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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebral edema and fluid-filled cysts are common accompaniments of brain tumors. They contribute to the mass effect imposed by the primary tumor and are often responsible for a patient's signs and symptoms. Cerebral edema significantly increases the morbidity associated with tumor biopsy, excision, radiation therapy, and chemotherapy. Both edema and cyst formation are thought to result from a deficiency in the blood-brain barrier, with consequent extravasation of water, electrolytes, and plasma proteins from altered tumor microvessels. The resultant expansion of the cerebral interstitial space contributes to the elevated intracranial pressure observed with brain tumors. Departure from the typical blood-brain barrier microvascular architecture may only partially explain the occurrence of edema and tumor cyst formation. Biochemical mediators have also been implicated in vascular extravasation. Vascular permeability factor or vascular endothelial growth factor (VPF/VEGF) is a protein that has recently been isolated from a variety of tumors including human brain tumors. VPFb is an extraordinarily potent inducer of both microvascular extravasation (edemagenesis) and the formation of new blood vessels (angiogenesis). Its role in tumor growth and progression would therefore appear pivotal. Herein, the author presents an updated account of the investigation of VPF. Historical and clinical perspectives of the study and treatment of tumor associated edema are provided. The efficacy of high-dose dexamethasone in the treatment of neoplastic brain edema is discussed. A hypothetical role for VPF in edemagenesis is presented and discussed. It is hoped that an expanded understanding of the mechanisms responsible for the genesis of edema will ultimately facilitate therapeutic intervention.
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PMID:The genesis of peritumoral vasogenic brain edema and tumor cysts: a hypothetical role for tumor-derived vascular permeability factor. 751 4

The progressive emergence of a close relationship between the formation of blood vessels in the vicinity of tumour cells and the development and spreading of tumours, strongly suggests that angiogenesis might be a prerequisite for tumour development. Angiogenesis starts and develops in response to two sets of extracellular signals: soluble angiogenic factors and extracellular matrix. Different experimental models have been used to study angiogenesis in vivo, but they have numerous limitations. Three-dimensional culture systems reconstitute normal interactions between endothelial cells and the surrounding extracellular matrix. Numerous parameters including angiogenic growth factors and cytokines, cell-to-cell interactions and cell-to-extracellular matrix adhesion influence the growth and differentiation of endothelial cells in vitro as well as in vivo. Angiogenesis plays a major role not only in tumour growth but also in metastasis development. Mechanisms of switching to angiogenic phenotype have been recently described and onset of angiogenic activity is now recognized as another discrete step in tumorigenesis. Tumour cells can induce b-FGF expression and exportation, VEGF and VEGF receptor expression and inactivation of the cancer suppressor gene encoding for a fragment of thrombospondin. A controlled net proteolytic balance produced by tumour cells or endothelial cells is required to favour migration and invasion of endothelial cells and angiogenesis. The hypothesis that assessment of tumour angiogenesis might predict tumour aggressiveness in human cancer has recently gained support from several clinical studies. This has been shown for cutaneous melanoma, breast carcinoma, and non-small-cell lung cancer by quantitation of microvessels in human biopsies using von Willebrand factor or CD3 antigen labelling with specific antibodies. However, more specific and sensitive markers are needed to improve this approach for predicting tumour aggressiveness. Folkman proposed twenty years ago that inhibition of angiogenesis might represent a suitable complementary strategy for the treatment of various forms of cancer. Since then numerous angiostatic compounds have been identified but very few of them fit the required criteria of a potential drug. Fumagillin and particularly its synthetic analogue AGM 1470 might be developed for use in humans in the near future.
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PMID:Tumour angiogenesis. 751 38

Meth-A sarcoma cells were stable transfected to overexpress (sense construct) or underexpress (antisense construct) tissue factor. In vitro, there was no difference in plating efficiency or growth between these cell lines. In vivo, tumor cells transfected to overexpress tissue factor grew more rapidly, and established larger and more vascularized tumors than control transfectants. Antisense transfectants grew the slowest and were the least vascularized. Anticoagulation of mice with warfarin did not alter the difference between these tumor lines. Tumor cells over-expressing tissue factor released more (compared with control transfectants) mitogenic activity for endothelial cells in parallel with enhanced transcription of vascular permeability factor/vascular endothelial cell growth factor (VEGF/VPF), and diminished transcription of thrombospondin (TSP2), a molecule with anti-angiogenic properties. Antisense tissue factor transfectants, while releasing the lowest amount of mitogenic activity, had increased thrombospondin and decreased VEGF/VPF transcription compared with control transfectants or wild-type cells. Experiments with these sense, antisense, truncated sense, or vector tumor lines gave comparable results in complete medium, serum free medium or in the presence of hirudin, indicating that the activation of the coagulation mechanism was not likely to be responsible for changes in tumor cell properties. These results suggest that tissue factor regulates angiogenic properties of tumor cells by altering the production of growth regulatory molecules of endothelium by a mechanism distinct from tissue factor activation of the coagulation mechanism.
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PMID:Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. 752 87

