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Results for “Neovascularization, Pathologic”

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PubMed2006

Phospho-Stat3 expression and correlation with VEGF, p53, and Bcl-2 in gastric carcinoma using tissue microarray.

The signal transducer and activator of the transcription (Stat)-family of proteins are latent cytoplasmic transcription factors that transmit signals from cytokines and growth-factor receptors to the nucleus. Stat proteins, especially Stat3 and Stat5, are constitutively activated in various solid tumors and hematological malignancies. However, the role of Stat3 signaling in gastric carcinoma has not yet been fully determined. This study was conducted to investigate the clinical value of phospho-Stat3 expression in gastric carcinoma. Expression of phospho-Stat3 (Tyr705), vascular endothelial growth factor (VEGF), p53, and Bcl-2 was determined by immunohistochemical staining of tissue microarrays from 137 cases of resected gastric cancer specimens. We evaluated the relationships among phospho-Stat3, VEGF, p53, and Bcl-2 expression and the correlation between expression of these proteins and various clinicopathological factors, including overall survival. Phospho-Stat3 nuclear expression was observed in 18.2% of the cases. Of the total number of cases, 68.6% were positive for VEGF, 40.1% for p53, and 11.7% for Bcl-2. Phospho-Stat3 expression correlated with VEGF (p=0.021) and Bcl-2 (p=0.005) expression. Positive phospho-Stat3 staining was significantly associated with poor pathological grade. However, there was no significant difference in other clinicopathological parameters, such as tumor stage (T, N, M), pathological type, relapse-free survival, and overall survival between the phospho-Stat3-positive and -negative groups. Co-expression of phospho-Stat3 and VEGF was found in many patients with N3 and Stage IV disease. These results suggest that phospho-Stat3 expression might be associated with angiogenesis, anti-apoptosis, and tumor progression. Further studies are needed to determine the role of phospho-Stat3 in gastric cancer.

Adenocarcinoma↗

PubMed2002

From pollutant gas to biological messenger: the diverse actions of nitric oxide in cancer.

Nitric oxide (NO) has undergone an image change in recent years. Previously regarded as a toxic pollutant gas, it has now become the subject of intense research in many fields of medicine and science. It is a free radical, with a diverse range of actions in both physiological and pathological processes. Although over 44,000 research papers have now been written on NO, only a small number have originated from the surgical specialties. Its role in tumour biology remains incompletely understood. NO is known to have both tumour promoting and inhibitory effects, presumed to be dependent on its local concentration within the tumour. NO appears to be pivotal in the angiogenic process, and the p53 tumour suppressor gene may influence its production. This review summarises the brief history of this molecule, gives an overview of its many effects in the common solid tumours and discusses how targeting of NO production may have possible future therapeutic benefit.

Cell Division↗

PubMedDate not supplied

Clinical experience with bevacizumab in colorectal cancer.

Angiogenesis, the process of generating new capillary blood vessels, is a fundamental requirement for normal physiological processes including embryogenesis, reproductive function and wound healing. Angiogenesis is also implicated in various pathological conditions including age-related retinal macular degeneration, diabetic retinopathy, rheumatoid arthritis, psoriasis and cancer growth and metastasis. Vascular endothelial growth factor (VEGF) is one of the best characterized of the pro-angiogenic growth factors, and multiple strategies have been developed to inhibit this pathway. Bevacizumab, a monoclonal antibody developed against VEGF, has shown initial preclinical and clinical activity. This review discusses the critical role of VEGF and summarizes the available data on the use of bevacizumab in colorectal cancer.

Antibodies, Monoclonal↗

PubMed1999

Prognostic value of tumour vascularity in metastatic melanoma and association of blood vessel density with vascular endothelial growth factor expression.

