

Our recent studies show that progestins induce vascular endothelial growth factor (VEGF) in breast cancer cells that express mutant p53 protein. Here, we show that natural and synthetic progestins also induce thrombospondin-1 (TSP-1) mRNA and protein in T47-D and BT-474 breast cancer cells. Antiprogestin RU-486 inhibits the induction of VEGF and TSP-1 by progestins, suggesting that this effect of progestin is mediated by the progesterone receptor (PR). Actinomycin-D, but not puromycin, also blocks progestin-dependent induction of TSP-1. A putative progestin-response element was identified in the human TSP-1 promoter, which is consistent with the hypothesis that a progestin-PR complex might directly regulate transcription of the TSP-1 gene in human cells. Conditioned medium from progestin-treated breast cancer cells stimulates endothelial cell proliferation in the absence though not in the presence of antibody to TSP-1, indicating that TSP-1 secreted by breast cancer cells could be pro-angiogenic. Since tumor cell-derived TSP-1 has the potential to promote angiogenesis in the tumor microenvironment, it could be a potential target for breast cancer therapy.

angiogenic

angiogenesis

tumor

proliferation

endothelial cell

express

secreted

breast cancer cells

inhibits

Antiprogestin RU-486

induction

blocks

Actinomycin-D

induction

blocks

puromycin

induction

treated

progestin

breast cancer cells

therapy

breast cancer

induce

progestins

vascular endothelial growth factor

induce

progestins

induction

VEGF

progestins

induction

progestins

dependent

progestin

induction

induction

stimulates

breast cancer cells

proliferation

promote

angiogenesis

Regulation

progestins

mediated

progestin

progesterone receptor

regulate

progestin

transcription

regulate

PR

transcription

transcription


Input:
c-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-beta signaling in diffuse-type gastric carcinoma.

c-Ski, originally identified as a proto-oncogene product, is an important negative regulator of transforming growth factor (TGF)-beta family signaling through interaction with Smad2, Smad3, and Smad4. High expression of c-Ski has been found in some cancers, including gastric cancer. We previously showed that disruption of TGF-beta signaling by dominant-negative TGF-beta type II receptor in a diffuse-type gastric carcinoma model accelerated tumor growth through induction of tumor angiogenesis by decreased expression of the anti-angiogenic factor thrombospondin (TSP)-1. Here, we examined the function of c-Ski in human diffuse-type gastric carcinoma OCUM-2MLN cells. Overexpression of c-Ski inhibited TGF-beta signaling in OCUM-2MLN cells. Interestingly, c-Ski overexpression resulted in extensive acceleration of the growth of subcutaneous xenografts in BALB/c nu/nu female mice (6 weeks of age). Similar to tumors expressing dominant-negative TGF-beta type II receptor, histochemical studies revealed less fibrosis and increased angiogenesis in xenografted tumors expressing c-Ski compared to control tumors. Induction of TSP-1 mRNA by TGF-beta was attenuated by c-Ski in vitro, and expression of TSP-1 mRNA was decreased in tumors expressing c-Ski in vivo. These findings suggest that c-Ski overexpression promotes the growth of diffuse-type gastric carcinoma through induction of angiogenesis.

interaction

c-Ski

interaction

c-Ski

interaction

c-Ski

angiogenesis

gastric carcinoma

angiogenesis

tumor

angiogenic

angiogenesis

tumors

angiogenesis

tumors

angiogenesis

overexpression

c-Ski

expression

c-Ski

expression

thrombospondin (TSP)-1

Overexpression

c-Ski

overexpression

c-Ski

expressing

TGF-beta type II receptor

expressing

c-Ski

expressing

c-Ski

overexpression

c-Ski

growth

tumor

growth

tumor

growth

xenografts

growth

gastric carcinoma

inhibition

overexpression

signaling

disruption

signaling

TGF-beta type II receptor

decreased

expression

inhibited

Overexpression

signaling

attenuated

Induction

c-Ski

decreased

expression

signaling

transforming growth factor-beta

signaling

transforming growth factor (TGF)-beta

signaling

TGF-beta

signaling

TGF-beta

promotes

growth

inhibition

promotes

angiogenesis

inhibition

accelerated

growth

induction

induction

angiogenesis

decreased

increased

angiogenesis

Induction

TGF-beta

promotes

growth

induction

induction

overexpression

angiogenesis

expression


Input:
Angiogenesis-a novel therapeutic approach for ischemic heart disease.

