Input:
Novel biological agents for the treatment of hormone-refractory prostate cancer (HRPC).

Hormone-refractory prostate cancer (HRPC) is an inevitable evolution of prostate carcinogenesis, through which the normal dependence on hormones for growth and survival is bypassed. Although advances in terms of symptoms palliation and quality of life improvement have been addressed with current treatment options, innovative approaches are needed to improve survival rates. A thorough understanding of HRPC-associated molecular pathways and mechanisms of resistance are a prerequisite for novel potential therapeutic interventions. Preclinical and early clinical studies are ongoing to evaluate new therapies that target specific molecular entities. Agents under development include growth factor receptor inhibitors, small molecules targeting signal transduction pathways, apoptosis and cell-cycle regulators, angiogenesis and metastasis inhibitors, differentiation agents, telomerase inactivators, and epigenetic therapeutics. Incorporation of these agents into existing treatment regimens will guide us in the development of a multidisciplinary treatment strategy of HRPC. This article critically reviews published data on new biological agents that are being tested in HRPC clinical trials, highlights ongoing research and considers the future perspectives of this new class of agents.

angiogenesis

carcinogenesis

prostate

treatment

hormone-refractory prostate cancer


Input:
Role of thrombogenic factors in the development of atherosclerosis.

Hemostatic factors play a crucial role in generating thrombotic plugs at sites of vascular damage (atherothrombosis). However, whether hemostatic factors contribute directly or indirectly to the pathogenesis of atherosclerosis remains uncertain. Autopsy studies have revealed that intimal thickening represents the first stage of atherosclerosis and that lipid-rich plaque arises from such lesions. Several factors contribute to the start of intimal thickening. Platelets release several growth factors and bioactive agents that play a central role in development of not only thrombus but also of intimal thickening. We have been investigating which coagulation factors simultaneously, or subsequently with platelet aggregation, participate in thrombus formation. Tissue factor (TF) is an essential initiator of blood coagulation that is expressed in various stages of atherosclerotic lesions in humans and other animals. Factors including thrombin and fibrin, which are downstream of the coagulation cascade activated by TF, also contribute to atherosclerosis. TF is involved in cell migration, embryogenesis and angiogenesis. Thus TF, in addition to factors downstream of the coagulation cascade and the protease-activated receptor 2 activation system, would be a multifactorial regulator of atherogenesis.

aggregation

platelet

angiogenesis

damage

vascular

generating

thrombotic plugs

development

thrombus

formation

thrombus

expressed

Tissue factor

thickening

intimal

thickening

intimal

thickening

intimal

migration

cell

coagulation cascade

coagulation cascade

activation system

protease-activated receptor 2

play a crucial role

Hemostatic factors

generating

contribute

thickening

play a central role

development

play a central role

thickening

participate

formation

activated

coagulation cascade

TF

involved

TF

migration

involved

TF

angiogenesis

downstream

thrombin

coagulation cascade

downstream

fibrin

coagulation cascade


Input:
Rofecoxib as adjunctive therapy for haemophilic arthropathy.

Joint haemorrhage and subsequent haemophilic arthropathy are significant complications in haemophilia. The pathophysiology involves inflammation and angiogenesis. Cyclooxygenase-2 (COX-2) inhibitors are anti-inflammatory agents, which have potent anti-inflammatory, anti-angiogenic and analgesic properties yet do not affect platelet function in the manner of traditional non-steroidal anti-inflammatory drugs. These properties make such agents potentially useful as adjunctive therapy in haemophilia. There is only one prior report describing rofecoxib treatment in a single haemophilia patient. Our objectives were to determine the safety and efficacy of rofecoxib in treating acute haemarthrosis, chronic synovitis, target joints and pain. We conducted a retrospective medical record review of patients treated with rofecoxib for acute haemarthrosis, chronic synovitis, target joint or pain. The safety and efficacy of rofecoxib treatment were determined based on subjective patient reports and physical examinations during follow-up clinic visits. A total of 28 patients between 3 and 37 years of age were treated for a total of 42 courses of rofecoxib treatment. All courses were evaluated for safety and 31 for efficacy. Rofecoxib was used for eight acute haemarthrosis, four target joints, seven cases of synovitis and 12 episodes of pain. Efficacy was demonstrated particularly for chronic synovitis and pain and no serious adverse events occurred. This is the largest study to date evaluating COX-2 inhibitors as adjunctive therapy in haemophilia and suggests that these agents may be an important adjunctive therapy in the management of haemophilia.

angiogenesis

angiogenic

properties

angiogenic

treatment

rofecoxib

patient

treating

rofecoxib

joints

treated

patients

rofecoxib

treatment

rofecoxib

patient

treated

patients

treatment

rofecoxib

used

Rofecoxib

joints

affect

platelet


Input:
Thalidomide and angiostatin inhibit tumor growth in a murine xenograft model of human cervical cancer.

OBJECTIVE: To determine the impact of thalidomide and angiostatin on tumor growth, angiogenesis, and apoptosis in a xenograft model of cervical cancer. METHODS: Human umbilical endothelial cells were treated with angiostatin or thalidomide and bFGF-induced proliferation was assessed with the MTT assay. Human cervical cancer cells (CaSki and SiHa) were injected into the flanks of nude mice. After tumors developed, mice were treated with angiostatin 20 mg/kg/day or thalidomide 200 mg/kg/day for 30 days. Fractional tumor growth was determined and immunohistochemical analysis of tumors was used to determine degree of angiogenesis. TUNEL assay was used to assess apoptosis. RESULTS: Angiostatin inhibited endothelial cell proliferation by 50-60%. Thalidomide had no direct effect on endothelial cells. Angiostatin and thalidomide both inhibited tumor growth by about 55%. We found no additive or synergistic effect when the two agents were combined. Both agents inhibited angiogenesis and induced apoptosis when compared to tumors from control animals. CONCLUSIONS: Angiostatin and thalidomide inhibit tumor growth, angiogenesis, and induce apoptosis in this xenograft model of cervical cancer.

angiogenesis

cervical cancer

angiogenesis

angiogenesis

angiogenesis

cervical cancer

proliferation

endothelial cell

apoptosis

cervical cancer

apoptosis

cervical cancer

developed

tumors

growth

tumor

growth

tumor

growth

tumor

growth

tumor

growth

tumor

inhibit

Thalidomide

tumor

inhibit

angiostatin

tumor

inhibited

Angiostatin

proliferation

inhibited

Angiostatin

tumor

inhibited

thalidomide

tumor

inhibited

Angiostatin

angiogenesis

inhibited

thalidomide

angiogenesis

inhibit

Angiostatin

growth

inhibit

Angiostatin

angiogenesis

inhibit

thalidomide

growth

inhibit

thalidomide

angiogenesis

treated

endothelial cells

angiostatin

treated

endothelial cells

thalidomide

injected

CaSki

flanks

injected

SiHa

flanks

treated

mice

angiostatin

treated

mice

thalidomide

induce

Angiostatin

apoptosis

induce

thalidomide

apoptosis

no direct effect

Thalidomide

endothelial cells


Input:
Therapeutic Electromagnetic Field (TEMF) and gamma irradiation on human breast cancer xenograft growth, angiogenesis and metastasis.

BACKGROUND: The effects of a rectified semi-sinewave signal (15 mT amplitude, 120 pulses per second, EMF Therapeutics, Inc.) (TEMF) alone and in combination with gamma irradiation (IR) therapy in nude mice bearing a human MDA MB231 breast cancer xenograft were tested. Green fluorescence protein transfected cancer cells were injected into the mammary fat pad of young female mice. Six weeks later, mice were randomly divided into four treatment groups: untreated controls; 10 minute daily TEMF; 200 cGy of IR every other day (total 800 cGy); IR plus daily TEMF. Some mice in each group were euthanized 24 hours after the end of IR. TEMF treatment continued for 3 additional weeks. Tumor sections were stained for: endothelial cells with CD31 and PAS or hypoxia inducible factor 1alpha (HIF). RESULTS: Most tumors  less than 35 mm3 were white but tumors  greater than 35 mm3 were pink and had a vascularized capsule. The cortex within 100 microns of the capsule had little vascularization. Blood vessels, capillaries, and endothelial pseudopods were found at  greater than 100 microns from the capsule (subcortex). Tumors  greater than 35 mm3 treated with IR 24 hours previously or with TEMF had decreased blood vessels in the subcortex and more endothelial pseudopods projecting into hypoxic, HIF positive areas than tumors from the control group. Mice that received either IR or TEMF had significantly fewer lung metastatic sites and slower tumor growth than did untreated mice. No harmful side effects were attributed to TEMF. CONCLUSION: TEMF therapy provided a safe means for retarding tumor vascularization, growth and metastasis.

angiogenesis

breast cancer xenograft

vascularization

cortex

vascularization

tumor

growth

breast cancer xenograft

growth

tumor

growth

tumor

metastasis

tumor

decreased

blood vessels

retarding

vascularization

retarding

growth

retarding

metastasis

transfected

Green fluorescence protein

cancer cells

injected

cancer cells

mammary fat pad

euthanized

mice

treated

Tumors

received

Mice

untreated

mice


Input:
The merits of vascular targeting for gynecologic malignancies.

Neovascularization is an early and critical step in tumor development and progression. Tumor vessels are distinct from their normal counterparts morphologically as well as at a molecular level. Recent studies on factors involved in tumor vascular development have identified new therapeutic targets for inhibiting tumor neovascularization and thus tumor progression. However, the process of tumor blood vessel formation is complex, and each tumor exhibits unique features in its vasculature. An understanding of the relative contribution of various pathways in the development of tumor vasculature is critical for developing effective and selective therapeutic approaches. Several such agents are currently in clinical trials, and many others are under development. In this review, the mechanisms and factors involved in tumor blood vessel formation are discussed. In addition, selected novel classes of antivascular therapies, including those targeting tumor endothelial cells and other components of the tumor vasculature, are summarized.

Neovascularization

neovascularization

tumor

development

tumor

progression

tumor

development

tumor vascular

progression

tumor

formation

tumor blood vessel

development

tumor vasculature

formation

tumor blood vessel

inhibiting

neovascularization

inhibiting

progression

targeting

tumor endothelial cells


Input:
Domain 5 of cleaved high molecular weight kininogen inhibits endothelial cell migration through Akt.