Tumour angiogenesis is essential for tumour growth and metastasis. Several lines of evidence indicate that vascular endothelial growth factor (VEGF) is a major regulator both of physiological and pathological angiogenesis. In this study we assessed the blood vessel density and VEGF expression of 94 melanoma metastases of 70 patients by immunohistochemistry, utilizing antibodies against human platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) and VEGF. The number of blood vessels ranged from 4 to 131 vessels/high power field (HPF), with a mean value of 32 vessels/HPF (+/-21) and a median of 29 vessels/ HPF. Survival since diagnosis of the primary disease and from the start of chemoimmunotherapy, as well as the disease-free survival period, was significantly shorter in the high vascularity group of patients compared with the low vascularity group (P< 0.05 and P< 0.01, respectively). A high overall expression of VEGF in the metastatic melanoma samples was observed. The degree of VEGF expression appeared to have a strong association with the blood vessel density (P= 0.017). This study demonstrates the clinical role of tumour vascularity in the prognosis of patients with metastatic melanoma. In addition, the strong association between vascularity and VEGF expression suggests a crucial role for this growth factor in the neovascularization of metastatic melanoma.

Adult↗

PubMed2005

Angiogenesis in gliomas: imaging and experimental therapeutics.

Much of the interest in angiogenesis and hypoxia has led to investigating diagnostic imaging methodologies and developing efficacious agents against angiogenesis in gliomas. In many ways, because of the cytostatic effects of these agents on tumor growth and tumor-associated endothelial cells, the effects of therapy are not immediately evident. Hence finding clinically applicable imaging tools and pathologic surrogate markers is an important step in translating glioma biology to therapeutics. There are a variety of strategies in the approach to experimental therapeutics that target the hypoxia-inducible factor pathway, the endogenous antiangiogenic and proangiogenic factors and their receptors, adhesion molecules, matrix proteases and cytokines, and the existing vasculature. We discuss the rationale for antiangiogenesis as a treatment strategy, the preclinical and clinical assessment of antiangiogenic interventions and finally focus on the various treatment strategies, including combining antiangiogenic drugs with radiation and chemotherapy.

Algorithms↗

PubMed2002

The vasculature and its role in the damaged and healing tendon.

Tendon pathology has many manifestations, from spontaneous rupture to chronic tendinitis or tendinosis; the etiology and pathology of each are very different, and poorly understood. Tendon is a comparatively poorly vascularised tissue that relies heavily upon synovial fluid diffusion to provide nutrition. During tendon injury, as with damage to any tissue, there is a requirement for cell infiltration from the blood system to provide the necessary reparative factors for tissue healing. We describe in this review the response of the vasculature to tendon damage in a number of forms, and how and when the revascularisation or neovascularisation process occurs. We also include a section on the revascularisation of tendon during its use as a tendon graft in both ligament reconstruction and tendon-tendon grafting.

Animals↗

PubMedDate not supplied

The principles of inflammation in the development of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory condition that involves all elements of the immune response. The aetiology of RA is complex and centres on the development of autoantibodies and immune complexes. The pathogenesis is multistage and involves cytokines, angiogenesis and rheumatoid factor. Nurses managing patients who suffer with RA need to be aware of the pathological changes involved in the disease and its contribution to the progression of the condition. The diagnosis of RA involves blood screening for rheumatoid factor, raised erythrocyte sedimentation rate (ESR), use of arthroscopy to provide evidence of histological changes in the synovium, presenting symptoms, and changes on X-ray. Patient assessment will consider both patient-specific and disease-specific variables, including evidence of non-articular manifestations of RA. Long-term care revolves around trying to maintain patient mobility and the protection of unaffected joints, monitoring for the side-effects from medication and progression of the disease or development of non-articular manifestations.

Arthritis, Rheumatoid↗

PubMed2006

Sphingosine 1-phosphate in vascular biology: possible therapeutic strategies to control vascular diseases.