Angiogenesis is the biologic process of forming new blood vessels. Undoubtedly, blood vessels growth regulation is a vital aspect in health and disease. Under physiological conditions, angiogenesis is regulated by local balance between endogenous stimulators and inhibitors of this process. In many diseases state body loses control over angiogenesis. Angiogenesis-dependent diseases result when new blood vessels either grow excessively or insufficiently. Insufficient angiogenesis occurs in diseases such as coronary artery disease, stroke and chronic wounds. Myocardial ischemia both acute and chronic has been clearly shown to stimulate angiogenesis in many experimental models. Therapeutic angiogenesis is the biological agents or bioactive material to stimulate the growth of new blood vessels. Traditional coronary revascularization therapies such as coronary angioplasty or bypass graft surgery, act by restoring blood flow through the preexisting coronary vessels. One limitation of these approaches, however, may be the failure to normalize myocardial perfusion, due to the concomitant presence or small of resistance vessel disease. In contrast, therapeutic angiogenesis is based on the concept that coronary collateral development may be stimulated by pharmacological or molecular means and can limit myocardial ischemia. Studies, both in human and animal models support the notion that, various angiogenic growth factors and progenitor cells can enhance new blood vessels. Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), recombinant proteins and bone marrow stem cells are currently used therapeutic stimulators for angiogenesis. As coronary artery disease is the major cause of death in the developed societies and also an emerging health problem in developing countries like Bangladesh therapeutic angiogenesis may provide hope as a new treatment modality for ischemic heart disease with or in place of current therapies.

Angiogenesis

Angiogenesis

angiogenesis

angiogenesis

Angiogenesis

angiogenesis

angiogenesis

angiogenesis

revascularization

angiogenesis

angiogenic

angiogenesis

angiogenesis

forming

blood vessels

development

coronary collateral

growth

blood vessels

grow

blood vessels

growth

blood vessels

preexisting

coronary vessels

stimulate

angiogenesis

stimulate

growth

stimulated

development

enhance

progenitor cells

blood vessels

enhance

blood vessels

regulation

growth

regulated

angiogenesis

control

angiogenesis

restoring

blood


Input:
Use of uteroglobin for the engineering of polyvalent, polyspecific fusion proteins.

We report a novel strategy to engineer and express stable and soluble human recombinant polyvalent/polyspecific fusion proteins. The procedure is based on the use of a central skeleton of uteroglobin, a small and very soluble covalently linked homodimeric protein that is very resistant to proteolytic enzymes and to pH variations. Using a human recombinant antibody (scFv) specific for the angiogenesis marker domain B of fibronectin, interleukin 2, and an scFv able to neutralize tumor necrosis factor-alpha, we expressed various biologically active uteroglobin fusion proteins. The results demonstrate the possibility to generate monospecific divalent and tetravalent antibodies, immunocytokines, and dual specificity tetravalent antibodies. Furthermore, compared with similar fusion proteins in which uteroglobin was not used, the use of uteroglobin improved properties of solubility and stability. Indeed, in the reported cases it was possible to vacuum dry and reconstitute the proteins without any aggregation or loss in protein and biological activity.

angiogenesis

neutralize

tumor necrosis factor-alpha


Input:
[Prognostic significance of cellular vascular endothelial growth factor (VEGF) expression in the course of chronic myeloid leukaemia]

INTRODUCTION: Increased angiogenesis in bone marrow is one of the characteristics of chronic myeloid leukaemia (CML), a clonal myeloproliferative disorder that expresses a chimeric bcr/abl protein. Vascular endothelial growth factor (VEGF) is one of the most potent and a specific regulator of angiogenesis which principally targets endothelial cells and regulates several of their functions, including mitogenesis, permeability and migration. The impact of elevated VEGF expression on the course of chronic myeloid leukaemia is unknown. OBJECTIVE: The aim of this study was the follow-up of VEGF expression during the course of CML. METHODS: We studied VEGF expression of 85 CML patients (median age 50 years, range 16-75 years). At the commencement of the study, 29 patients were in chronic phase (CP), 25 in an accelerated phase (AP), and 31 in the blast crisis (BC). The temporal expression (percentage positivity per 1000 analysed cells) VEGF proteins over the course of CML were studied using the immunohistochemical technique utilizing relevant monoclonal antibodies. It was correlated with the laboratory (Hb, WBC and platelet counts, and the percentage of blasts) and clinical parameters (organomegaly, duration of CP, AP, and BC) of disease progression. RESULTS: The expression ofVEGF protein was most pronounced in AP (ANOVA, p=0.033). The level of VEGF expression correlated inversely with the degree of splenomegaly (Pearson, r=-0.400, p=0.011). High expression of VEGF correlated with a shorter overall survival (log rank, p=0.042). CONCLUSION: Immunohistochemically confirmed significance of the expression of VEGF in dependence of the CML stage could be of clinical importance in deciding on the timing therapy. These data suggest that VEGF plays a role in the biology of CML and that VEGF inhibitors should be investigated in CML.