Domain 5 (D5) of cleaved high molecular weight kininogen (HKa) inhibits angiogenesis in vivo and endothelial cell migration in vitro, but the cell signaling pathways involved in HKa and D5 inhibition of endothelial cell migration are incompletely delineated. This study examines the mechanism of HKa and D5 inhibition of two potent stimulators of endothelial cell migration, sphingosine 1-phosphate (S1P) and vascular endothelial growth factor (VEGF), that act through the P13-kinase-Akt signaling pathway. HKa and D5 inhibit bovine pulmonary artery endothelial cell (BPAE) or human umbilical vein endothelial cell chemotaxis in the modified-Boyden chamber in response toVEGF or S1P. The inhibition of migration by HKa is reversed by antibodies to urokinase-type plasminogen activator receptor. Both HKa and D5 decrease the speed of BPAE cell migration and alter the morphology in live, time-lapse microscopy after stimulation with S1P or VEGF. HKa and D5 reduce the localization of paxillin to the focal adhesions after S1P and VEGF stimulation. To better understand the intracellular signaling pathways, we examined the effect of HKa on the phosphorylation of Akt and its downstream effector, GSK-3alpha HKa and D5 inhibit phosphorylation of Akt and GSK-3alpha after stimulation withVEGF and S1P. Inhibitors of Akt and P13-kinase, the upstream activator of Akt, block endothelial cell migration and disrupt paxillin localization to the focal adhesions after stimulation with VEGF and S1P. Therefore we suggest that HKa through its D5 domain alters P13-kinase-Akt signaling to inhibit endothelial cell migration through alterations in the focal adhesions.

angiogenesis

migration

endothelial cell

migration

endothelial cell

migration

endothelial cell

migration

endothelial cell

chemotaxis

pulmonary artery endothelial cell

chemotaxis

umbilical vein endothelial cell

migration

pulmonary artery endothelial cell

migration

umbilical vein endothelial cell

migration

BPAE cell

localization

paxillin

focal adhesions

migration

endothelial cell

localization

paxillin

focal adhesions

migration

endothelial cell

inhibits

inhibits

migration

inhibits

Domain 5

high molecular weight kininogen

migration

inhibition

HKa

migration

inhibition

sphingosine 1-phosphate

act

inhibition

vascular endothelial growth factor

act

inhibit

HKa

chemotaxis

inhibition

migration

HKa

reversed

inhibition

antibodies to urokinase-type plasminogen activator receptor

decrease

HKa

migration

reduce

HKa

localization

inhibit

HKa

phosphorylation

block

migration

disrupt

localization

inhibit

alters

migration

signaling pathways

signaling pathway

Akt

signaling

Akt

phosphorylation

Akt

phosphorylation

phosphorylation

Akt

phosphorylation

response

chemotaxis

VEGF

response

chemotaxis

stimulation

BPAE cell

stimulation

BPAE cell

VEGF

stimulation

BPAE cell

stimulation

BPAE cell

VEGF

stimulation

BPAE cell

withVEGF

stimulation

BPAE cell

stimulation

BPAE cell

VEGF

stimulation

BPAE cell

cleaved

high molecular weight kininogen

cleaved

high molecular weight kininogen

inhibits

Domain 5

high molecular weight kininogen

Akt

involved

signaling pathways

inhibition

act

HKa

signaling pathway

effect

HKa

phosphorylation

alters

HKa

signaling

alterations

focal adhesions


Input:
Effect of thalidomide affecting VEGF secretion, cell migration, adhesion and capillary tube formation of human endothelial EA.hy 926 cells.

Angiogenesis, new blood vessel formation, is a multistep process, precisely regulated by pro-angiogenic cytokines, which stimulate endothelial cells to migrate, proliferate and differentiate to form new capillary microvessels. Excessive vascular development and blood vessel remodeling appears in psoriasis, rheumatoid arthritis, diabetic retinopathy and solid tumors formation. Thalidomide [alpha-(N-phthalimido)-glutarimide] is known to be a potent inhibitor of angiogenesis, but the mechanism of its inhibitory action remains unclear. The aim of the study was to investigate the potential influence of thalidomide on the several steps of angiogenesis, using in vitro models. We have evaluated the effect of thalidomide on VEGF secretion, cell migration, adhesion as well as in capillary formation of human endothelial cell line EA.hy 926. Thalidomide at the concentrations of 0.01 microM and 10 microM inhibited VEGF secretion into supernatants, decreased the number of formed capillary tubes and increased cell adhesion to collagen. Administration of thalidomide at the concentration of 0.01 microM increased cell migration, while at 10 microM, it decreased cell migration. Thalidomide in concentrations from 0.1 microM to 10 microM did not change cell proliferation of 72-h cell cultures. We conclude that anti-angiogenic action of thalidomide is due to direct inhibitory action on VEGF secretion and capillary microvessel formation as well as immunomodulatory influence on EA.hy 926 cells migration and adhesion.

adhesion

endothelial EA.hy 926 cells

adhesion

endothelial cell line EA.hy 926

adhesion

cell

collagen

adhesion

EA.hy 926 cells

Angiogenesis

angiogenic

angiogenesis

angiogenesis

angiogenic

proliferate

endothelial cells

proliferation

cell

formation

capillary tube

formation

blood vessel

differentiate

endothelial cells

form

capillary microvessels

development

vascular

formation

solid tumors

formation

capillary

formed

capillary tubes

formation

capillary microvessel

secretion

VEGF

cell migration

endothelial EA.hy 926 cells

migrate

endothelial cells

secretion

VEGF

cell migration

endothelial cell line EA.hy 926

secretion

VEGF

migration

cell

migration

cell

secretion

VEGF

migration

EA.hy 926 cells

inhibitory action

Thalidomide

angiogenesis

inhibited

Thalidomide

secretion

decreased

Thalidomide

formed

decreased

Administration

migration

action

angiogenic

thalidomide

inhibitory action

secretion

inhibitory action

formation

Administration

thalidomide

stimulate

migrate

stimulate

proliferate

stimulate

differentiate

increased

Thalidomide

adhesion

increased

Administration

migration

due

action

inhibitory action

affecting

thalidomide

secretion

affecting

thalidomide

cell migration

affecting

thalidomide

adhesion

affecting

thalidomide

formation

regulated

Angiogenesis

influence

thalidomide

angiogenesis

effect

thalidomide

secretion

effect

thalidomide

cell migration

effect

thalidomide

adhesion

effect

thalidomide

formation

change

Thalidomide

proliferation

influence

thalidomide

migration

influence

thalidomide

adhesion

remodeling

blood vessel


Input:
Regulation of skin microvasculature angiogenesis, cell migration, and permeability by a specific inhibitor of PKCalpha.

Activation of protein kinase C (PKC) induces phenotypic changes in the morphology of microvascular endothelial cells that affect major functions of the microvasculature. These functions include the first stages of sprouting in angiogenesis, cell migration following wounding, and vascular permeability. The specific isoform(s) of PKC responsible for each of these changes has not been previously identified. In this study, we used two inflammatory agents, IL-1beta and phorbol myristic acetate, to activate PKC isozymes and specific inhibitors of PKCalpha (Go6976) and PKCbeta (hispidin) to distinguish how each of these isoform(s) controls angiogenesis, wound healing, and permeability. In all cases, only inhibition of PKCalpha inhibited each of these functions when compared to the inhibition of PKCbeta. Additional analysis of the mechanism of action of Go6976 (RT-PCR, Western blots, and immunohistochemistry) of the changes in the phosphorylated and nonphosphorylated forms of PKCalpha in the cell membrane and cytoplasm confirmed the specificity of PKCalpha inhibition by Go6976. These studies therefore indicate a specific and a regulatory role of the PKCalpha isoform in three major endothelial cell functions that are important in the maintenance of microvascular homeostasis.

angiogenesis

skin microvasculature

angiogenesis

angiogenesis

migration

cell

migration

cell

inhibition

PKCalpha

inhibition

PKCbeta

inhibition

PKCalpha

phosphorylated

PKCalpha

nonphosphorylated

PKCalpha

Activation

protein kinase C

induces

Activation

changes

activate

PKC

activate

phorbol myristic acetate

PKC

Regulation

angiogenesis

Regulation

migration

changes

microvascular endothelial cells

affect

changes

microvasculature

responsible

PKC

controls

PKCalpha

angiogenesis

controls

PKCbeta

angiogenesis

changes

phosphorylated

changes

nonphosphorylated


Input:
The differential regulation of human telomerase reverse transcriptase and vascular endothelial growth factor may contribute to the clinically more aggressive behavior of p63-positive breast carcinomas.

p63, a p53 homologue, is a myoepithelial cell marker in the normal mammary gland but p63-positive neoplastic cells may be found in up to 11% of invasive breast carcinomas. This study aims to verify the relationship between p63 expression and several clinicopathological features and tumor markers of clinical significance in breast pathology including key regulators of the cell cycle, oncogenes, apoptosis-related proteins, metalloproteinases and their inhibitors. Immunohistochemistry with 27 primary antibodies was performed in 100 formalin-fixed paraffin-embedded samples of invasive ductal carcinomas. p63-positive cells were found in 16% of carcinomas. p63-positive carcinomas were poorly differentiated, hormone receptor-negative neoplasms with a high proliferation rate. p63 also correlated with advanced pathological stage, tumor size, and the expression of human telomerase reverse transcriptase (hTERT), tissue inhibitor of matrix metalloproteinase 1 (TIMP1) and vascular endothelial growth factor (VEGF). The expression of TIMP1 suggests that the anti-proteolytic stimuli may be preponderant in p63-positive carcinomas. hTERT activity is associated with nodal metastases and cellular proliferation. VEGF regulates angiogenesis, which is also a fundamental event in the process of tumor growth and metastatic dissemination. Thus, the differential regulation of hTERT and VEGF in p63-positive breast carcinomas may contribute to the clinically more aggressive behavior of these neoplasms.

angiogenesis

differentiated

p63-positive carcinomas

expression

expression

telomerase reverse transcriptase

expression

tissue inhibitor of matrix metalloproteinase 1

expression

vascular endothelial growth factor

expression

proliferation

neoplasms

growth

tumor

found

p63-positive cells

carcinomas

metastatic dissemination

tumor

regulation

telomerase reverse transcriptase

regulation

vascular endothelial growth factor

regulates

VEGF

angiogenesis

regulation

hTERT

p63-positive breast carcinomas

regulation

VEGF

p63-positive breast carcinomas


Input:
Regulation of tumor angiogenesis by thrombospondin-1.

Angiogenesis plays a critical role in the growth and metastasis of tumors. Thrombospondin-1 (TSP-1) is a potent angiogenesis inhibitor, and down-regulation of TSP-1 has been suggested to alter tumor growth by modulating angiogenesis in a variety of tumor types. Expression of TSP-1 is up-regulated by the tumor suppressor gene, p53, and down-regulated by oncogenes such as Myc and Ras. TSP-1 inhibits angiogenesis by inhibiting endothelial cell migration and proliferation and by inducing apoptosis. In addition, activation of transforming growth factor beta (TGF-beta) by TSP-1 plays a crucial role in the regulation of tumor progression. An understanding of the molecular basis of TSP-1-mediated inhibition of angiogenesis and tumor progression will aid in the development of novel therapeutics for the treatment of cancer.

angiogenesis

tumor

Angiogenesis

angiogenesis

angiogenesis

tumor

angiogenesis

angiogenesis

proliferation

endothelial cell

progression

tumor

progression

tumor

Expression

growth

tumors

growth

tumor

metastasis

tumors

migration

endothelial cell

down-regulation

down-regulated

Expression

Myc

down-regulated

Expression

Ras

inhibits

angiogenesis

inhibiting

inhibiting

migration

inhibiting

proliferation

inhibition

angiogenesis

inhibition

progression

up-regulated

Expression

activation

transforming growth factor beta

Regulation

angiogenesis

plays a critical role

Angiogenesis

metastasis

plays a critical role

Angiogenesis

growth

alter

growth

modulating

modulating

down-regulation

angiogenesis

plays a crucial role

activation

regulation

regulation

progression


Input:
Regulation of the composition of the extracellular matrix by low density lipoprotein receptor-related protein-1: activities based on regulation of mRNA expression.