Blood platelets are very unique in that they store sphingosine 1-phosphate (Sph-1-P) abundantly (possibly due to the existence of highly active sphingosine kinase and a lack of Sph-1-P lyase) and release this bioactive lipid extracellularly upon stimulation. Vascular endothelial cells (ECs) and smooth muscle cells (SMCs) respond dramatically to this platelet-derived bioactive lipid mainly through a family of G protein-coupled Sph-1-P receptors named S1P1, 2, 3, 4, and 5, originally referred to as EDG-1, 5, 3, 6, and 8, respectively. In fact, the importance of Sph-1-P in platelet-vascular cell interactions has been revealed in a number of recent reports. Through interaction with ECs, Sph-1-P can mediate physiological wound healing processes such as vascular repair, although this important bioactive lipid can become atherogenic and thrombogenic, and cause or aggravate cardiovascular diseases especially under certain pathological conditions. On the other hand, Sph-1-P induces vasoconstriction through interaction with SMCs. It is likely that regulation of Sph-1-P biological activities is important for the therapeutical purpose to control vascular disorders. Particularly, the development of specific S1P receptor agonists or antagonists seems a reasonable strategy to selectively regulate the bioactivity of Sph-1-P, considering that a great diversity of Sph-1-P actions has been reported and that this diversity depends mainly on the S1P receptor subtype involved. In this review, I will summarize recent findings on possible roles of Sph-1-P in vascular biology and its therapeutical implications.

Animals↗

PubMed1994

Pathology from hydroxyapatite deposits in periarticular tissues. First conclusions on etiopathogenesis.

Biopsies of periarticular tissues from patients with episodes of chronic periarthritis were examinated by histological, ultrastructural and chemico-crystallographic methods. In all samples the mineralogical observations at the optical microscope, showed aggregates of microcrystalline incrustations, whose ultrastructural morphology has been characterized by SEM. The histological observations showed necrosis of collagen fibres and microcrystallization process in cavities and in metaplastic fibrocartilage. The HA deposits in the periarticular tissues, in the next stage of the process, are surrounded and demolished by macrophages and multinucleated giant cells. At the same time granulation tissue carries out the repair process, that begins with the formation of thin parallel collagen fibers interposed with many fibroblasts and numerous small vessels.

Biopsy↗

PubMed2002

Adenovirus-mediated delivery of a soluble form of the VEGF receptor Flk1 delays the growth of murine and human pancreatic adenocarcinoma in mice.

BACKGROUND: Because pancreatic adenocarcinoma is poorly responsive to chemotherapy and radiation therapy, novel treatments such as antiangiogenic gene therapy may have use in the adjuvant treatment of this malignancy. We evaluated the antitumor effects of the in vivo administration of an adenovirus vector encoding a soluble form of Flk1 (Flk1-Fc), a receptor for vascular endothelial growth factor, in 3 murine models of pancreatic adenocarcinoma. METHODS: In a first model, immunocompetent C57Bl/6 mice were injected subcutaneously with Panc02 murine pancreatic adenocarcinoma cells before treatment. In a second model, immunodeficient severe combined immunodeficiency mice were injected subcutaneously with BxPc-3 human pancreatic adenocarcinoma cells before treatment. In a third model, C57Bl/6 mice were injected with Panc02 cells through an intrasplenic route before treatment, in an effort to model metastatic disease. In each model, half the tumor-bearing mice were injected intravenously with 10(9) Flk1-Fc adenovirus particles and half with control adenovirus. RESULTS: In subcutaneous tumor models, Ad Flk1-Fc-treated animals were found to have 75% smaller murine and 78% smaller human pancreatic tumor volumes, relative to tumor volumes of Ad Fc-treated animals, 6 weeks after vector administration. In animals injected with tumor through the intrasplenic route, pathologic and histologic analyses made 10 days after injection of tumor revealed hepatic, pancreatic, and splenic tumors, together with a desmoplastic response consistent with pathologic findings in human pancreatic cancer. Cohorts of these tumor-bearing mice treated with Ad Flk1-Fc demonstrated significantly longer survival and decreased liver replacement with tumor at the time of death, relative to animals treated with Ad Fc. CONCLUSION: A recombinant adenovirus encoding soluble Flk-1 inhibited pancreatic tumor growth in mice. These studies suggest that the delivery of gene products such as Flk1-Fc through in vivo gene transfer may be useful in the future treatment of patients with pancreatic cancer.

