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Query: UNIPROT:P06889 (Mol)
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Tumor angiogenesis has been shown to be important for growth and metastasis in human neoplasms. Angiogenesis is usually determined by immunohistochemical staining of tumor tissue using various antibodies specific for endothelial cells. CD34 has been the one most commonly used in studies of tumor angiogenesis. Nestin, a class VI intermediate filament protein, was reported to be a good angiogenic marker in animal models. The aim of the current study was to compare the predictive value of angiogenesis as determined by CD34 and nestin on the same group of patients with advanced gastric carcinomas and to evaluate the possibility of nestin being a newer, better angiogenesis marker. Immunohistochemical staining using antinestin polyclonal antibody and anti-CD34 monoclonal antibody was carried out on surgical specimens from 61 patients with advanced gastric adenocarcinomas. The sensitivity of each of the two antibodies was evaluated by microvessel density (MVD) measurement by counting vessels in three 200x fields of intense neovascularization ("hot spots") of invasive tumors using a digital image analyzer. Immunoreactivity for nestin and CD34 was seen in the endothelial cells, and no stain was noted in the negative controls. MVD determined by nestin [87.74 +/- 29.30 (mean +/- standard deviation)] staining was significantly greater than that obtained by CD34 (82.48 +/- 32.27), and the difference was statistically significant. There was no correlation between MVD and patient clinical outcome with either antibody. Interestingly, in patients with larger carcinomas, MVD determined by nestin correlated better with longer survival than CD34. The difference was statistically significant. These results indicate that nestin is the better marker to evaluate neovascularity in endothelial cells. Evaluation of MVD determined by immunohistochemistry has limited value in patients with gastric carcinomas.
Appl Immunohistochem Mol Morphol 2002 Jun
PMID:Comparative evaluation of angiogenesis in gastric adenocarcinoma by nestin and CD34. 1205 29

Angiogenesis is essential for tumor growth and progression. It has been demonstrated that tumor growth beyond a size 1 to 2 mm(3) requires the induction of new vessels. Angiogenesis is regulated by several endogenous stimulators and inhibitors of endothelial cell migration, proliferation and tube formation. Under physiological conditions these mediators of endothelial cell growth are in balance and vessel growth is limited. In fact, within the angiogenic balance endothelial cell turnover is sufficient to maintain a functional vascular wall but does not allow vessel growth. Tumor growth an progression has successfully been correlated to the serum concentration of angiogenic mediators. Furthermore, the vascular density of tumor tissues could be correlated to the clinical course of the disease in several tumor entities. Within the last years several new mediators of endothelial cell growth have been isolated e.g. angiopoietin 1, angiopoietin 2, midkine, pleiotropin, leptin and maspin. In this review we discuss the mechanisms leading to tumor angiogenesis and describe some of the newer mediators of endothelial cell stimulation and inhibition.
J Cell Mol Med
PMID:New molecular mediators in tumor angiogenesis. 1206 60

Brn-3a, a member of the POU gene family (so-called because of the similarity with the group of transcription factors Pit, Oct, and Unc), was found in neuronal cells engaged in the transcription activity of the p1 and p2 promoters of the most powerful antiapoptotic gene, namely, Bcl-2. The alternative splicing of Brn-3a mRNA produces two molecular forms: a longer, Bcl-2 transactivating form, and a shorter inactive form, lacking 84 AA in the aminoterminus. In neuronal cells, following Brn-3a gene transfection and superexpression, an increase of 30 fold of the Bcl-2 protein occurs, leading to apoptosis protection. However, recent works demonstrate that Brn-3a expression is not restricted to neuronal cells, as its activity was detected also in cancer cells of non-neuronal nature. Looking for mechanisms linking Brn-3a to carcinogenesis, we discuss the role of this transcription factor in influencing Bcl-2/p53 antagonism and Bcl-2/VEGF induction of tumor angiogenesis, concluding this review with a proposal for the oncogenic nature of Brn-3a.
Mol Biotechnol 2002 Oct
PMID:Brn-3a, a neuronal transcription factor of the POU gene family: indications for its involvement in cancer and angiogenesis. 1240 60