Low density lipoprotein receptor-related protein-1 (LRP-1) is a catabolic receptor for extracellular matrix (ECM) structural proteins and for proteins that bind to ECM. LRP-1 also is implicated in integrin maturation. In this study, we applied a proteomics strategy to identify novel proteins involved in ECM modeling that are regulated by LRP-1. We show that LRP-1 deficiency in murine embryonic fibroblasts (MEFs) is associated with increased levels of type III collagen and pigment epithelium-derived factor, which accumulate in the substratum surrounding cells. The collagen receptor, uPAR-AP/Endo-180, is also increased in LRP-1-deficient MEFs. Human LRP-1 reversed the changes in protein expression associated with LRP-1 deficiency; however, the endocytic activity of LRP-1 was not involved. Instead, regulation occurred at the mRNA level. Inhibition of c-Jun amino-terminal kinase (JNK) blocked type III collagen expression in LRP-1-deficient MEFs, suggesting regulation of JNK activity as a mechanism by which LRP-1 controls mRNA expression. The ability of LRP-1 to regulate expression of the factors identified here suggests a role for LRP-1 in determining blood vessel structure and in angiogenesis.

bind

ECM

angiogenesis

modeling

ECM

deficiency

deficient

deficiency

expression

type III collagen

deficient

Inhibition

c-Jun amino-terminal kinase

blocked

Inhibition

expression

increased

type III collagen

increased

pigment epithelium-derived factor

increased

uPAR-AP

increased

maturation

integrin

Regulation

extracellular matrix

low density lipoprotein receptor-related protein-1

implicated

maturation

regulated

modeling

regulation

JNK

role

blood vessel

role

angiogenesis


Input:
Pericytes limit tumor cell metastasis.

Previously we observed that neural cell adhesion molecule (NCAM) deficiency in beta tumor cells facilitates metastasis into distant organs and local lymph nodes. Here, we show that NCAM-deficient beta cell tumors grew leaky blood vessels with perturbed pericyte-endothelial cell-cell interactions and deficient perivascular deposition of ECM components. Conversely, tumor cell expression of NCAM in a fibrosarcoma model (T241) improved pericyte recruitment and increased perivascular deposition of ECM molecules. Together, these findings suggest that NCAM may limit tumor cell metastasis by stabilizing the microvessel wall. To directly address whether pericyte dysfunction increases the metastatic potential of solid tumors, we studied beta cell tumorigenesis in primary pericyte-deficient Pdgfb(ret/ret) mice. This resulted in beta tumor cell metastases in distant organs and local lymph nodes, demonstrating a role for pericytes in limiting tumor cell metastasis. These data support a new model for how tumor cells trigger metastasis by perturbing pericyte-endothelial cell-cell interactions.

cell-cell interactions

pericyte

endothelial

cell-cell interactions

pericyte

endothelial

dysfunction

pericyte

grew

blood vessels

deficiency

neural cell adhesion molecule

expression

NCAM

metastasis

tumor cell

metastasis

beta tumor cells

organs

metastasis

beta tumor cells

lymph nodes

deposition

perivascular

ECM components

recruitment

pericyte

deposition

perivascular

ECM molecules

metastasis

tumor cell

metastatic

solid tumors

metastases

beta tumor cell

organs

metastases

beta tumor cell

lymph nodes

metastasis

tumor cell

metastasis

tumor cells

limit

Pericytes

metastasis

limit

metastasis

stabilizing

limiting

metastasis

facilitates

deficiency

metastasis

improved

expression

recruitment

increased

expression

deposition

stabilizing

NCAM

microvessel wall

increases

dysfunction

metastatic

trigger

metastasis

perturbing

role

pericytes

limiting

perturbing

tumor cells

cell-cell interactions


Input:
NF-kappaB and IKK as therapeutic targets in cancer.

The transcription factor NF-kappaB and associated regulatory factors (including IkappaB kinase subunits and the IkappaB family member Bcl-3) are strongly implicated in a variety of hematologic and solid tumor malignancies. A role for NF-kappaB in cancer cells appears to involve regulation of cell proliferation, control of apoptosis, promotion of angiogenesis, and stimulation of invasion/metastasis. Consistent with a role for NF-kappaB in oncogenesis are observations that inhibition of NF-kappaB alone or in combination with cancer therapies leads to tumor cell death or growth inhibition. However, other experimental data indicate that NF-kappaB can play a tumor suppressor role in certain settings and that it can be important in promoting an apoptotic signal downstream of certain cancer therapy regimens. In order to appropriately move NF-kappaB inhibitors in the clinic, thorough approaches must be initiated to determine the molecular mechanisms that dictate the complexity of oncologic and therapeutic outcomes that are controlled by NF-kappaB.

associated

NF-kappaB

angiogenesis

cell proliferation

cancer cells

apoptosis

cancer cells

death

tumor cell

growth

tumor cell

invasion

cancer cells

metastasis

cancer cells

inhibition

NF-kappaB

inhibition

death

inhibition

growth

play

NF-kappaB

tumor

therapies

cancer

promotion

NF-kappaB

angiogenesis

stimulation

NF-kappaB

invasion

stimulation

NF-kappaB

metastasis

leads

therapies

inhibition

regulation

NF-kappaB

cell proliferation

control

NF-kappaB

apoptosis


Input:
Circulating endothelial cells in malignant disease.

Cancer is a disease largely dependent on neoangiogenesis. Cancer neoangiogenesis is often disordered and abnormal, with evidence of coexisting vascular endothelial dysfunction. A novel method of assessing vascular endothelial function in cancer is via the quantification of circulating endothelial cells (CEC). Unusual in healthy individuals, their presence in elevated numbers often indicates substantial vascular endothelial perturbation. Another interesting cell type is the endothelial progenitor cell (EPC), whose numbers increase in the presence of vascular damage. Recent research suggests that EPCs have an important role in tumor vasculogenesis. Another marker being investigated in the context of vascular dysfunction and coagulopathy is the endothelial microparticle (EMP). Thus, CECs, EPCs and EMPs may represent potentially novel methods for evaluating the vascular status of cancer patients. This review will summarize the current position of CECs, EPCs and EMPs in cell biology terms, with particular emphasis on their relationship to malignant disease.

neoangiogenesis

neoangiogenesis

Cancer

vasculogenesis

tumor

dysfunction

vascular endothelial

damage

vascular

dysfunction

vascular

dependent

Cancer

neoangiogenesis

increase

endothelial progenitor cell

have an important role

EPCs

vasculogenesis


Input:
GDP and AGE receptors: mechanisms of peritoneal damage.

Long-term peritoneal dialysis (PD) is limited by morphological changes of the peritoneal membrane. Structural changes were promoted by toxicity of glucose degradation products (GDPs) which are generated during heat sterilization in peritoneal dialysis fluids (PDFs). Besides their direct toxicity GDPs promote formation of advanced glycation endproducts (AGEs). RAGE (receptor for AGE) is the best characterized signal transduction receptor for AGEs and is expressed on mesothelial cells. The effects of PDFs with different amounts of GDPs were compared on morphological changes in the peritoneal membrane in a RAGE -/- mouse model. It could be demonstrated that RAGE plays a pivotal role in structural damage (e.g. inflammation, neoangiogenesis and fibrosis) of the peritoneal membrane. Further investigations of this pathway with regard to preventing peritoneal fibrosis should be performed to maintain the integrity of the peritoneal membrane in peritoneal dialysis patients.

neoangiogenesis

peritoneal membrane

damage

peritoneal

structural damage

peritoneal membrane

expressed

RAGE

promoted

morphological changes

glucose degradation products

promote

GDPs

formation

plays a pivotal role

RAGE

structural damage

plays a pivotal role

RAGE

neoangiogenesis

morphological changes

peritoneal membrane

morphological changes

peritoneal membrane

formation

advanced glycation endproducts


Input:
[Autologous bone marrow stem cell or peripheral blood endothelial progenitor cell therapy in patients with peripheral limb ischaemia]

No effective medical therapies have been developed sofar to enhance blood flow in the legs of patients with peripheral arterial disease (PAD). For patients with limb threatening ischaemia the only option for relief of rest pain or gangraena is amputation. There is evidence in experimental and clinical studies that adult bone marrow-derived stem cells and endothelial progenitor cells participate in the development of new blood vessels, called neoangiogenesis or neovascularization. Clinical results induced by autologous bone marrow stem cells or angiogenic growth/differentiation factors in end-stage patients with PAD are summarized. Considering the relatively few number of patients treated by angiogenic therapy, the interpretation of clinical results needs cautiousness.

neoangiogenesis

neovascularization

angiogenic

angiogenic

development

blood vessels

therapy

bone marrow stem cell

patients

therapy

peripheral blood endothelial progenitor cell

patients

treated

patients


Input:
Formation of new bone during vertical distraction osteogenesis of the human mandible is related to the presence of blood vessels.

We examined the effect of distraction rate on blood vessel growth in intramembraneous ossification after vertical distraction osteogenesis in the human mandible. Six edentulous patients (aged 60+/-9 years) with a severely atrophic mandible underwent bone augmentation with distraction osteogenesis. Two distraction rates (0.5 and 1 mm/day) were compared and for each group three patients were analyzed. Vascular histomorphometry was carried out in two different areas in the distraction gap: (1) in the first and (2) in the second 1 mm area from the osteotomy line, representing the oldest and younger new-bone area, respectively. Correlation analysis was performed between blood vessel parameters and the amount of new bone formed during distraction. Histological analysis demonstrated the presence of blood vessels throughout the soft connective tissue in the distraction gap. The volume density of blood vessels between the two investigated areas was significantly lower in the 1 mm/day groups, suggesting a delay in angiogenesis in this group of patients. A positive correlation between blood vessel volume and bone volume density was found in the younger new-bone area but not in the oldest new-bone area. This correlation was due to a higher number of blood vessels rather than to a larger size of the blood vessels. Our data suggest that the lower blood vessel density found in the patients with 1 mm/day distraction rate may be related to disruption of angiogenesis in the soft connective tissue of the gap or to a less optimal mechanical stimulation of cells involved in angiogenesis. This probably results in the slower rate of osteogenesis seen at the 1 mm/day distraction rate compared with the 0.5 mm/day distraction rate. The data support the concept that a positive relationship exists between the density of blood vessels and the formation of bone. For distraction of the human mandible in elderly patients, a distraction rate of 0.5 mm/day seems beneficial.

angiogenesis

angiogenesis

soft connective tissue

angiogenesis

Formation

bone

formed

bone

formation

bone

growth

blood vessel

delay

angiogenesis

disruption

angiogenesis

vertical distraction osteogenesis

mandible

vertical distraction osteogenesis

mandible

distraction

mandible

stimulation

cells


Input:
Imaging tumor angiogenesis.

Since the discovery of vascular-specific growth factors with angiogenic activity, there has been a significant effort to develop cancer drugs that restrict tumorigenesis by targeting the blood supply. In this issue of the JCI, Mancuso et al. use mouse models to better understand the plasticity of the tumor vasculature in the face of antiangiogenic therapy (see the related article beginning on page 2610). They describe a rapid regrowth of the tumor vasculature following withdrawal of VEGFR inhibitors, emphasizing the importance of fully understanding the function of these and similar treatments used in the clinic at the cellular and molecular level.

angiogenesis

tumor

angiogenic

regrowth

tumor vasculature


Input:
Collagen-poly glycolic acid hybrid matrix with basic fibroblast growth factor accelerated angiogenesis and granulation tissue formation in diabetic mice.