angiogenesis

bone marrow

angiogenesis

expression

vascular endothelial growth factor

expression

VEGF

expression

VEGF

expression

VEGF

expression

VEGF

expression

VEGF

expression

VEGF

expression

VEGF

expression

VEGF

Increased

angiogenesis

elevated

expression

regulator

Vascular endothelial growth factor

angiogenesis

regulates

Vascular endothelial growth factor

endothelial cells


Input:
Tumor Angiogenesis: Initiation and Targeting - Therapeutic Targeting of an FGF-Binding Protein, an Angiogenic Switch Molecule, and Indicator of Early Stages of Gastrointestinal Adenocarcinomas -.

Tumor angiogenesis has been related to the initiation as well as progression toward more aggressive behavior of human tumors. In particular, the activity of angiogenic factors is crucial for tumor progression. We previously characterized a secreted fibroblast growth factor-binding protein (FGF-BP) as a chaperone molecule, which binds to various FGFs, enhances FGF-mediated biochemical and biologic events and importantly is a crucial rate-limiting factor for tumor-dependent angiogenesis. We generated monoclonal antibodies that target FGF-BP protein and used them as a tool to evaluate frequency and pattern of FGF-BP expression during the malignant progression of pancreas and colorectal carcinoma in archival tissue samples. We found that FGF-BP is dramatically upregulated during the initiation of colorectal and pancreatic adenocarcinoma. Crucial genetic events underlying the initiation and progression of colorectal and pancreatic adenocarcinoma with a particular focus on the modulation of angiogenesis and antiangiogenic therapies are discussed. We propose that the upregulation of the secreted FGF-BP protein during early phases of pancreas and colon cancer could make this protein a possible serum marker indicating the presence of high-risk premalignant lesions. Furthermore, the biological activity of FGF-BP is neutralized by monoclonal antibodies suggesting the potential for antibody-based therapeutic targeting.

various

fibroblast growth factor-binding protein

FGFs

Angiogenesis

Tumor

Angiogenic

angiogenesis

Tumor

angiogenic

angiogenesis

angiogenesis

angiogenic

progression

tumor

progression

pancreas

progression

colorectal carcinoma

initiation

colorectal

initiation

pancreatic adenocarcinoma

initiation

colorectal

initiation

pancreatic adenocarcinoma

progression

colorectal

progression

pancreatic adenocarcinoma

expression

FGF-BP

secreted

fibroblast growth factor-binding protein

secreted

FGF-BP

Therapeutic Targeting

FGF-Binding Protein

generated

monoclonal antibodies that target FGF-BP protein

therapies

angiogenic

initiation

angiogenesis

tumors

progression

tumors

crucial

fibroblast growth factor-binding protein

angiogenesis

dependent

tumor

angiogenesis

upregulated

FGF-BP

upregulation

secreted

modulation

angiogenesis


Input:
Experimental drug therapy of peritumoral brain edema.

Four drugs with potential anti-peritumoral brain edema activity were studied using the VX2 rabbit brain tumor model. Meclofenamate and indomethacin were tested in an attempt to confirm recent reports of anti-edema activity in non steroidal anti-inflammatory drugs (NSAID's). The 'angiostatic' steroids 17 hydroxyprogesterone and epicortisol were tested because of their lack of glucocorticoid and mineralocorticoid effects and their structural similarity to glucocorticoids. The protein and water component of brain edema were indirectly quantitated. None of the test drugs demonstrated significant anti-edema activity. This work does not confirm reports that NSAID's have anti-edema activity and suggests that there may be no correlation between 'angiostatic' and anti-edema activity in certain steroid compounds.

activity

peritumoral brain edema

activity

edema

non steroidal anti-inflammatory drugs

activity

edema

activity

NSAID

edema

activity

edema


Input:
Low-level X-radiation effects on functional vascular changes in Syrian hamster cheek pouch epithelium during hydrocarbon carcinogenesis.