Adenocarcinoma↗

PubMed2004

A small interfering RNA targeting vascular endothelial growth factor as cancer therapeutics.

Vascular endothelial growth factor (VEGF) plays a critical role during normal embryonic angiogenesis and also in the pathological angiogenesis that occurs in a number of diseases, including cancer. We developed a novel VEGF blockade system using RNA interference. The small interfering RNA (siRNA) targeting human VEGF almost completely inhibited the secretion of VEGF in a human prostate cancer cell line, PC-3, whereas the control scramble siRNA showed no effects. The VEGF siRNA with atelocollagen dramatically suppressed tumor angiogenesis and tumor growth in a PC-3 s.c. xenograft model. Atelocollagen provided a beneficial delivering means by which stabilization and efficient transfection of the siRNA injected into the tumors were achieved.

Animals↗

PubMed1999

Angiogenesis in lipoma: An experimental study in the chick embryo chorioallantoic membrane.

Lipoma is one of the most common benign mesenchymal tumors. Its ability to trigger an angiogenic response is a critical step for its growth. Because adipose tissue serves as an important conduit for the vasculature, it is conceivable that the angiogenic properties of this tissue may modulate the growth of the vasculature in a paracrine manner. We investigated in vivo the angiogenic potential of bioptic fragments of human lipoma by using the chick embryo chorioallantoic membrane (CAM), a useful model for such an investigation. The angiogenic response in pathological and control implants was assessed on histologic sections by a morphometric method, 96 h after grafting. Results showed that pathological samples were surrounded by numerous allantoic vessels with a radially arranged pattern around the implant. The vascular counts in the CAMs treated with lipoma implants were comparable to that of FGF-2. The role played in vasoproliferative response by angiogenic cytokines (FGF-2, VEGF) released by adipocytes, by endogenous cytokines, such as FGF-2, stored in the CAM extracellular matrix and by angiogenic growth factors released by perivascular mononuclear cells around the newly-formed blood vessels, were supported by this study.

Adult↗

PubMed2007

Expression of the Endothelin-axis in the different histologic subtypes of renal cell carcinoma: a tissue microarray analysis.

Endothelin-1 and its receptors ETAR and ETBR, commonly referred to as the Endothelin-axis, are emerging to play a role in cancer. The Endothelin-axis has been shown to be involved in proliferation, angiogenesis and metastasis in various human tumours. To assess the role of the Endothelin-axis in renal cell carcinoma, we analysed its expression in archival tumour tissue of 183 patients. Representative tumour blocks were selected for constructing a tissue microarray. Paraffin sections were assessed immunohistochemically using monoclonal and polyclonal antibodies for Endothelin-1, ETAR and ETBR. Staining intensities were analysed semiquantitatively and the results were correlated with various histopathologic factors. Overexpression of Endothelin-1, ETAR and ETBR was identified in 12.8%, 84.1% and 93.3% of cases, respectively. No association with pathological tumour stage and histologic grading was found. Papillary renal cell carcinomas expressed highly significantly more Endothelin-1 than clear cell renal cell carcinomas (34.5% vs. 6.7%, p<0.001), while there was no difference between ETAR- and ETBR-expression in these histologic subtypes. However, ETAR tended to be overexpressed in the subgroup of G3-tumours (p=0.044). Studies are underway assessing the role of the Endothelin-axis and its potential use as a molecular target in renal cell carcinoma.

Antibodies, Monoclonal↗

PubMed2004

[Relationship between expression of matrix metalloproteinase-9 (MMP-9) and angiogenesis in renal cell carcinoma].