Because poor skin wound healing associated with diabetes is thought to be partly a result from impaired angiogenesis, treatments that improve angiogenesis could have important clinical applications. We herein report the effects of novel developed material, collagen-poly glycolic acid fiber hybrid matrix, being used together with basic fibroblast growth factor to promote wound healing of full-thickness skin defects on the back of type 2 diabetic Lepr(db) mice. Our data indicates that this therapeutic approach markedly promotes angiogenesis and granulation tissue formation in comparison with other conditions 14 days after wounding.

angiogenesis

angiogenesis

angiogenesis

angiogenesis

formation

granulation tissue

formation

granulation tissue

impaired

angiogenesis

accelerated

Collagen

formation

accelerated

Collagen

angiogenesis

accelerated

basic fibroblast growth factor

formation

accelerated

basic fibroblast growth factor

angiogenesis

accelerated

poly glycolic acid

formation

accelerated

poly glycolic acid

angiogenesis

improve

angiogenesis

promotes

angiogenesis

promotes

formation


Input:
Punica granatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer.

The last 7 years have seen over seven times as many publications indexed by Medline dealing with pomegranate and Punica granatum than in all the years preceding them. Because of this, and the virtual explosion of interest in pomegranate as a medicinal and nutritional product that has followed, this review is accordingly launched. The pomegranate tree, Punica granatum, especially its fruit, possesses a vast ethnomedical history and represents a phytochemical reservoir of heuristic medicinal value. The tree/fruit can be divided into several anatomical compartments: (1) seed, (2) juice, (3) peel, (4) leaf, (5) flower, (6) bark, and (7) roots, each of which has interesting pharmacologic activity. Juice and peels, for example, possess potent antioxidant properties, while juice, peel and oil are all weakly estrogenic and heuristically of interest for the treatment of menopausal symptoms and sequellae. The use of juice, peel and oil have also been shown to possess anticancer activities, including interference with tumor cell proliferation, cell cycle, invasion and angiogenesis. These may be associated with plant based anti-inflammatory effects, The phytochemistry and pharmacological actions of all Punica granatum components suggest a wide range of clinical applications for the treatment and prevention of cancer, as well as other diseases where chronic inflammation is believed to play an essential etiologic role.

angiogenesis

proliferation

tumor cell

invasion

tumor cell


Input:
Activation of vascular endothelial growth factor through reactive oxygen species mediates 20-hydroxyeicosatetraenoic acid-induced endothelial cell proliferation.

20-Hydroxyeicosatetraenoic acid (20-HETE) is formed by the omega-hydroxylation of arachidonic acid by cytochrome P450 4A and 4F enzymes, and it induces angiogenic responses in vivo. To test the hypothesis that 20-HETE increases endothelial cell (EC) proliferation via vascular endothelial growth factor (VEGF), we studied the effects of WIT003 [20-hydroxyeicosa-5(Z),14(Z)-dienoic acid], a 20-HETE analog on human macrovascular or microvascular EC. WIT003, as well as pure 20-HETE, stimulated EC proliferation by approximately 40%. These proliferative effects were accompanied by increased VEGF expression and release that were observed as early as 4 h after 20-HETE agonist addition. This was accompanied by increased phosphorylation of the VEGF receptor 2. The proliferative effects of 20-HETE were markedly inhibited by a VEGF-neutralizing antibody. Polyethylene glycol-superoxide dismutase (PEG-SOD) markedly inhibited both the increases in VEGF expression and the proliferative effects of 20-HETE. In contrast, administration of the NAD(P)H oxidase inhibitor apocynin had no effect to the proliferative response to 20-HETE. The 20-HETE agonist markedly increased superoxide formation as reflected by an increase in dihydroethidium staining of EC, and this increase was inhibited by PEG-SOD but not by apocynin. 20-HETE also increased the phosphorylation of p42/p44 mitogen-activated protein kinase (MAPK) in EC, whereas an inhibitor of MAPK [U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene] suppressed the proliferative and the VEGF changes but not the pro-oxidant effects of 20-HETE. These data suggest that 20-HETE stimulates superoxide formation by pathways other than apocynin-sensitive NAD(P)H oxidase, thereby activating MAPK and then enhancing VEGF synthesis that drives EC proliferation. Thus, 20-HETE may be involved in the regulation of EC functions, such as angiogenesis.

angiogenic

angiogenesis

proliferation

endothelial cell

proliferation

endothelial cell

proliferation

EC

proliferation

EC

expression

VEGF

expression

VEGF

synthesis

VEGF

release

VEGF

inhibited

inhibited

Polyethylene glycol-superoxide dismutase

expression

inhibited

Polyethylene glycol-superoxide dismutase

inhibited

increased

PEG-SOD

inhibited

increased

apocynin

suppressed

1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene

changes

suppressed

1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene

phosphorylation

VEGF receptor 2

phosphorylation

p42/p44 mitogen-activated protein kinase

administration

apocynin

staining

dihydroethidium

EC

Activation

vascular endothelial growth factor

induced

20-hydroxyeicosatetraenoic acid

proliferation

induces

20-Hydroxyeicosatetraenoic acid

angiogenic

increases

proliferation

stimulated

proliferation

stimulated

proliferation

increased

expression

increased

release

increased

phosphorylation

increases

expression

increased

formation

increased

phosphorylation

stimulates

formation

activating

MAPK

enhancing

synthesis

mediates

Activation

proliferation

effects

macrovascular

effects

microvascular EC

effect

administration

changes

VEGF

drives

synthesis

proliferation

involved

regulation

regulation

EC

regulation

angiogenesis

formed

20-Hydroxyeicosatetraenoic acid

formation

superoxide

formation

superoxide


Input:
Hyperforin blocks neutrophil activation of matrix metalloproteinase-9, motility and recruitment, and restrains inflammation-triggered angiogenesis and lung fibrosis.

Hyperforin (Hyp), a polyphenol-derivative of St. John's wort (Hypericum perforatum), has emerged as key player not only in the antidepressant activity of the plant but also as an inhibitor of bacteria lymphocyte and tumor cell proliferation, and matrix proteinases. We tested whether as well as inhibiting leukocyte elastase (LE) activity, Hyp might be effective in containing both polymorphonuclear neutrophil (PMN) leukocyte recruitment and unfavorable eventual tissue responses. The results show that, without affecting in vitro human PMN viability and chemokine-receptor expression, Hyp (as stable dicyclohexylammonium salt) was able to inhibit in a dose-dependent manner their chemotaxis and chemoinvasion (IC50=1 microM for both); this effect was associated with a reduced expression of the adhesion molecule CD11b by formyl-Met-Leu-Phe-stimulated neutrophils and block of LE-triggered activation of the gelatinase matrix metalloproteinase-9. PMN-triggered angiogenesis is also blocked by both local injection and daily i.p. administration of the Hyp salt in an interleukin-8-induced murine model. Furthermore, i.p. treatment with Hyp reduces acute PMN recruitment and enhances resolution in a pulmonary bleomycin-induced inflammation model, significantly reducing consequent fibrosis. These results indicate that Hyp is a powerful anti-inflammatory compound with therapeutic potential, and they elucidate mechanistic keys.

angiogenesis

angiogenesis

proliferation

lymphocyte

proliferation

tumor cell

expression

motility

neutrophil

recruitment

neutrophil

recruitment

polymorphonuclear neutrophil (PMN) leukocyte

chemotaxis

PMN

chemoinvasion

PMN

recruitment

PMN

blocks

Hyperforin

angiogenesis

blocks

Hyperforin

activation

blocks

Hyperforin

motility

blocks

Hyperforin

recruitment

inhibiting

leukocyte elastase

Hyp

inhibit

Hyp

chemotaxis

inhibit

Hyp

chemoinvasion

reduced

expression

neutrophils

block

gelatinase matrix metalloproteinase-9

blocked

angiogenesis

injection

blocked

angiogenesis

administration

reduces

treatment

recruitment

injection

Hyp

murine

administration

Hyp

murine

treatment

Hyp

activation

neutrophil

matrix metalloproteinase-9

triggered

angiogenesis

stimulated

formyl-Met-Leu-Phe

neutrophils

triggered

LE

activation

activation

gelatinase matrix metalloproteinase-9

triggered

PMN

angiogenesis

induced

murine

effective

Hyp

recruitment


Input:
New vectors and strategies for cardiovascular gene therapy.

Cardiovascular diseases are the major cause of morbidity and mortality in both men and women in industrially developed countries. These disorders may result from impaired angiogenesis, particularly in response to hypoxia. Despite many limitations, gene therapy is still emerging as a potential alternative for patients who are not candidates for traditional revascularization procedures, like angioplasty or vein grafts. This review focuses on recent approaches in the development of new gene delivery vectors, with great respect to newly discovered AAV serotypes and their modified forms. Moreover, some new cardiovascular gene therapy strategies have been highlighted, such as combination of different angiogenic growth factors or simultaneous application of genes and progenitor cells in order to obtain stable and functional blood vessels in ischemic tissue.

angiogenesis

revascularization

angiogenic

obtain

blood vessels

impaired

angiogenesis


Input:
Impaired apoptosis of pulmonary endothelial cells is associated with intimal proliferation and irreversibility of pulmonary hypertension in congenital heart disease.

OBJECTIVES: This study sought to assess the cellular and histologic basis of irreversible pulmonary hypertension (PHT) in the clinical setting of congenital heart disease (CHD). BACKGROUND: Although many children with CHD develop pulmonary vascular disease, it is unclear why this complication is reversible after complete repair in some cases but irreversible in others. Because failure of endothelial cell apoptosis might lead to intimal proliferation and lack of reversibility of PHT, we investigated this and other key markers of vasoactivity and angiogenesis in subjects with PHT and CHD. METHODS: We assessed antiapoptotic and proapoptotic markers in vascular and perivascular cells in lung biopsy samples from 18 patients with CHD, 7 with reversible and 11 with irreversible PHT, and 6 control patients. Immunostaining for endothelial nitric oxide synthase, vascular endothelial growth factor, and CD34 (markers of vasoactivity and neoangiogenesis) was also performed. RESULTS: The antiapoptotic protein Bcl-2 was highly expressed by pulmonary endothelial cells in all cases of irreversible PHT but in no cases of reversible PHT, nor in control patients (p  less than  0.001). Intimal proliferation was present in 10 of 11 irreversible PHT cases, but never observed in reversible PHT (p  less than  0.001). Similarly, perivascular inflammatory T-cells expressed more antiapoptotic proteins in irreversible PHT (p  less than  0.01). Irreversible PHT cases were also more likely to show compensatory upregulation of vascular endothelial growth factor and new small vessel formation at the sites of native vessel stenosis or occlusion (p  less than  0.001). CONCLUSIONS: Irreversible PHT is strongly associated with impaired endothelial cell apoptosis and antiapoptotic signaling from perivascular inflammatory cells. These changes are associated with intimal proliferation and vessel narrowing, and thereby may contribute to clinical outcomes associated with pulmonary hypertension.

angiogenesis

neoangiogenesis

apoptosis

pulmonary endothelial cells

apoptosis

endothelial cell

apoptosis

endothelial cell

formation

vessel

expressed

proliferation

intimal

proliferation

intimal

proliferation

Intimal

proliferation

intimal

impaired

apoptosis

impaired

antiapoptotic signaling

antiapoptotic signaling

upregulation

vascular endothelial growth factor

upregulation

formation


Input:
Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion.