Effects of repeated low-level X radiation on functional microvascular changes in hamster cheek pouch epithelium during and following carcinogenesis by 7,12-dimethylbenz[a]anthracene (DMBA) were studied. Prior studies showed enhancement of such carcinogenesis by repeated 20 rad head and neck X-radiation exposures, and it was proposed that one possible mechanism was radiogenic alteration of the functional microvasculature in a manner which favored subsequent tumor development. Hamsters were treated with either radiation, DMBA, radiation + DMBA, or no treatment. Animals were sacrificed at 3-week intervals from 0 to 39 weeks after treatments began. Pouch vascular volume and permeability changes were studied by fractional distributions of radiotracers and were analyzed by a variety of statistical methods which explored the vascular parameters, treatment types, elapsed time, presence of the carcinogen, and histopathologic changes. All treatments resulted in significant changes in vascular volume with time, while only DMBA treatments alone resulted in significant changes in vascular permeability with time. Prior to the appearances of frank neoplasms, volumetric changes in DMBA only and radiation only groups were similar, while volume changes in DMBA + radiation groups increased slowly to a peak later than in other groups and then declined steadily to levels similar to the radiation only group. As in prior studies, there were significant vascular volume differences between DMBA and DMBA + radiation groups of tumor-bearing cheek pouches. DMBA maxima were significantly higher than those of DMBA + radiation. Radiation significantly affected DMBA-associated vascular volume and permeability changes during carcinogenesis. Several possible explanations for the relationship of these changes to the enhancement of DMBA carcinogenesis include: radiation blocking normal capillary proliferative and/or dilatory responses to inflammation secondary to neoplastic changes; radiation-induced focal increases in the pericapillary connective tissue histohematic barrier, stimulating angiogenesis but reducing nutrient diffusion; radiation exposures sensitizing vascular endothelium to subsequent angiogenic stimulation from premalignant tissues; DMBA vascular and epithelial effects partially or completely blocking radiation effects on epithelial and/or endothelial cells; and radiation damage to vessel walls partially or fully inhibiting normal physiologic mechanisms of repairing DMBA damage to the vessels.

angiogenesis

angiogenic

damage

vessel walls

damage

vessels

development

tumor

proliferative

capillary

blocking

DMBA

effects

X-radiation exposures

head

X-radiation exposures

neck

treated

Hamsters

DMBA

treated

Hamsters

DMBA

treatment

Hamsters

favored

alteration

development

increased

changes

enhancement

DMBA

stimulating

angiogenesis

stimulation

angiogenic

effects

changes

changes

vascular

Effects

changes

changes

microvascular

alteration

X-radiation exposures

microvasculature

changes

vascular

changes

DMBA

vascular

changes

neoplasms

DMBA

changes

neoplasms

DMBA

affected

vascular

associated

DMBA

vascular

effects

epithelial

effects

endothelial cells


Input:
Scanning electron microscopy of vascular casts in experimental ocular vasoproliferation.

Scanning electron microscopy of vascular casts was used to investigate three experimental models of neovascularization. In each experimental situation, the casts provided a valuable three dimensional representation of the newly formed blood vessels and permitted subclassification of the vessels within normal and proliferating vascular networks. They defined also the predominant origin of new vessels from venules and capillaries, and enabled the evolution of proliferating vessels into arterioles and venules to be documented. Although vascular casts must be interpreted with caution in light of the possibility of incomplete filling and other artifacts, they are a valuable tool in the study of ocular vasoproliferation.

vasoproliferation

neovascularization

vasoproliferation

ocular

formed

blood vessels

evolution

arterioles

evolution

venules

proliferating

vascular networks

proliferating

vessels


Input:
Mast cell heparin stimulates migration of capillary endothelial cells in vitro.

Migration of capillary endothelial cells is an important component of angiogenesis in vivo. Increased numbers of mast cells have been associated with several types of angiogenesis. We have used a quantitative assay in vitro to demonstrate that mast cells release a factor that significantly increases bovine capillary endothelial cell migration. The factor is present in medium conditioned by mast cells as well as lysates of mast cells. The stimulatory effect of mast cells on migration is specific for capillary endothelial cells. Furthermore, mast cells have no mitogenic activity for capillary endothelial cells. Of all the secretory products of mast cells tested, only heparin stimulated capillary endothelial cell migration in vitro. Heparin preparations from a variety of sources stimulated capillary endothelial cell migration to the same degree but did not stimulate migration of several other cell types. The migration activity of heparin and mast cell conditioned medium was blocked by specific antagonists of heparin (protamine and heparinase), but not by chondroitinase ABC. The migration activity of mast cell conditioned medium was resistant to heat (100 degrees C) and incubation with proteolytic enzymes. These results suggest that the role of mast cells in angiogenesis may be to enhance migration of the endothelial cells of growing capillaries.