BACKGROUND & OBJECTIVE: Matrix metalloproteinase-9 (MMP-9) is closely related to tumor invasion and metastasis. It has been recently found that MMP-9 also plays a role in tumor angiogenesis. This study was designed to investigate the relationship between MMP-9 and angiogenesis in renal cell carcinoma (RCC) and its clinical significance. METHODS: SP immunohistochemistry was used to determine the expression of MMP-9, vascular endothelial growth factor (VEGF), and microvessel density (MVD) in 78 RCC tissues. RESULTS: The expression of MMP-9 was related to the pathological stage and the histological grade in RCC (P< 0.05). The MVD value in MMP-9-positive group (110.46+/-50.16) was much higher than that in MMP-9-negative group (84.77+/-44.52)(P< 0.05). There was a positive correlation between the intensity of the expression of MMP-9 and that of VEGF in RCC tissues (r=0.4096,P< 0.01). MMP-9 and VEGF took synergistic effect on angiogenesis in RCC. CONCLUSION: MMP-9 is associated with angiogenesis in RCC, and can serve as a biomarker for the potentialities of invasion and metastasis of RCC.

Adult↗

PubMed2004

[Expression of pituitary tumor-transforming gene in endometrial carcinoma].

OBJECTIVE: To study the expression of pituitary tumor-transforming gene (PTTG) and its relationship with the expression of basic fibroblast growth factor (bFGF) protein and microvessel density (MVD) in endometrial carcinoma. METHODS: Expressions of PTTG mRNA and protein were assessed by semi-quantitive RT-PCR and immunohistochemistry methods respectively in 50 cases of endometrial carcinomas, 15 cases of hyperplasia endometria and 12 cases of normal endometrial tissue. Expressions of bFGF protein were detected by immunohistochemistry. Microvessels were highlighted by staining endothelial cells with CD(34) antigen, and MVDs were counted. RESULTS: The expression rate and average quantity of PTTG mRNA were detected in a significantly greater proportion endometrial carcinomas (96%, 0.84 +/- 0.08) than in hyperplasia endometria (60%, 0.78 +/- 0.06) and normal endometrial tissue (33%, 0.48 +/- 0.12, P < 0.01, respectively). The expression of PTTG protein in endometrial carcinomas (70%) was significantly higher than in hyperplasia endometria (40%) and normal endometrial tissue (17%, P < 0.01). The expression of PTTG was related to surgical-pathological stage, myometrial infiltration depth, lymphatic metastasis and pathological subtype (P < 0.05, respectively), but was irrelevant to patients' age and pathological grade (P > 0.05, respectively). The average quantity of PTTG mRNA and expression rate of PTTG protein in tissues with bFGF protein coexpression (0.86 +/- 0.07, 87%) were higher than in those without bFGF protein coexpression (0.80 +/- 0.06, 42%, P < 0.01, respectively). The MVD in tissues with PTTG protein expression (62 +/- 18) was higher than in those without PTTG protein expression (51 +/- 12, P < 0.05). CONCLUSIONS: PTTG may play an important role in carcinogenesis and development of endometrial carcinoma. PTTG induces an angiogenesis through bFGF which is a key determinant step in tumor progression and metastatic spread.

Adult↗

PubMed2005

Update on inflammatory breast cancer.

Inflammatory breast cancer (IBC) is both the least frequent and the most severe form of epithelial breast cancer. The diagnosis is based on clinical inflammatory signs and is reinforced by pathological findings. Significant progress has been made in the management of IBC in the past 20 years. Yet survival among IBC patients is still only one-half that among patients with non-IBC. Identification of the molecular determinants of IBC would probably lead to more specific treatments and to improved survival. In the present article we review recent advances in the molecular pathogenesis of IBC. A more comprehensive view will probably be obtained by pan-genomic analysis of human IBC samples, and by functional in vitro and in vivo assays. These approaches may offer better patient outcome in the near future.

Animals↗

PubMed1996

Neurogenic inflammation. A model for studying efferent actions of sensory nerves.