Vascular development is dependent on various growth factors and certain modifiers critical for providing arterial or venous identity, interaction with the surrounding stroma and tissues, hierarchic network formation, and recruitment of pericytes. Notch receptors and ligands (Jagged and Delta-like) play a critical role in this process in addition to VEGF. Dll4 is one of the Notch ligands that regulates arterial specification and maturation events. In the current study, we have shown that loss of function by either targeted allele deletion or use of a soluble form of Dll4 extracellular domain leads to inhibition of Notch signaling, resulting in increased vascular proliferation but defective maturation. Newly forming vessels have thin caliber, a markedly reduced vessel lumen, markedly reduced pericyte recruitment, and deficient vascular perfusion. sDll4 similarly induced defective vascular response in tumor implants leading to reduced tumor growth. Interference with Dll4-Notch signaling may be particularly desirable in tumors that have highly induced Dll4-Notch pathway.

interaction

stroma

tissues

development

Vascular

formation

hierarchic network

specification

arterial

maturation

arterial

maturation

vascular

forming

vessels

response

vascular

proliferation

vessels

proliferation

vascular

growth

tumor

recruitment

pericytes

recruitment

pericyte

Inhibition

signaling

inhibition

signaling

defective

maturation

reduced

vessel lumen

reduced

recruitment

defective

response

reduced

growth

signaling

signaling

Notch

signaling

Notch

pathway

Notch

mediated

signaling

induces

Inhibition

proliferation

dependent

development

leads

Dll4 extracellular domain

inhibition

increased

proliferation

induced

defective

leading

defective

growth

induced

pathway

play a critical role

development

Jagged

play a critical role

development

Delta

regulates

specification

regulates

maturation


Input:
An antibody directed against PDGF receptor beta enhances the antitumor and the anti-angiogenic activities of an anti-VEGF receptor 2 antibody.

Platelet-derived growth factor (PDGF) and its receptors (PDGFR) play important roles in tumorigenesis through stimulating tumor growth and promoting angiogenesis via enhancing pericyte recruitment and vessel maturation. Here we produced a neutralizing antibody, 1B3, directed against mouse PDGFRbeta. 1B3 binds to PDGFRbeta with high affinity (9x10(-11)M) and blocks PDGF-BB from binding to the receptor with an IC(50) of approximately 1.2 nM. The antibody also blocks ligand-stimulated activation of PDGFRbeta and downstream signaling molecules, including Akt and MAPK p42/44, in tumor cells. In animal studies, 1B3 significantly enhanced the antitumor and the anti-angiogenic activities of DC101, an antibody directed against mouse vascular endothelial growth factor receptor 2, in a pancreatic (BxPC-3) and a non-small cell lung (NCI-H460) tumor xenograft models. Treatment with the combination of 1B3 and DC101 in BxPC-3 xenograft-bearing mice resulted in tumor regression in 58% of mice compared to that in 18% of mice treated with DC101 alone. Taken together, these results lend great support to use PDGFRbeta antagonists in combinations with other antitumor and/or anti-angiogenic agents in the treatment of a variety of cancers.

binds

PDGFRbeta

binding

PDGF-BB

angiogenic

angiogenesis

angiogenic

angiogenic

maturation

vessel

growth

tumor

recruitment

pericyte

activities

tumor

anti-VEGF receptor 2 antibody

activities

angiogenic

anti-VEGF receptor 2 antibody

blocks

binding

blocks

activation

activities

tumor

activities

angiogenic

regression

tumor

Treatment

mice

treated

mice

treatment

cancers

enhances

PDGF receptor beta

anti-VEGF receptor 2 antibody

enhances

PDGF receptor beta

activities

stimulating

Platelet-derived growth factor

growth

stimulating

Platelet-derived growth factor

promoting

stimulating

PDGFR

growth

stimulating

PDGFR

promoting

promoting

angiogenesis

enhancing

Platelet-derived growth factor

enhancing

PDGFR

enhancing

recruitment

enhancing

maturation

activation

PDGFRbeta

activation

Akt

activation

MAPK p42/44

enhanced

activities

resulted

Treatment

regression


Input:
Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and interleukin-8 expression in hypoxic human colon cancer cells.

Frequent coffee consumption has been associated with a reduced risk of colorectal cancer in a number of case-control studies. Coffee is a leading source of methylxanthines, such as caffeine. The induction of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) is an essential feature of tumor angiogenesis, and the hypoxia-inducible factor-1 (HIF-1) transcription factor is known to be a key regulator of this process. In this study, we investigated the effects of caffeine on HIF-1 protein accumulation and on VEGF and IL-8 expression in the human colon cancer cell line HT29 under hypoxic conditions. Our results show that caffeine significantly inhibits adenosine-induced HIF-1alpha protein accumulation in cancer cells. We show that HIF-1alpha and VEGF are increased through A3 adenosine receptor stimulation, whereas the effects on IL-8 are mediated via the A2B subtype. Pretreatment of cells with caffeine significantly reduces adenosine-induced VEGF promoter activity and VEGF and IL-8 expression. The mechanism of caffeine seems to involve the inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and Akt, leading to a marked decrease in adenosine-induced HIF-1alpha accumulation, VEGF transcriptional activation, and VEGF and IL-8 protein accumulation. From a functional perspective, we observe that caffeine also significantly inhibits the A3 receptor-stimulated cell migration of colon cancer cells. Conditioned media prepared from colon cells treated with an adenosine analog increased human umbilical vein endothelial cell migration. These data provide evidence that adenosine could modulate the migration of colon cancer cells by an HIF-1alpha/VEGF/IL-8-dependent mechanism and that caffeine has the potential to inhibit colon cancer cell growth.

angiogenesis

tumor

growth

colon cancer cell

expression

expression

hypoxia-inducible factor-1alpha

expression

vascular endothelial growth factor

expression

VEGF

expression

expression

VEGF

expression

migration

colon cancer cells

migration

human umbilical vein endothelial cell

migration

colon cancer cells

inhibits

Caffeine

accumulation

inhibits

caffeine

accumulation

reduces

Pretreatment

induced

reduces

Pretreatment

expression

inhibition

extracellular signal-regulated kinase 1

inhibition

inhibition

inhibition

Akt

decrease

accumulation

decrease

activation

decrease

accumulation

inhibits

caffeine

migration

inhibit

caffeine

growth

mechanism

Pretreatment

cells

caffeine

treated

colon cells

adenosine

accumulation

adenosine

expression

induction

vascular endothelial growth factor

induction

essential

induction

angiogenesis

accumulation

induced

adenosine

accumulation

accumulation

increased

stimulation

increased

VEGF

stimulation

stimulation

A3 adenosine receptor

induced

adenosine

VEGF

promoter

leading

caffeine

decrease

induced

adenosine

accumulation

accumulation

activation

transcriptional

accumulation

VEGF

accumulation

stimulated

A3 receptor

migration

increased

migration

dependent

mechanism

dependent

VEGF

mechanism

dependent

mechanism

effects

caffeine

accumulation

effects

caffeine

expression

effects

mediated

effects

involve

caffeine

inhibition

modulate

adenosine

migration

transcriptional

VEGF


Input:
Medical therapy for intermittent claudication.

Medical therapy to improve symptoms, stabilise the underlying vascular disease and improve lower limb outcomes is an important and effective adjunct to lifestyle modification and surgical or endovascular interventions in patients with IC. Randomised placebo controlled trials have shown that the phosphodiesterase III inhibitor cilostazol 100mg bid improves pain-free and maximum walking distance, as well as quality of life, in a range of patients with intermittent claudication in whom there is no evidence of tissue necrosis or rest pain. This review summarises the evidence from 8 pivotal trials of cilostazol involving over 2000 patients with intermittent claudication treated for up to 6 months. There is comparatively less evidence to support the use of other treatment modalities for relief of symptoms in intermittent claudication, but there is considerable interest in therapeutic angiogenesis to promote new vessel formation and enhance collateralisation of the lower limb using recombinant growth factor proteins or gene transfer strategies. The rationale for therapeutic angiogenesis is discussed, together with the most recent results from randomised trials in patients with peripheral arterial disease.

angiogenesis

collateralisation

angiogenesis

necrosis

tissue

formation

vessel

treated

cilostazol

patients

randomised trials

patients

promote

angiogenesis

formation

enhance

angiogenesis

collateralisation


Input:
An assay to measure angiogenesis in human fat tissue.

BACKGROUND: Inhibition of angiogenesis reverses rodent obesity. A validated assay in human fat tissue is needed to study the role of angiogenesis in human obesity. METHODS: Human fat tissue fragments from surgery were placed in 96-well plates, embedded in fibrin thrombin clot and overlaid with cell culture media containing 20% fetal bovine serum. After 15 days, the clots were examined by histology and electron microscopy. The effect of taxol, cobalt chloride and a heparin-steroid combination was tested in the fat tissue assay and compared to the validated human placental vein angiogenesis model (HPVAM). RESULTS: Blood vessels initiated growth and elongated from the fat tissue fragments over 15 days. Presence of blood vessels was confirmed with histology and electron microscopy. Taxol at 10(-6) and 10(-7) M completely inhibited angiogenesis, while Taxol 10(-8) and 10(-9) M and the heparin-steroid partially inhibited angiogenesis. The response to taxol and heparin-steroid was similar to that of the HPVAM, a validated angiogenesis assay. Cobalt chloride, a stimulator of vascular endothelial growth factor (VEGF) stimulated angiogenesis initiation at 10(-9) M in fat tissue and the HPVAM, but at 10(-10) M blood vessel growth was stimulated only in the fat assay. CONCLUSION: This angiogenesis assay based on human fat tissue uses three-dimensionally intact human tissue. The vessels are derived from quiescient vessels within the fat. These properties allow the angiogenic switch to be evaluated in an in vitro setting. The angiogenic response of fat tissue is not identical to placental tissue. This assay allows exploration of angiogenesis in fat tissue.

angiogenesis

fat tissue

angiogenesis

angiogenesis

angiogenesis

placental vein

angiogenesis

angiogenesis

angiogenesis

angiogenesis

angiogenesis

angiogenic

angiogenic

fat tissue

angiogenic

placental tissue

angiogenesis

fat tissue

growth

Blood vessels

elongated

Blood vessels

growth

blood vessel

Inhibition

angiogenesis

inhibited

Taxol

angiogenesis

inhibited

Taxol

angiogenesis

inhibited

heparin-steroid

angiogenesis

surgery

Human

placed

fat tissue

embedded

fat tissue

clot

overlaid

fat tissue

serum

culture

cell

initiated

growth

stimulated

Cobalt chloride

initiation

initiation

angiogenesis

stimulated

Cobalt chloride

growth

exploration

angiogenesis

role

angiogenesis


Input:
Ovarian cancers overexpress the antimicrobial protein hCAP-18 and its derivative LL-37 increases ovarian cancer cell proliferation and invasion.