angiogenesis

angiogenesis

angiogenesis

growing

capillaries

migration

capillary endothelial cells

Migration

capillary endothelial cells

migration

capillary endothelial cell

migration

capillary endothelial cells

migration

capillary endothelial cell

migration

capillary endothelial cell

migration

cell

migration

endothelial cells

blocked

mast cell

protamine

blocked

mast cell

heparinase

blocked

mast cell

chondroitinase ABC

stimulates

heparin

migration

Increased

mast cells

increases

migration

stimulatory effect

mast cells

migration

stimulated

heparin

migration

stimulated

Heparin

migration

stimulate

Heparin

migration

enhance

role

migration

associated

Increased

angiogenesis

mitogenic activity

mast cells

capillary endothelial cells

role

mast cells

angiogenesis


Input:
Heparin-steroid conjugates: new angiogenesis inhibitors with antitumor activity in mice.

Inhibitors of angiogenesis hold potential in the treatment of cancer and other diseases where the disease is caused or maintained by the inappropriate growth of blood vessels. In the present study, a novel inhibitor of angiogenesis was synthesized by covalently linking a nonanticoagulating derivative of heparin, heparin adipic hydrazide (HAH), by an acid-labile bond to the antiangiogenic steroid, cortisol. The rationale was that the heparin derivative, which binds to sulfated polyanion receptors on endothelial cells, should concentrate the steroid on the surface of vascular endothelial cells. Endocytosis of the conjugate and decomposition of the acid-labile linkage inside lysosomes and other acidic intracellular compartments should then lead to release of the cortisol and expression of its antiproliferative activity. Analysis of the stability of HAH-cortisol showed that it was stable at pH 7.4 and broke down rapidly (t1/2 15 min) at pH 4.8 at 37 degrees C. Treatment of murine pulmonary capillary endothelial cells with HAH-cortisol at 10(-5) M (with respect to cortisol) suppressed their DNA synthesis by 50% and inhibited their migration into wounded areas of confluent monolayers. HAH-cortisol at 10(-4) M (with respect to cortisol) did not suppress the DNA synthesis of Lewis lung carcinoma cells. Daily i.p. injections of HAH-cortisol into mice bearing s.c. sponge implants retarded vascularization of the sponge, and injections directly into the sponge abolished vascularization for as long as the injections were continued. Daily i.v. injections of HAH-cortisol at doses causing no apparent toxicity retarded the growth of solid s.c. Lewis lung carcinomas in mice by up to 65%. In all of these assays, equivalent treatments with a mixture of the HAH plus cortisol was significantly less effective. The antiproliferative effect of HAH-cortisol on endothelial cells appeared independent of the glucocorticoid activity of the steroid since HAH conjugated to 5 beta-pregnane-3 alpha,17 alpha,21-triol-20-one, a steroid lacking glucocorticoid or mineralocorticoid activity, was even more effective at inhibiting DNA synthesis by murine pulmonary capillary endothelial cells than was HAH-cortisol. In conclusion, HAH-cortisol represents the prototype of a new class of angiogenesis inhibitors for the treatment of cancer and other angiogenic diseases.

binds

endothelial cells

angiogenesis

angiogenesis

angiogenesis

angiogenic

vascularization

vascularization

angiogenesis

angiogenic

broke down

HAH-cortisol

proliferative

endothelial cells

growth

blood vessels

growth

Lewis lung carcinomas

release

cortisol

migration

pulmonary capillary endothelial cells

activity

tumor

inhibited

Treatment

migration

retarded

injections

vascularization

abolished

injections

vascularization

retarded

injections

growth

effect

proliferative

HAH-cortisol

treatment

cancer

Treatment

pulmonary capillary endothelial cells

HAH-cortisol

injections

HAH-cortisol

mice

injections

HAH-cortisol

mice

treatments

HAH

cortisol

conjugated

HAH

5 beta-pregnane-3 alpha,17 alpha,21-triol-20-one

treatment

cancer


Input:
[Treatment of the diabetic foot by hyperbaric oxygen]