A number of cancer chemotherapeutic drugs designed to have cytotoxic actions on tumor cells have recently been shown to also have antiangiogenic activities. Endothelial cell migration and proliferation are key components of tumor angiogenesis, and agents that target the microtubule cytoskeleton can interfere with these processes. In this study, the effect on endothelial cell functions of the microtubule-stabilizing drugs Taxotere and Taxol were evaluated in three in vitro assays: a chemokinetic migration assay, an angiogenesis factor-mediated chemotactic migration assay, and a three-dimensional Matrigel tubule formation assay, using rat fat pad endothelial cells (RFPECs) and/or human umbilical vein endothelial cells (HUVECs). Taxotere was active in all three assays at concentrations that were not cytotoxic and did not inhibit endothelial cell proliferation. In the RFPEC chemokinetic migration and in vitro tubule formation assays, the IC50 values were approximately 10(-9) M for both Taxotere and Taxol. HUVEC migration, however, was more sensitive to Taxotere, with an observed IC50 of 10(-12) M in a chemokinetic assay. In a Boyden chamber assay, HUVEC chemotaxis stimulated by either of two angiogenic factors, thymidine phosphorylase or vascular endothelial growth factor, was inhibited by Taxotere with an IC50 of 10(-11) M and was ablated at 10(-9) M. Taxotere was also up to 1000-fold more potent than Taxol in inhibiting either chemokinetic or chemotactic migration. When the microtubule cytoskeleton was visualized using immunofluorescence staining of alpha-tubulin, there were no gross morphological changes observed in HUVECs or RFPECs treated with Taxotere at concentrations that inhibited endothelial cell migration but not proliferation. The effects of Taxotere on migration were associated with a reduction in the reorientation of the cell's centrosome, at concentrations that did not affect gross microtubule morphology or proliferation. Reorientation of the centrosome, which acts as the microtubule organizing center, in the intended direction of movement is a critical early step in the stabilization of directed cell migration. These data indicate that endothelial cell migration correlates more closely with changes in microtubule plasticity than with microtubule gross structure. The antiangiogenic activity of Taxotere in vivo was assessed in a Matrigel plug assay. In this assay, the angiogenic response to fibroblast growth factor 2 was inhibited in vivo by Taxotere with an ID50 of 5.4 mg/kg when injected twice weekly over a 14-day period, and angiogenesis was completely blocked in mice that received 10 mg/kg Taxotere. The in vivo data further suggested that Taxotere had selectivity for endothelial cell migration and/or microvessel formation because infiltration of inflammatory cells into the Matrigel plug was much less sensitive to inhibition by Taxotere. In conclusion, Taxotere is a potent and potentially specific inhibitor of endothelial cell migration in vitro and angiogenesis in vitro and in vivo.
Mol Cancer Ther 2002 Nov
PMID:Inhibition of endothelial cell function in vitro and angiogenesis in vivo by docetaxel (Taxotere): association with impaired repositioning of the microtubule organizing center. 1247

The rabbit immune repertoire has long been a rich source of diagnostic polyclonal antibodies. Now it also holds great promise as a source of therapeutic monoclonal antibodies. On the basis of phage display technology, we recently reported the first humanization of a rabbit monoclonal antibody. The allotypic diversity of rabbit immunoglobulins prompted us to compare different rabbit immune repertoires for the generation and humanization of monoclonal antibodies that bind with strong affinity to antigens involved in tumor angiogenesis. In particular, we evaluated the diversity of unselected and selected chimeric rabbit/human Fab libraries that were derived from different kappa light chain allotypes. Most rabbit light chains have an extra disulfide bridge that links the variable and constant domains in addition to the two intrachain disulfide bridges shared with mouse and human kappa light chains. Here we evaluate the impact of this increased disulfide bridge complexity on the generation and selection of chimeric rabbit/human Fab libraries. We demonstrate that rabbits with mutant bas and wild-type parental b9 allotypes are excellent sources for therapeutic monoclonal antibodies. Featured among the selected clones with b9 allotype is a rabbit/human Fab that binds with a dissociation constant of 1nM to both human and mouse Tie-2, which will facilitate its evaluation in mouse models of human cancer. Examination of 228 new rabbit antibody sequences allowed for a comprehensive comparison of the LCDR3 and HCDR3 length diversity in rabbits. This study revealed that rabbits exhibit an HCDR3 length distribution more closely related to human antibodies than mouse antibodies.
J Mol Biol 2003 Jan 10
PMID:Rabbit immune repertoires as sources for therapeutic monoclonal antibodies: the impact of kappa allotype-correlated variation in cysteine content on antibody libraries selected by phage display. 1248 98