The role of the pro-inflammatory peptide, LL-37, and its pro-form, human cationic antimicrobial protein 18 (hCAP-18), in cancer development and progression is poorly understood. In damaged and inflamed tissue, LL-37 functions as a chemoattractant, mitogen and pro-angiogenic factor suggesting that the peptide may potentiate tumor progression. The aim of this study was to characterize the distribution of hCAP-18/LL-37 in normal and cancerous ovarian tissue and to examine the effects of LL-37 on ovarian cancer cells. Expression of hCAP-18/LL-37 was localized to immune and granulosa cells of normal ovarian tissue. By contrast, ovarian tumors displayed significantly higher levels of hCAP-18/LL-37 where expression was observed in tumor and stromal cells. Protein expression was statistically compared to the degree of immune cell infiltration and microvessel density in epithelial-derived ovarian tumors and a significant correlation was observed for both. It was demonstrated that ovarian tumor tissue lysates and ovarian cancer cell lines express hCAP-18/LL-37. Treatment of ovarian cancer cell lines with recombinant LL-37 stimulated proliferation, chemotaxis, invasion and matrix metalloproteinase expression. These data demonstrate for the first time that hCAP-18/LL-37 is significantly overexpressed in ovarian tumors and suggest LL-37 may contribute to ovarian tumorigenesis through direct stimulation of tumor cells, initiation of angiogenesis and recruitment of immune cells. These data provide further evidence of the existing relationship between pro-inflammatory molecules and ovarian cancer progression.

angiogenic

angiogenesis

damaged

tissue

proliferation

ovarian cancer cell

proliferation

ovarian cancer cell lines

development

cancer

progression

cancer

progression

tumor

progression

ovarian cancer

overexpress

overexpress

Expression

Expression

expression

expression

express

express

expression

matrix metalloproteinase

overexpressed

overexpressed

invasion

ovarian cancer cell

localized

immune

localized

granulosa cells

localized

immune

localized

granulosa cells

infiltration

immune cell

chemotaxis

ovarian cancer cell lines

invasion

ovarian cancer cell lines

recruitment

immune cells

Treatment

ovarian cancer cell lines

increases

overexpress

proliferation

increases

overexpress

invasion

stimulated

Treatment

proliferation

stimulated

Treatment

chemotaxis

stimulated

Treatment

invasion

stimulated

Treatment

expression

stimulation

tumor cells

initiation

angiogenesis

role

development

role

progression

role

human cationic antimicrobial protein 18

development

role

human cationic antimicrobial protein 18

progression

effects

ovarian cancer cells

contribute

stimulation

contribute

initiation

contribute

recruitment


Input:
Role of telomeres in vascular senescence.

Telomeres are DNA regions composed of TTAGGG repeats that are located at the ends of chromosomes. Specific proteins associate with the telomeres and form non-nucleosomal DNA-protein complexes that serve as protective caps for the chromosome ends. There is accumulating evidence that progressive telomere shortening is closely related to cardiovascular disease. For example, vascular cell senescence has been reported to occur in human atherosclerotic lesions and this change is associated with telomere shortening. Impairment of telomere integrity causes vascular dysfunction, which is prevented by the activation of telomerase. Mice with short telomeres develop hypertension and exhibit impaired neovascularization. Short telomeres have also been reported in the leukocytes of patients with cardiovascular disease or various cardiovascular risk factors. Although it remains unclear whether short telomeres directly cause cardiovascular disease, manipulation of telomere function is potentially an attractive strategy for the treatment of vascular senescence.

neovascularization

dysfunction

vascular

prevented

dysfunction

activation

activation

telomerase


Input:
Tumor microenvironment, a dangerous society leading to cancer metastasis. From mechanisms to therapy and prevention.

Cancer is no longer considered by scientists just a jumble of mutated cells. To grow, invade and metastasize, a treacherous society between cancer and host cells must be formed, and this association provides novel and effective clinical targets for cancer control and prevention. This collection of reviews at the front-edge of scientific knowledge focuses on host-tumor cell interactions, the disastrous consequences they can produce and approaches the ways to break up these cellular conspiracies, to leave the tumor cells unattended and vulnerable.

interactions

host

tumor cell

grow

cancer

metastasis

cancer

invade

cancer

metastasize

cancer

prevention

cancer

control

cancer


Input:
[Photodynamic therapy in severe chronic central serous chorioretinopaty]

OBJECTIVE: To determine the efficacy of Photodynamic Therapy (PDT) in chronic Central Serous Chorioretinopathy (CSC). METHODS: Patients diagnosed with chronic CSC, with clinical evidence of activity and treated with Photodynamic Therapy, are included in this report. All were assessed by a complete ophthalmological examination, including assessment of the best corrected visual acuity (BCVA) using an ETDRS chart, fluorescein and indocyanine angiography and optical coherence tomography (OCT). The main objective of the study was to determine the mean visual acuity change. RESULTS: 11 eyes of 11 patients were included in the study, which had a mean follow-up period of 11 months. The mean BCVA increased from 20/76 to 20/64. 35% of eyes improved their BCVA by 2 lines or more, 45% remained stable and 18% lost 2 lines or more. Choroidal hyperpermeability was reduced in every case. Neurosensorial retinal detachment decreased in 80% of cases. Only one eye received a second PDT treatment due to choroidal neovascularization. An increase of atrophy over the Retinal Pigment Epithelium (RPE) was observed in another patient. CONCLUSIONS: PDT can reduce the clinical signs of activity, such as choroidal hyperpermeability or neurosensorial retinal detachment, in patients affected by chronic CSC. However, the increase in visual acuity is variable, probably due to the extent of RPE damage.

neovascularization

treated

Patients

PDT treatment

eye

improved

eyes

increase

Retinal Pigment Epithelium


Input:
Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia.

Vascular endothelial growth factor (VEGF) and Angiopoietin 1 (Ang1) are both potent proangiogenic factors, but, whereas VEGF causes vascular permeability, Ang1 stabilizes blood vessels and protects them from VEGF-induced plasma leakage. The antivascular permeability mechanisms deployed by Ang1 are still undefined. Here, we demonstrate that Ang1 halts the ability of VEGF to induce the phosphorylation-dependent redistribution of the adhesion molecule VE-cadherin, thereby rescuing the endothelial barrier function. Ang1 inhibits the activation of Src by VEGF, the most upstream component of the pathway linking VEGF receptors to VE-cadherin internalization. Indeed, Ang1 promotes the activation of mDia through RhoA, resulting in the association of mDia with Src. This ultimately deprives VEGF receptors of an essential molecule required for promoting the disruption of endothelial cell-cell contacts and paracellular permeability.

association

mDia

Src

cell-cell contacts

endothelial

angiogenic

leakage

plasma

redistribution

VE-cadherin

internalization

VE-cadherin

prevents

induced

sequestering

sequestering

sequestering

Src

protects

leakage

halts

induce

inhibits

activation

disruption

cell-cell contacts

phosphorylation

VE-cadherin

induced

VEGF

endothelial

induced

VEGF

leakage

induce

VEGF

redistribution

dependent

phosphorylation

redistribution

activation

Src

VEGF

promotes

promotes

activation

activation

mDia

resulting

promotes

association

required

promoting

promoting

disruption

sequestering

mDia

stabilizes

blood vessels

promotes

RhoA


Input:
Suppression of lung tumor growth and metastasis in mice by adeno-associated virus-mediated expression of vasostatin.

PURPOSE: Angiogenesis inhibitors have strong therapeutic potential as antitumor agents in suppressing tumor growth and metastatic progression. Vasostatin, the N-terminal domain of calreticulin, is a potent angiogenesis inhibitor. In this study, we determined the effectiveness of vasostatin delivered by recombinant pseudotype adeno-associated virus 2/5 (rAAV2/5-VAS) as a gene therapy approach for lung cancer treatment. EXPERIMENTAL DESIGN: We used rAAV2/5 to deliver vasostatin intratumorally or systemically in different mouse lung tumor models--subcutaneous, orthotopic xenograft, and spontaneous metastasis lung tumor models. The therapeutic efficacy of rAAV2/5-VAS was determined by monitoring tumor volume, survival rate, and degree of neovascularization after treatment in these models. RESULTS: Mice bearing subcutaneous tumor of rAAV2/5-VAS pretreated Lewis lung carcinoma cells showed >50% reduction in primary tumor volume and reduced spontaneous pulmonary metastases. The tumor-suppressive action of rAAV2/5-VAS in subcutaneous human lung tumor A549 xenograft correlated with a reduced number of capillary vessels in tumors. In the orthotopic xenograft model, rAAV2/5-VAS suppressed metastasis of A549 tumors to mediastinal lymph nodes and contralateral lung. Furthermore, treatment of immunocompetent mice in the spontaneous lung metastases model with rAAV2/5-VAS after primary tumor excision prolonged their median survival from 21 to 51.5 days. CONCLUSION: Our results show the effectiveness of rAAV2/5-VAS as an angiogenesis inhibitor in suppressing tumor growth during different stages of tumor progression, validating the application of rAAV2/5-VAS gene therapy in treatment against lung cancer.

Angiogenesis

angiogenesis

neovascularization

angiogenesis

metastatic progression

tumor

progression

tumor

expression

vasostatin

growth

lung tumor

growth

tumor

growth

tumor

metastasis

lung tumor

metastases

tumor

pulmonary

metastasis

A549 tumors

lymph nodes

metastasis

A549 tumors

lung

Suppression

growth

expression

Suppression

metastasis

expression

suppressing

growth

suppressing

metastatic progression

reduction

pretreated

tumor

reduced

pretreated

pulmonary

tumor-suppressive action

lung tumor A549 xenograft

tumor-suppressive action

lung tumor A549 xenograft

reduced

capillary vessels

suppressed

metastasis

suppressed

metastasis

effectiveness

angiogenesis

effectiveness

angiogenesis

suppressing

growth

suppressing

growth

against

gene therapy

lung cancer

delivered

vasostatin

recombinant pseudotype adeno-associated virus 2

gene therapy

lung cancer

deliver

vasostatin

lung tumor

deliver

vasostatin

lung tumor

pretreated

Lewis lung carcinoma cells

treatment

mice

excision

tumor

gene therapy

gene therapy

mediated

adeno-associated virus

expression

effectiveness

delivered

gene therapy


Input:
Radiation retinopathy is treatable with anti-vascular endothelial growth factor bevacizumab (Avastin).

PURPOSE: To report on bevacizumab treatment for radiation retinopathy affecting the macula. PATIENTS AND METHODS: Twenty-one patients with radiation retinopathy (edema, hemorrhages, capillary dropout, and neovascularization) and a subjective or objective loss of vision were treated. Treatment involved intravitreal injection of bevacizumab (1.25 mg in 0.05 mL) every 6-12 weeks. Treatment was discontinued at patient request or if there was no measurable response to therapy. Main outcome measures included best corrected visual acuity, ophthalmic examination, retinal photography, and angiography. RESULTS: Bevacizumab treatment was followed by reductions in retinal hemorrhage, exudation, and edema. Visual acuities were stable or improved in 86% (n=18). Three patients discontinued therapy. Each was legally blind before treatment (n=1), experienced little to no subjective improvement (n=2), or was poorly compliant (n=2). Three patients (14%) regained 2 or more lines of visual acuity. No ocular or systemic bevacizumab-related side effects were observed. CONCLUSIONS: Intravitreal bevacizumab can be used to treat radiation retinopathy. In most cases treatment was associated with decreased vascular leakage, stabilization, or improved vision. An anti-vascular endothelial growth factor strategy may reduce tissue damage associated with radiation vasculopathy and neuropathy.

neovascularization

damage

tissue

reduce

damage

treatment

bevacizumab

intravitreal injection

bevacizumab

treatment

Bevacizumab

affecting

treatment

macula


Input:
Mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma.