Diabetic foot wounds are consequences of the neuropathy and the small and large vessel disease that complicate diabetes. At the cellular level, the result is hypoxia which impairs wound healing. Hyperbaric oxygenation (HBO) may be a useful adjuvant to wound care. It leads to enhanced oxygenation of the affected tissues, has an antiseptic effect, reduces edema, and accelerates collagen production and angiogenesis, thus enhancing tissue repair. 14 diabetics with chronic nonhealing wounds which did not respond to treatment for at least 3 months were treated by HBO. All had palpable pedal pulses. Transcutaneous measurements of tissue pO2 showed elevation from 20 +/- 10 mm Hg during air breathing to 643 +/- 242 mm Hg while breathing pure oxygen at 2.5 ATA. They were treated with HBO in 56 +/- 10 consecutive HBO sessions. In 11 there was complete wound healing, while in 1 there was partial response, in 1 minimal response, and in 1 a transient response. HBO is useful in chronic nonhealing wounds of the diabetic foot and of the diabetic foot with impending amputation. It is a safe mode of therapy, but further studies are required to establish its efficacy and to ascertain which diabetic patients and wounds will benefit the most from it.

angiogenesis

repair

tissue

production

collagen

reduces

edema

Treatment

foot

hyperbaric oxygen

amputation

foot

accelerates

production

accelerates

angiogenesis

enhancing

repair

affected

tissues


Input:
Immune consequences of burn injury.

The purpose of the immune system is to protect cells from invasion by microorganisms. The body has three equally important interactive immune defense systems, all of which are profoundly disrupted with major burn injury. The immune response to burn injury is immediate, prolonged, and severe. The end result in individuals surviving burn shock is immunosuppression, with increased susceptibility to potentially fatal systemic burn wound or pulmonary sepsis. Nursing actions to support the humoral and cell-mediated immune system of the burned patient include providing nutritional support to maintain serum protein levels at optimal levels; measures to decrease edema and promote angiogenesis in areas of partial-thickness injury; meticulous treatment of the wound to prevent infection and promote healing; monitoring of antibiotic use; conservative use of invasive techniques, including intubation and vascular access devices; maintenance of fluid and electrolyte balance and body temperature; and energy conservation measures.

angiogenesis

decrease

edema

promote

angiogenesis


Input:
Autocrine angiogenic vascular prosthesis with bone marrow transplantation.

Synthetic vascular prostheses are foreign bodies, so that blood coagulation can occur on their luminal surfaces, causing graft occlusion very frequently in prostheses of small diameter. A vascular prosthesis needs angiogenesis for endothelialization of the luminal surface, as endothelial cells have natural and permanent antithrombogenic properties. To induce capillary growth into the graft, we developed a method of transplanting bone marrow cells, which are primitive, strong enough to survive, and create blood cells, resulting in the inducement of capillary growth. In an animal experiment, marrow cells were infiltrated into the walls of long-fibril expanded polytetrafluoroethylene (ePTFE) vascular grafts. The grafts were implanted in the abdominal aortic position of 24 dogs autologously. Marrow cells survived and continued exogenous hemopoiesis for up to six months and were immunohistochemically reactive to basic fibroblast growth factor (bFGF). All the grafts older than three weeks had complete endothelialization and maintained their patency. Twenty grafts without bone marrow were implanted as controls. Endothelialization was present at anastomotic sites, but other areas were covered with fresh thrombi. Four out of seven control grafts were patent with endothelial cell lining at six months, but three were occluded and one of the four grafts was still covered with a thrombus layer. Bone marrow with its unique native properties produced autocrine angiogenicity in the graft.

angiogenic

angiogenesis

endothelialization

endothelialization

Endothelialization

angiogenicity

survived

Marrow cells

create

blood cells

growth

capillary

growth

capillary

infiltrated

marrow cells

transplantation

bone marrow

transplanting

bone marrow cells

implanted

abdominal aortic

induce

growth

resulting

create

inducement

inducement

growth


Input:
The effects of radiation on neovascularization in a rat model.

It is thought that radiation treatment inhibits neovascularization of recipient and/or graft tissues, and this may account in part for abnormalities in wound healing associated with radiation therapy. We have examined this hypothesis using a model that measures the neovascularization of an implanted foreign material. Expanded polytetrafluoroethylene (PTFE) sheets were implanted adjacent to both superficial epigastric vascular pedicles of 63 rats distributed into 7 groups (n = 7) that differed with respect to dose and timing of irradiation. Zero to 10 daily fractions of electron-beam radiation (300 cGy each) were delivered to the implant in the right groin, while the implant in the left groin served as a nonirradiated internal control. Unirradiated animals showed equal neovascularization of both implants. Rats that were irradiated twice (single fractions at 0 and 24 hours after implantation) did not show a significant decrease in the neovascularization of the irradiated implant compared with the contralateral control implant. In contrast, the implants that were irradiated three times (single fractions at 0, 24, and 48 hours after implantation) demonstrated significantly diminished (  greater than  25 percent, p  less than  0.05) neovascularization beyond day 7, whereas implants irradiated only at 48 hours after implantation did not. Interestingly, neovascularization of the implants irradiated with 10 fractions (3000 cGy) was not significantly decreased compared with irradiation with three fractions (900 cGy). Irradiation delivered before implantation (900 cGy) inhibited neovascularization significantly less than the same dose administered after implantation. The results of this study suggest that a subclinical cumulative dose of 900 cGy is the threshold for impaired tissue revascularization provided that treatment is delivered immediately after implantation over a 48-hour interval.