Interaction between vascular endothelial growth factor (VEGF) and its cognate receptors, KDR/Flk-1 and Flt-1, of vascular endothelial cells is expected to induce an angiogenesis "switch" in tumors and other angiogenesis-associated diseases. SU5416, a selective inhibitor of the KDR/Flk-1 tyrosine kinase, is known to be a potent inhibitor of tumor angiogenesis. In this study, we first observed that SU5416 inhibited Flt-1 tyrosine kinase activity at similar doses, in addition to inhibiting KDR/Flk-1 tyrosine kinase activity in response to VEGF. SU5416 inhibited cell migration of human vascular endothelial cells expressing both Flt-1 and KDR in response to VEGF and also inhibited the cell migration in response to placenta growth factor (PIGF), a specific ligand for Flt-1. Chemotaxis of monocytes expressing only Flt-1 was also inhibited by SU5416 in a dose-dependent manner. Moreover, SU5416 was found to inhibit tyrosine kinase of Flt-1 in response to PIGF in vitro. And angiogenesis induced by PIGF in a Matrigel plug assay was inhibited by administration of SU5416. The antiangiogenic effects by this VEGF receptor-targeting compound appeared to be mediated through interference not only with KDR/Flk-1 but also with Flt-1. Cell migration of vascular endothelial cells and monocytic cells through Flt-1, thus, might play a key role in VEGF-induced tumor angiogenesis in concert with KDR/Flk-1.
Mol Cancer Ther 2002 Mar
PMID:Antiangiogenic effect by SU5416 is partly attributable to inhibition of Flt-1 receptor signaling. 1248 45

The formation of new blood vessels, angiogenesis, is an essential process during development and disease. Angiogenesis is well known as a crucial step in tumor growth and progression. Angiogenesis is induced by hypoxic conditions and regulated by the hypoxia-inducible factor 1 (HIF-1). The expression of HIF-1 correlates with hypoxia-induced angiogenesis as a result of the induction of the major HIF-1 target gene, vascular endothelial cell growth factor (VEGF). In this review, a brief overview of the mechanism of angiogenesis is discussed, focusing on the regulatory processes of the HIF-1 transcription factor. HIF-1 consists of a constitutively expressed HIF-1 beta (HIF-1beta) subunit and an oxygen-regulated HIF-1 alpha (HIF-1a) subunit. The stability and activity of HIF-1alpha are regulated by the interaction with various proteins, such as pVHL, p53, and p300/CBP as well as by post-translational modifications, hydroxylation, acetylation, and phosphorylation. It was recently reported that HIF-1alpha binds a co-activator of the AP-1 transcription factor, Jab-1, which inhibits the p53-dependent degradation of HIF-1 and enhances the transcriptional activity of HIF-1 and the subsequent VEGF expression under hypoxic conditions. ARD1 acetylates HIF-1alpha and stimulates pVHL-mediated ubiquitination of HIF-1alpha. With a growing knowledge of the molecular mechanisms in this field, novel strategies to prevent tumor angiogenesis can be developed, and from these, new anticancer therapies may arise.
J Biochem Mol Biol 2003 Jan 31
PMID:Hypoxia-induced angiogenesis during carcinogenesis. 1254 82