We hypothesized that signaling through multiple mitogen-activated protein kinase (MAPK) kinase (MKK) pathways is essential for the growth and vascularization of soft-tissue sarcomas, which are malignant tumors derived from mesenchymal tissues. We tested this using HT-1080, NCI, and Shac fibrosarcoma-derived cell lines and anthrax lethal toxin (LeTx), a bacterial toxin that inactivates MKKs. Western blots confirmed that LeTx treatment reduced the levels of phosphorylated extracellular signal-regulated kinase and p38 MAPK in vitro. Although short treatments with LeTx only modestly affected cell proliferation, sustained treatment markedly reduced cell numbers. LeTx also substantially inhibited the extracellular release of angioproliferative factors including vascular endothelial growth factor, interleukin-8, and basic fibroblast growth factor. Similar results were obtained with cell lines derived from malignant fibrous histiocytomas, leiomyosarcomas, and liposarcomas. In vivo, LeTx decreased MAPK activity and blocked fibrosarcoma growth. Growth inhibition correlated with decreased cellular proliferation and extensive necrosis, and it was accompanied by a decrease in tumor mean vessel density as well as a reduction in serum expression of angioproliferative cytokines. Vital imaging using high-resolution ultrasound enhanced with contrast microbubbles revealed that the effects of LeTx on tumor perfusion were remarkably rapid ( less than 24 h) and resulted in a marked reduction of perfusion within the tumor but not in nontumor tissues. These results are consistent with our initial hypothesis and lead us to propose that MKK inhibition by LeTx is a broadly effective strategy for targeting neovascularization in fibrosarcomas and other similar proliferative lesions.

vascularization

fibrosarcoma

vascularization

soft-tissue sarcomas

angioproliferative

angioproliferative

neovascularization

fibrosarcomas

neovascularization

proliferative lesions

proliferation

cell

proliferation

cellular

perfusion

tumor

perfusion

tumor

growth

fibrosarcoma

growth

soft-tissue sarcomas

growth

fibrosarcoma

Growth

fibrosarcoma

release

vascular endothelial growth factor

release

release

basic fibroblast growth factor

inactivates

lethal toxin

MKKs

reduced

treatment

phosphorylated

inhibited

LeTx

release

decreased

LeTx

MAPK

blocked

LeTx

growth

inhibition

Growth

decrease

vessel

reduction

serum

reduction

perfusion

inhibition

MKK

LeTx

signaling

Mitogen-activated protein kinase kinase

pathways

mitogen-activated protein kinase (MAPK) kinase

phosphorylated

extracellular signal-regulated kinase

phosphorylated

p38 MAPK

treatment

LeTx

treatments

LeTx

promotes

signaling

growth

promotes

signaling

vascularization

essential

pathways

growth

essential

pathways

vascularization

resulted

reduction

affected

treatments

proliferation

effects

LeTx

perfusion

targeting

inhibition

neovascularization


Input:
Acute ethanol exposure disrupts VEGF receptor cell signaling in endothelial cells.

Physiological angiogenesis is regulated by various factors, including signaling through vascular endothelial growth factor (VEGF) receptors. We previously reported that a single dose of ethanol (1.4 g/kg), yielding a blood alcohol concentration of 100 mg/dl, significantly impairs angiogenesis in murine wounds, despite adequate levels of VEGF, suggesting direct effects of ethanol on endothelial cell signaling (40). To examine the mechanism by which ethanol influences angiogenesis in wounds, we employed two different in vitro angiogenesis assays to determine whether acute ethanol exposure (100 mg/dl) would have long-lasting effects on VEGF-induced capillary network formation. Ethanol exposure resulted in reduced VEGF-induced cord formation on collagen and reduced capillary network structure on Matrigel in vitro. In addition, ethanol exposure decreased expression of endothelial VEGF receptor-2, as well as VEGF receptor-2 phosphorylation in vitro. Inhibition of ethanol metabolism by 4-methylpyrazole partially abrogated the effect of ethanol on endothelial cell cord formation. However, mice treated with t-butanol, an alcohol not metabolized by alcohol dehydrogenase, exhibited no change in wound vascularity. These results suggest that products of ethanol metabolism are important factors in the development of ethanol-induced changes in endothelial cell responsiveness to VEGF. In vivo, ethanol exposure caused both decreased angiogenesis and increased hypoxia in wounds. Moreover, in vitro experiments demonstrated a direct effect of ethanol on the response to hypoxia in endothelial cells, as ethanol diminished nuclear hypoxia-inducible factor-1alpha protein levels. Together, the data establish that acute ethanol exposure significantly impairs angiogenesis and suggest that this effect is mediated by changes in endothelial cell responsiveness to both VEGF and hypoxia.

angiogenesis

angiogenesis

wounds

angiogenesis

wounds

angiogenesis

angiogenesis

wounds

angiogenesis

formation

capillary network

formation

cord

formation

endothelial cell cord

expression

VEGF receptor-2

metabolism

ethanol

metabolized

t-butanol

metabolism

ethanol

disrupts

exposure

cell signaling

impairs

ethanol

angiogenesis

reduced

formation

reduced

capillary network

decreased

exposure

phosphorylation

decreased

exposure

expression

Inhibition

metabolism

abrogated

Inhibition

effect

decreased

exposure

angiogenesis

diminished

ethanol

hypoxia-inducible factor-1alpha

impairs

exposure

angiogenesis

cell signaling

VEGF receptor

signaling

phosphorylation

VEGF receptor-2

exposure

ethanol

exposure

ethanol

exposure

Ethanol

exposure

ethanol

treated

mice

t-butanol

exposure

ethanol

exposure

ethanol

induced

VEGF

formation

resulted

exposure

reduced

resulted

exposure

reduced

induced

VEGF

formation

metabolized

metabolized

alcohol dehydrogenase

induced

ethanol

changes

regulated

angiogenesis

vascular endothelial growth factor (VEGF) receptors

effects

ethanol

signaling

influences

ethanol

angiogenesis

effects

exposure

formation

effect

ethanol

formation

important

metabolism

changes

changes

responsiveness

responsiveness

endothelial cell

VEGF

mediated

impairs

changes

changes

responsiveness

responsiveness

endothelial cell

VEGF


Input:
Adenomatoid tumour of the liver.

An unusual primary adenomatoid tumour arising in the normal liver is described. Hepatectomy was performed, and the patient is alive and free of disease 1 year postsurgery. Grossly, the tumour showed a haemorrhagic cut surface with numerous microcystic structures. Histological examination revealed cystic or angiomatoid spaces of various sizes lined by cuboidal, low-columnar, or flattened epithelioid cells with vacuolated cytoplasm and round to oval nuclei. The epithelioid cells were entirely supported by proliferated capillaries and arteries together with collagenous stroma. Immunohistochemical studies showed that the epithelioid cells were strongly positive for a broad spectrum of cytokeratins (AE1/AE3, CAM5.2, epithelial membrane antigen and cytokeratin 7) and mesothelial markers (calretinin, Wilms' tumour 1 and D2-40). These cells were negative for Hep par-1, carcinoembryonic antigen, neural cell adhesion molecule, CD34, CD31 and HMB45. Atypically, abundant capillaries were observed; however, the cystic proliferation of epithelioid cells with vacuoles and immunohistochemical profile of the epithelioid element were consistent with hepatic adenomatoid tumour.

angiomatoid

proliferation

epithelioid cells

proliferated

capillaries

proliferated

arteries

Hepatectomy

patient

flattened

epithelioid cells


Input:
Research advances of endostatin and its short internal fragments.

Endostatin, the C-terminal fragment of collagen XVIII, is a potent angiogenesis inhibitor. At present, there are a large number of research papers on endostatin. However, the action mechanism of endostatin is still a matter of ongoing discussion. The objective of this review is to elucidate its origin and elementary structure, and to discuss its structure basis of activity and action mechanisms based on the latest research. Furthermore, some published studies reporting the antiangiogenic effects of endostatin-derived peptides were also reviewed. It is proposed that the amino acid sequence of endostatin contains both angiosuppressive and angiostimulatory domains. Short endostatin fragments may be exploited as a new angiogenesis inhibitor for therapeutic applications, in substitution of the full length endostatin. These studies on endostatin fragments also shed light on our understanding of the molecular action mechanisms of endostatin.

angiogenesis

angiogenic

angiosuppressive

angiostimulatory

angiogenesis

effects

angiogenic


Input:
Contemporary perspectives on vital pulp therapy: views from the endodontists and pediatric dentists.

The purpose of this study was to determine the level of agreement between pediatric dentists and endodontists at a pulp therapy symposium conjointly sponsored by the American Association of Endodontists (AAE) and the American Academy of Pediatric Dentistry (AAPD) on November 2-3, 2007. Presymposium and postsymposium tests were administered, and respondent answers were compared between pediatric dentists and endodontists. Opinions on 3 areas were sought: pulp therapy for cariously involved primary teeth; indirect pulp treatment (IPT) for cariously involved immature permanent teeth; and innovative treatment options including pulpal revascularization and regeneration. Results were analyzed with chi2 tests. Comparisons of presymposium and postsymposium responses and between the 2 groups of attendees indicated that the pediatric dentistry and endodontic communities agree that formocresol will be replaced as a primary tooth pulpotomy agent, that mineral trioxide is the first choice to take its place, that IPT in primary teeth holds hope as a replacement for pulpotomy, and that IPT is an acceptable pulp therapy technique for cariously involved young permanent teeth. Both groups believe that pulp revascularization and regeneration will be viable treatment modalities in the future. The AAE and the AAPD are positioned to begin preparation of best practice guidelines that share common language and treatment recommendations for pulp therapies performed by both specialties.

revascularization

pulpal

revascularization

pulp

regeneration

pulpal

regeneration

pulp

therapy

pulp

therapy

pulp

therapy

pulp

treatment

pulp

therapy

pulp

therapies

pulp


Input:
The role of platelet-derived endothelial cell growth factor/thymidine phosphorylase in tumor behavior.

Platelet-derived endothelial cell growth-factor (PD-ECGF) is similar to the pyrimidine enzyme thymidine phosphorylase (TP). A high TP expression at tumor sites is correlated with tumor growth, induction of angiogenesis, and metastasis. Therefore, high TP is most likely associated with a poor prognosis. TP is not only expressed in tumor cells but also in tumor surrounding tissues, such as tumor infiltrating macrophages. TP catalyzes the conversion of thymidine to thymine and doxyribose-1-phosphate (dR-1-P). The latter in its parent form or in its sugar form, deoxyribose (dR) may play a role in the induction of angiogenesis. It may modulate cellular energy metabolism or be a substrate in a chemical reaction generating reactive oxygen species. L-deoxyribose (L-dR) and thymidine phosphorylase inhibitor (TPI) can reverse these effects. The mechanism of TP induction is not yet completely clear, but TNF, IL10 and other cytokines have been clearly shown to induce its expression. The various complex interactions of TP give it an essential role in cellular functioning and, hence, it is an ideal target in cancer therapy.

angiogenesis

angiogenesis

expression

TP

expressed

TP

expression

TNF

expression

growth

tumor

catalyzes

thymidine

catalyzes

thymine

catalyzes

induction

angiogenesis

induction

angiogenesis

induction

TP

induce

expression

role

platelet-derived endothelial cell growth factor

tumor

role

thymidine phosphorylase

tumor

catalyzes

TP

catalyzes

play a role

deoxyribose

induction


Input:
Allogeneic injection of fetal membrane-derived mesenchymal stem cells induces therapeutic angiogenesis in a rat model of hind limb ischemia.