Several lines of evidence suggest that sensory nerves of the carotid body have an efferent function in addition to their afferent function of conducting chemoreceptive impulses to the brain. However, it has been difficult to document the release of substances from sensory nerve terminals on glomus cells and to determine whether such an efferent function plays a role in chemoreception. By comparison, the phenomenon of neurogenic inflammation has been relatively easy to study in rats and guinea pigs and has proven to be an informative model system for analyzing efferent actions of sensory nerves. The main characteristic of neurogenic inflammation is plasma leakage. Chemical irritants that activate unmyelinated sensory nerves cause plasma leakage in the skin, respiratory tract, and other organs by triggering the release of substances from sensory nerve fibers. Substance P, which is synthesized and released by some sensory neurons, appears to be the main active mediator, although other tachykinins, calcitonin gene-related peptide, and perhaps other peptides may also participate. Neurogenic inflammation results from the action of substance P on NK1 receptors, as demonstrated by selective NK1 receptor agonists and antagonists. The NK1 receptors involved in plasma leakage are located on the endothelial cells of postcapillary venules and collecting venules. Within seconds of the activation of NK1 receptors by substance P, gaps form in the endothelium of target vessels. The endothelial gaps are transient, and the leak normally ends in a few minutes. However, the magnitude of the response can increase in pathological conditions such as Mycoplasma pulmonis infection in rats, which results in a chronic inflammatory disease of the respiratory tract. The infected airway mucosa becomes abnormally vascular as a result of angiogenesis, and the endothelial cells of the newly formed vessels express increased numbers of NK1 receptors and thus are abnormally sensitive to substance P. Studies of neurogenic inflammation not only have helped to understand the efferent actions of sensory nerves but also have given insight into the mechanism and consequences of inflammatory changes in endothelial cells and in the plasma leakage that follows.

Afferent Pathways↗

PubMed1995

A quantitative investigation of immunocytochemically stained blood vessels in normal, benign, premalignant and malignant human oral cheek epithelium.

The present study was designed to determine whether increased vascularity occurs during malignant transformation of human oral cheek epithelium. Nine normal (N) samples were taken from the resection margins of benign lesions; the pathological lesions were classified as chronic inflammation (CI; n = 11), fibrous hyperplasia (FH; n = 12), lichen planus (LIP; n = 8), dysplasia (DYS; n = 5), squamous cell carcinoma (SCC; n = 25; well differentiated [SCCWD]; n = 10; moderately to poorly differentiated [SCCMPD]; n = 15) and epithelium adjacent to carcinomas (EAC; n = 6). Sections were stained with monoclonal antibody (mAb) against vimentin using an ABC immunoperoxidase technique. All blood vessels present within a depth of 0.9 mm of lamina propria were quantified irrespective of their morphology. The blood vessel parameters quantified were volume density (VVBV, CT), number per unit area (NABV, CT), length per unit volume (LVBV, CT) and mean transverse sectional area (ABV). VVBV, CT increased significantly between normal and all pathological groups. Amongst the pathological groups, statistical differences were detected between CI and SCC, CI and EAC, FH and SCCWD, FH and EAC, LIP and SCC, LIP and EAC, DYS and SCCWD and DYS and EAC. The EAC group had the highest VVBV, CT and the values of NABV, CT and LVBV, CT were significantly higher in all the pathological groups when compared with the normal group. No significant differences were detected between any of the pathological group. The parameter ABV increased significantly between normal and DYS, FH, SCC, EAC, FH and EAC, FH and SCC, CI and EAC, CI and SCC, LIP and EAC and LIP and SCC. Spearman rank correlations detected a positive correlation between the severity of oral lesions and all of the blood vessel parameters. We conclude that a mAb against vimentin improved the identification of smaller blood vessels and the blood vessel data suggest that angiogenesis occurs in premalignant and malignant lesions of human oral cheek epithelium. Angiogenesis seems to play an essential role in sustaining the actively growing and transforming cells.

Adolescent↗