Pancreatic cancer remains a challenging disease with an overall cumulative 5-year survival rate below 1%. The process of cancer initiation, progression and metastasis is still not understood well. Invasion and tumor metastasis are closely related and both occur within a tumour-host microecology, where stroma and tumour cells exchange enzymes and cytokines that modify the local extracellular matrix, stimulate cell migration, and promote cell proliferation and tumor cell survival. During the last decade considerable progress has been made in understanding genetic alterations of genes involved in local and systemic tumor growth. The most important changes occur in genes which regulate cell cycle progression, extracellular matrix homeostasis and cell migration. Furthermore, there is growing evidence that epigenetic factors including angiogenesis and lymphangiogenesis may participate in the formation of tumor metastasis. In this review we highlight the most important genetic alterations involved in tumor invasion and metastasis and further outline the role of tumor angiogenesis and lymphangiogenesis in systemic tumor dissemination.
Mol Cancer 2003 Jan 22
PMID:Invasion and metastasis in pancreatic cancer. 1260 17

As with other solid tumors, the growth and metastasis of pancreatic cancer is critically dependent on tumor angiogenesis. A major stimulus for a tumor's recruitment of additional blood vessels is cellular hypoxia, a condition which is especially pronounced in this neoplasm. Hypoxia induces transcriptional activation of genes that alter cellular metabolism and promote neoangiogenesis. Pancreatic cancer cells have demonstrated activation of such adaptive pathways even in the absence of hypoxia. A highly-angiogenic response in this neoplasm correlates with increased tumor growth, increased metastasis, and decreased survival. Pancreatic cancers expressing high levels of vascular endothelial growth factor, a potent pro-angiogenic cytokine, also have a higher incidence of metastasis and poorer prognosis. Pancreatic cancer cells uniquely express receptors for vascular endothelial growth factor, indicating a role for an autocrine loop in tumor proliferation and invasion. Multiple experimental anti-angiogenic strategies, many of which target vascular endothelial growth factor, reduce pancreatic cancer growth, spread, and angiogenesis. Anti-angiogenic treatments for pancreatic cancer will likely be most effective when used as an integral part of a combination chemotherapeutic regimen.
Mol Cancer 2003 Jan 22
PMID:Influence of hypoxia and neoangiogenesis on the growth of pancreatic cancer. 1260 18

The vascular endothelial growth factor (VEGF) appears to play an important role in tumor angiogenesis. The p53 and HER-2/neu genes have been thought to regulate VEGF expression. Although the most common genetic alterations described in human breast cancer are p53 gene mutations and HER-2/neu gene amplification, there is a paucity of reports concerning a possible association between VEGF expression and p53 and HER-2/neu expression. Ninety-nine invasive ductal carcinoma cases were examined by immunohistochemical studies with anti-VEGF, anti-p53, anti-HER-2/neu, and anti-CD34 antibodies. Computerized image analysis was used to evaluate the microvessel density (MVD). Eighty-eight tumors (88.9%) were classified as being VEGF positive. Twenty-five tumors (25.3%) showed p53 protein expression, while 36 tumors (35.4%) expressed the HER-2/neu protein. The MVD ranged from 22.0 to 197.0, with a median value of 58.5 (65.4 +/- 27.9). The tumors expressing VEGF had a significantly higher MVD than those that did not (P < 0.05). VEGF expression was significantly associated with p53 protein expression (P < 0.01). In double VEGF and p53 immunohistochemical stained sections, the two markers were generally expressed in the same tumor cells. The cancer stage was the only independent prognostic factor of disease-free and overall survival. The authors' results suggest that VEGF expression plays a role in promoting angiogenesis in invasive ductal carcinoma of the breast, and p53 is likely to be involved in regulating VEGF expression.
Appl Immunohistochem Mol Morphol 2002 Dec
PMID:Expression of vascular endothelial growth factor in invasive ductal carcinoma of the breast and the relation to angiogenesis and p53 and HER-2/neu protein expression. 1260 95


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