neovascularization

neovascularization

graft tissues

neovascularization

neovascularization

neovascularization

neovascularization

neovascularization

neovascularization

revascularization

tissue

inhibits

neovascularization

decrease

irradiated

neovascularization

diminished

neovascularization

decreased

neovascularization

inhibited

neovascularization

impaired

revascularization

implanted

polytetrafluoroethylene

epigastric vascular pedicles

irradiated

Rats

effects

neovascularization


Input:
Prognostic value of angiogenesis in operable non-small cell lung cancer.

Tumour angiogenesis is an important factor for tumour growth and metastasis. Although some recent reports suggest that microvessel counts in non-small cell lung cancer are related to a poor disease outcome, the results were not conclusive and were not compared with other molecular prognostic markers. In the present study, the vascular grade was assessed in 107 (T1,2-N0,1) operable non-small cell lung carcinomas, using the JC70 monoclonal antibody to CD31. Three vascular grades were defined with appraisal by eye and by Chalkley counting: high (Chalkley score 7-12), medium (5-6), and low (2-4). There was a significant correlation between eye appraisal and Chalkley counting (P  less than  0.0001). Vascular grade was not related to histology, grade, proliferation index (Ki67), or EGFR or p53 expression. Tumours from younger patients had a higher grade of angiogenesis (P = 0.05). Apart from the vascular grade, none of the other factors examined was statistically related to lymph node metastasis (P  less than  0.0001). A univariate analysis of survival showed that vascular grade was the most significant prognostic factor (P = 0.0004), followed by N-stage (P = 0.001). In a multivariate analysis, N-stage and vascular grade were not found to be independent prognostic factors, since they were strongly related to each other. Excluding N-stage, vascular grade was the only independent prognostic factor (P = 0.007). Kaplan-Meier survival curves showed a statistically significant worse prognosis for patients with high vascular grade, but no difference was observed between low and medium vascular grade. These data suggest that angiogenesis in operable non-small cell lung cancer is a major prognostic factor for survival and, among the parameters tested, is the only factor related to cancer cell migration to lymph nodes. The integration of vascular grading in clinical trials on adjuvant chemotherapy and/or radiotherapy could substantially contribute in defining groups of operable patients who might benefit from cytotoxic treatment.

angiogenesis

non-small cell lung cancer

angiogenesis

Tumour

angiogenesis

angiogenesis

non-small cell lung cancer

expression

EGFR

expression

growth

tumour

metastasis

tumour

migration

cancer cell

lymph nodes

chemotherapy

patients

radiotherapy

patients


Input:
Integrin alphavbeta3 requirement for sustained mitogen-activated protein kinase activity during angiogenesis.

Angiogenesis depends on growth factors and vascular cell adhesion events. Integrins and growth factors are capable of activating the ras/MAP kinase pathway in vitro, yet how these signals influence endothelial cells during angiogenesis is unknown. Upon initiation of angiogenesis with basic fibroblast growth factor (bFGF) on the chick chorioallantoic membrane (CAM), endothelial cell mitogen-activated protein (MAP) kinase (ERK) activity was detected as early as 5 min yet was sustained for at least 20 h. The initial wave of ERK activity (5-120 min) was refractory to integrin antagonists, whereas the sustained activity (4-20 h) depended on integrin alphavbeta3, but not beta1 integrins. Inhibition of MAP kinase kinase (MEK) during this sustained alphavbeta3-dependent ERK signal blocked the formation of new blood vessels while not influencing preexisting blood vessels on the CAM. Inhibition of MEK also blocked growth factor induced migration but not adhesion of endothelial cells in vitro. Therefore, angiogenesis depends on sustained ERK activity regulated by the ligation state of both a growth factor receptor and integrin alphavbeta3.