Bone marrow-derived mesenchymal stem cells (BM-MSC) have been demonstrated to be an attractive therapeutic cell source for tissue regeneration and repair. However, it remains unknown whether or not allogeneic transplantation of mesenchymal stem cells (MSC) derived from fetal membranes (FM), which are generally discarded as medical waste after delivery, has therapeutic potential. FM-MSC were obtained from Lewis rats and had surface antigen expression and multipotent potential partly similar to those of BM-MSC. Compared with BM-MSC, FM-MSC secreted a comparable amount of hepatocyte growth factor despite a small amount of vascular endothelial growth factor. FM-MSC and BM-MSC both expressed major histocompatibility complex (MHC) class I but not MHC class II antigens and did not elicit allogeneic lymphocyte proliferation in mixed lymphocyte culture. FM-MSC or BM-MSC obtained from Lewis rats were injected into a MHC-mismatched August-Copenhagen-Irish rat model of hind limb ischemia. Three weeks after injection, blood perfusion and capillary density were significantly higher in the FM-MSC and BM-MSC groups than in the phosphate-buffered saline group, and allogeneic FM-MSC and BM-MSC were still observed. In nonischemic hind limb tissues, allogeneic FM-MSC and BM-MSC injection were associated with a comparatively small amount of T lymphocyte infiltration, compared with the injection of allogeneic splenic lymphocytes. In conclusion, allogeneic FM-MSC injection did not elicit a lymphocyte proliferative response and provided significant improvement in a rat model of hind limb ischemia, comparable to the response to BM-MSC. Thus, allogeneic injection of FM-MSC may be a new therapeutic strategy for the treatment of severe peripheral vascular disease. Disclosure of potential conflicts of interest is found at the end of this article.

angiogenesis

proliferation

lymphocyte

proliferative response

lymphocyte

regeneration

tissue

repair

tissue

secreted

FM-MSC

hepatocyte growth factor

secreted

FM-MSC

vascular endothelial growth factor

infiltration

T lymphocyte

injection

fetal membrane-derived mesenchymal stem cells

transplantation

mesenchymal stem cells

obtained

FM-MSC

obtained

BM-MSC

obtained

FM-MSC

injected

BM-MSC

rat

injected

FM-MSC

rat

observed

FM-MSC

observed

BM-MSC

injection

FM-MSC

injection

BM-MSC

injection

splenic lymphocytes

injection

FM-MSC

injection

FM-MSC

induces

injection

angiogenesis

elicit

injection

proliferative response


Input:
Intracerebral grafting of cultured autologous skin fibroblasts into the rat striatum: an assessment of graft size and ultrastructure.

To identify a suitable donor cell population for gene therapy applications to the central nervous system, primary fibroblasts isolated from skin biopsies and maintained in culture are employed as autologous cells for intracerebral grafting within the adult rat striatum. Results from the present investigation reveal that cultured primary skin fibroblasts cease to proliferate once they reach confluence; these cells are thus contact inhibited in vitro. Following implantation within the striatum, the volume of the primary fibroblast grafts, stained immunohistochemically for fibronectin, does not differ significantly at 3 and 8 weeks. The graft size is dependent on the density of the cell suspension, but not dependent on either the number of passages the cells are taken through in culture prior to grafting or on the postoperative survival period. Ultrastructural evidence reveals that at 8 weeks the grafts are composed primarily of collagen and fibroblasts with rough endoplasmic reticulum and vesicles. Reactive astrocytic processes and phagocytic cells are also present in the grafts. The grafts are extensively vascularized with capillaries composed of nonfenestrated endothelium; intercellular junctions are evident at sites of apposition between endothelial cells. It is concluded that primary skin fibroblasts are able to survive for at least 8 weeks following intracerebral implantation and continue to synthesize collagen and fibronectin in vivo. Also, the grafts maintain a constant volume between 3 and 8 weeks, thereby indicating that primary skin fibroblasts do not produce tumors. Finally, dynamic host-to-graft interactions--including phagocytic migration, astrocytic hypertrophy and infiltration within the grafts, and angiogenesis--are features that constitute the structural integration of primary skin fibroblasts grafted within the adult rat central nervous system.

contact

cells

angiogenesis

proliferate

skin fibroblasts

survive

skin fibroblasts

produce

tumors

synthesize

collagen

synthesize

fibronectin

inhibited

contact

Intracerebral grafting

skin fibroblasts

striatum

isolated

fibroblasts

intracerebral grafting

cells

striatum

cultured

skin fibroblasts

implantation

striatum

fibroblast grafts

passages

cells

culture

cells

grafting

cells

grafted

skin fibroblasts

central nervous system


Input:
Angiogenesis associated with visceral and subcutaneous adipose tissue in severe human obesity.

OBJECTIVE: The expansion of adipose tissue is linked to the development of its vasculature. However, the regulation of adipose tissue angiogenesis in humans has not been extensively studied. Our aim was to compare the angiogenesis associated with subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from the same obese patients in an in vivo model. RESEARCH DESIGN AND METHODS: Adipose tissue samples from visceral (VAT) and subcutaneous (SAT) sites, obtained from 36 obese patients (mean BMI 46.5 kg/m(2)) during bariatric surgery, were layered on chick chorioallantoic membrane (CAM). RESULTS: Both SAT and VAT expressed angiogenic factors without significant difference for vascular endothelial growth factor (VEGF) expression. Adipose tissue layered on CAM stimulated angiogenesis. Angiogenic stimulation was macroscopically detectable, with engulfment of the samples, in 39% and was evidenced by angiography in 59% of the samples. A connection between CAM and adipose tissue vessels was evidenced by immunohistochemistry, with recruitment of both avian and human endothelial cells. The angiogenic potency of adipose tissue was not related to its localization (with an angiogenic stimulation in 60% of SAT samples and 61% of VAT samples) or to adipocyte size or inflammatory infiltrate assessed in adipose samples before the graft on CAM. Stimulation of angiogenesis by adipose tissue was nearly abolished by bevacizumab, which specifically targets human VEGF. CONCLUSIONS: We have established a model to study the regulation of angiogenesis by human adipose tissue. This model highlighted the role of VEGF in angiogenesis in both SAT and VAT.

connection

CAM

adipose tissue vessels

Angiogenesis

visceral

Angiogenesis

subcutaneous adipose tissue

angiogenesis

adipose tissue

angiogenesis

subcutaneous adipose tissue

angiogenesis

visceral adipose tissue

angiogenic

angiogenesis

Angiogenic

angiogenic

adipose tissue

angiogenic

angiogenesis

angiogenesis

angiogenesis

SAT

angiogenesis

VAT

expansion

adipose tissue

development

vasculature

expression

vascular endothelial growth factor

recruitment

endothelial cells

localization

adipose tissue

abolished

Stimulation

bevacizumab

obtained

VAT

obtained

SAT

layered

VAT

layered

SAT

layered

Adipose tissue

stimulated

Adipose tissue

angiogenesis

stimulation

Angiogenic

stimulation

angiogenic

Stimulation

angiogenesis

adipose tissue

linked

expansion

development

regulation

angiogenesis

targets

bevacizumab

VEGF

regulation

angiogenesis

adipose tissue

role

VEGF

angiogenesis


Input:
M-CSF signals through the MAPK/ERK pathway via Sp1 to induce VEGF production and induces angiogenesis in vivo.

BACKGROUND: M-CSF recruits mononuclear phagocytes which regulate processes such as angiogenesis and metastases in tumors. VEGF is a potent activator of angiogenesis as it promotes endothelial cell proliferation and new blood vessel formation. Previously, we reported that in vitro M-CSF induces the expression of biologically-active VEGF from human monocytes. METHODOLOGY AND RESULTS: In this study, we demonstrate the molecular mechanism of M-CSF-induced VEGF production. Using a construct containing the VEGF promoter linked to a luciferase reporter, we found that a mutation reducing HIF binding to the VEGF promoter had no significant effect on luciferase production induced by M-CSF stimulation. Further analysis revealed that M-CSF induced VEGF through the MAPK/ERK signaling pathway via the transcription factor, Sp1. Thus, inhibition of either ERK or Sp1 suppressed M-CSF-induced VEGF at the mRNA and protein level. M-CSF also induced the nuclear localization of Sp1, which was blocked by ERK inhibition. Finally, mutating the Sp1 binding sites within the VEGF promoter or inhibiting ERK decreased VEGF promoter activity in M-CSF-treated human monocytes. To evaluate the biological significance of M-CSF induced VEGF production, we used an in vivo angiogenesis model to illustrate the ability of M-CSF to recruit mononuclear phagocytes, increase VEGF levels, and enhance angiogenesis. Importantly, the addition of a neutralizing VEGF antibody abolished M-CSF-induced blood vessel formation. CONCLUSION: These data delineate an ERK- and Sp1-dependent mechanism of M-CSF induced VEGF production and demonstrate for the first time the ability of M-CSF to induce angiogenesis via VEGF in vivo.

binding

HIF

VEGF

promoter

angiogenesis

angiogenesis

tumors

angiogenesis

angiogenesis

angiogenesis

angiogenesis

proliferation

endothelial cell

formation

blood vessel

formation

blood vessel

production

VEGF

expression

VEGF

production

VEGF

production

luciferase

production

VEGF

production

VEGF

metastases

tumors

localization

nuclear

recruit

mononuclear phagocytes

reducing

binding

inhibition

ERK

inhibition

suppressed

inhibition

VEGF

blocked

localization

inhibition

inhibition

ERK

inhibiting

ERK

decreased

mutating

VEGF

promoter

decreased

inhibiting

VEGF

promoter

abolished

VEGF antibody

formation

pathway

MAPK

ERK

signaling pathway

MAPK

ERK

linked

promoter

luciferase

mutating

binding sites

treated

M-CSF

monocytes

induce

signals

production

induce

signals

angiogenesis

activator

VEGF

angiogenesis

promotes

VEGF

proliferation

promotes

VEGF

formation

induces

M-CSF

expression

induced

M-CSF

production

induced

production

stimulation

stimulation

M-CSF

induced

induced

VEGF

induced

M-CSF

VEGF

induced

M-CSF

localization

induced

M-CSF

production

increase

M-CSF

VEGF

enhance

M-CSF

angiogenesis

induced

M-CSF

formation

dependent

ERK

production

dependent

production

induced

M-CSF

production

induce

induce

angiogenesis

signals

M-CSF

recruits

M-CSF

mononuclear phagocytes

regulate

recruits

angiogenesis

regulate

recruits

metastases

effect

reducing

production

induced

M-CSF

ability

M-CSF

recruit

induce

M-CSF

VEGF


Input:
A novel integrin alpha5beta1 antagonistic peptide, A5-1, screened by Protein Chip system as a potent angiogenesis inhibitor.

Integrin alpha5beta1 immobilized on a ProteoChip was used to screen new antagonistic peptides from multiple hexapeptide sub-libraries of the positional scanning synthetic peptide combinatorial library (PS-SPCL). The integrin alpha5beta1-Fibronectin interaction was demonstrated on the chip. A novel peptide ligand, A5-1 (VILVLF), with high affinity to integrin alpha5beta1 was identified from the hexapeptide libraries with this chip-based screening method on the basis of a competitive inhibition assay. A5-1 inhibits the integrin-fibronectin interaction in a dose-dependent manner (IC(50); 1.56+/-0.28 microM. In addition, it inhibits human umbilical vein endothelial cell proliferation, migration, adhesion, tubular network formation, and bFGF-induced neovascularization in a chick chorioallantoic membrane. These results suggest that A5-1 will be a potent inhibitor of neovascularization.

interaction

integrin alpha5beta1

Fibronectin

interaction

integrin

fibronectin

adhesion

human umbilical vein endothelial cell

angiogenesis

neovascularization

chorioallantoic membrane

neovascularization

proliferation

human umbilical vein endothelial cell

formation

tubular network

migration

human umbilical vein endothelial cell

inhibits

interaction

inhibits

proliferation

inhibits

migration

inhibits

adhesion

inhibits

formation

inhibits

neovascularization

induced

bFGF

neovascularization