adhesion

vascular cell

adhesion

endothelial cells

angiogenesis

Angiogenesis

angiogenesis

angiogenesis

chorioallantoic membrane

angiogenesis

formation

blood vessels

migration

endothelial cells

Inhibition

MAP kinase kinase

blocked

Inhibition

formation

Inhibition

MEK

pathway

ras

MAP kinase

depends

Angiogenesis

adhesion

activating

Integrins

pathway

initiation

angiogenesis

basic fibroblast growth factor

depended

ERK

integrin alphavbeta3

depended

ERK

beta1 integrins

dependent

ERK

induced

Inhibition

migration

induced

Inhibition

adhesion

depends

angiogenesis

ERK

influence

activating

endothelial cells

refractory

ERK

integrin antagonists

influencing

Inhibition

blood vessels

regulated

ERK

integrin alphavbeta3


Input:
Basic fibroblast growth factor: a missing link between collagen VII, increased collagenase, and squamous cell carcinoma in recessive dystrophic epidermolysis bullosa.

BACKGROUND: Patients with recessive dystrophic epidermolysis bullosa (RDEB) have deficiencies of collagen type VII and have elevated levels of fibroblast collagenase, and a greatly increased risk of cutaneous squamous cell carcinoma. Patients with other genetic blistering disorders do not have elevated collagenase or an increased risk of squamous cell carcinoma, despite chronic wounding. The connection between collagen type VII deficiency, increased collagenase, and squamous cell carcinoma is not understood. MATERIALS AND METHODS: Urine from 81 patients with RDEB (39 patients), junctional epidermolysis bullosa (JEB; 12 patients), and epidermolysis bullosa simplex (EBS; 30 patients), as well as unaffected family members of RDEB patients (33 patients), was tested for the presence of basic fibroblast growth factor (bFGF) using a sensitive radioimmunoassay. These patients included many who were enrolled in the Epidermolysis Bullosa Registry and others who were referred by their physicians. RESULTS: Fifty-one percent of patients with RDEB had elevated levels ( greater than  5000 pg/g) of urinary bFGF. In contrast, none of the patients with JEB had elevated levels of bFGF. Twenty-one percent of clinically unaffected family members had elevated levels of bFGF, and 13% of patients with EBS had elevated levels of bFGF. The frequency of elevated bFGF values among all groups was statistically significant (p = 0.002), and the levels of bFGF in RDEB patients were significantly elevated compared with those of other groups (p  less than  0.05). CONCLUSIONS: We have found that patients with RDEB have elevated levels of bFGF, which may contribute to increased fibroblast collagenase and the development of squamous cell carcinoma. These results suggest a novel treatment for RDEB, namely, angiogenesis inhibitors, which may antagonize the effects of bFGF in this disorder. There are currently no other means of treatment for this disorder, which has a high morbidity and mortality rate.

angiogenesis

development

squamous cell carcinoma

deficiencies

collagen type VII

presence

basic fibroblast growth factor

antagonize the effects

bFGF

increased

collagenase

elevated

fibroblast collagenase

elevated

collagenase

increased

collagenase

elevated

bFGF

elevated

bFGF

elevated

bFGF

elevated

bFGF

elevated

bFGF

elevated

bFGF

elevated

bFGF

increased

fibroblast collagenase


Input:
The myoadipose flap: a new composite.

A prefabricated composite fat flap consisting of muscle woven into an anatomically distinct fat pad was studied in a rabbit model. In 17 rabbits, a 2-cm strip of latissimus dorsi was woven into the parascapular fat pad on one side, with the contralateral fat pad serving as a control. At 3 weeks, the endogenous blood supply of both the control and the experimental fat pads was isolated and ligated, and the composite fat/muscle flap was transferred to the chest wall. At 6 weeks, animals were killed, and flaps were analyzed for length, width, and weight; perfused with fluorescein or lead oxide; and examined histologically. Significant differences were found between the control and experimental fat pads with regard to weight and length. Experimental flaps were found to be perfused fully with fluorescein and lead oxide; control fat pads were found not to be perfused. The lead oxide group revealed extensive growth of blood vessels from the latissimus graft into the experimental fat pad. No vessels were visualized in the controls. Finally, sections of the control and experimental flaps were analyzed histologically. A preponderance of viable fat, with evidence of neovascularization, was found in experimental flaps, compared with the necrotic fat that characterized the controls. We conclude that prefabrication of a fat flap is possible and may have extensive application in various areas of plastic surgery.

neovascularization

growth

blood vessels

prefabricated

composite fat flap

woven

composite fat flap

fat pad

woven

strip

parascapular fat pad

transferred

composite fat/muscle flap

chest wall

perfused

flaps

fluorescein

perfused

flaps

lead oxide

perfused

flaps

fluorescein

perfused

flaps

lead oxide

perfused

fat pads

prefabrication

fat flap