In primary malignant brain tumors increased vascularity and marked edema strongly suggest a possible role of the vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). This was confirmed by earlier in situ hybridization studies, by analysis of the expression of the mitogen in different subsets of glioblastoma cells, and by the fact that the VEGF/VPF receptor flt-1 (fms-like tyrosine kinase) is up-regulated in tumor cells in vivo. To assess and quantify the expression of the VEGF/VPF gene and of the receptor gene, 26 surgical specimens of brain tumor tissue from 24 patients were analyzed. In most malignant gliomas, the expression level of the VEGF/VPF gene is elevated and can be increased up to 20- to 50-fold in comparison with low-grade tumors. Using polymerase chain reaction-based amplification, it could be shown that the messenger RNAs of three different VEGF/VPF forms are synthesized in tumor tissue samples. Northern blot studies revealed that in some samples a significant expression of the gene coding for placenta growth factor, a growth factor closely related to VEGF/VPF, was observed. In addition, using a radioreceptor assay it was possible to detect high VEGF/VPF-like activity in the cyst fluids of brain tumors, indicating the accumulation of the mitogen and permeability factor in brain tumor cysts. Further investigations revealed that astrocytoma and glioblastoma cells in culture express the VEGF/VPF gene and secrete the VEGF/VPF protein, whereas gene expression of the two known VEGF/VPF receptors, kinase insert domain-containing receptor and flt-1, could not be detected. These data support previous reports, which stated that VEGF/VPF acts as a paracrine growth and permeability factor in brain tumors and may contribute to tumor growth by initiating tumor angiogenesis.
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PMID:Detection and quantification of vascular endothelial growth factor/vascular permeability factor in brain tumor tissue and cyst fluid: the key to angiogenesis? 752 59

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a cytokine secreted by many animal and human tumors, activated macrophages, keratinocytes, rheumatoid synovial cells, embryonic tissues, and by cultured epithelial and mesenchymal cell lines. It acts selectively on vascular endothelial cells to increase their permeability to circulating macromolecules and to stimulate their replication. Although not detectably expressed by vascular cells in the human and animal tumors we have studied, VPF/VEGF accumulates in the microvessels supplying tumors and certain inflammatory reactions in which VPF/VEGF is also overexpressed. Light microscopic immunohistochemistry lacked the resolution necessary to localize VPF/VEGF precisely in such vessels. Therefore, we used a pre-embedding immunocytochemical method to localize VPF/VEGF at the ultrastructural level in the new blood vessels that are elicited in the peritoneal walls of mice bearing a transplantable mouse ascites tumor of ovarian origin. Intense immunostaining for VPF/VEGF was observed on the abluminal plasma membrane of tumor-associated microvascular endothelial cells and in vesiculovacuolar organelles (VVOs) present in these same endothelial cells. (VVOs are recently described cytoplasmic organelles present in tumor vascular endothelium that provide an important pathway for extravasation of circulating macromolecules.) In contrast to labeling of the abluminal plasma membrane and VVO vesicles and vacuoles, endothelial cytoplasmic organelles, such as multivesicular bodies and Weibel-Palade bodies, and the underlying basal lamina, did not stain with antibodies to VPF/VEGF. The distribution of VPF/VEGF here described corresponds to that anticipated for high-affinity VFP/VEGF receptors, although binding of VPF/VEGF to other endothelial cell surface structures, such as plasma membrane proteoglycans, is also a possibility.
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PMID:Ultrastructural localization of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) to the abluminal plasma membrane and vesiculovacuolar organelles of tumor microvascular endothelium. 753 83

Kaposi's sarcoma (KS) is a multicentric neoplasia of microvascular origin arising during development of immunodeficiency in human immunodeficiency virus (HIV)-infected individuals. More than 130 patients with HIV-associated KS (98% male homosexuals; median age, 35 years) have been diagnosed at the Department of Dermatology, University Medical Center Steglitz, Berlin, during the years 1982-1992. Mucocutaneous and visceral involvement was a common finding in patients with HIV-associated KS, increasing from 39% at the first visit to 65% at the last observation. In 90% of the patients significant immunosuppression was found (75% had a CD4+ count < 200/mm3) at the time of first diagnosis. However, immunosuppression was not a prerequisite for the development of KS, since the tumor had been diagnosed before severe immunosuppression was present in about 10% of the patients. Significant prognostic predictors for the final outcome were: (a) the degree of immunosuppression, (b) the presence of mucosal and visceral manifestation, and (c) the past history of opportunistic infections. The median survival time was 28 months in KS patients with more than 300 CD4+ lymphocytes (n = 18), but only 14 months in immunosuppressed (less than 300 CD4+ lymphocytes) individuals with KS (n = 70). The median survival time in the entire group evaluated (n = 89 patients) was 17 months after first diagnosis. In 71 HIV-infected individuals who died at the Berlin Department during the last 8 years, disseminated KS was the major direct or indirect cause of death (49% of cases). Therapeutic benefit for KS patients was observed after long-term administration of recombinant interferon alpha (rIFN-alpha; 9-18 million IU s.c. every 2 days) alone or combined with antiretroviral drugs such as zidovudine over several months. Prolongation of survival was found after such treatment modalities in 30%-40% of treated patients. Bleomycin and vincristine and other systemically used cytostatics have also been applied with moderate results. The etiology of HIV-associated KS is still unknown and coinfection with herpes simplex virus (HSV), cytomegalovirus (CMV), or human papillomavirus (HPV) as well as certain growth-stimulating cytokines (transforming growth factors, TGF; tumor necrosis factor alpha, TNF-alpha; interleukin-6, IL-6; tat; vascular endothelial growth factors, VEGF; oncostatin M) produced by HIV-infected cells may be cofactors. Overall, KS was found to be a tumor with high malignant potential, and the median survival times were short.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Kaposi's sarcoma: a reevaluation. 754 Nov 46

Vascular permeability factor (VPF/VEGF) is a highly conserved multifunctional cytokine that acts directly on endothelial cells (ECs) to activate phospholipase C and induce [CA2+]i transients. Two high-affinity receptors, both tyrosine kinases, have been described. VPF/VEGF has at least two important roles in tumor biology: (1) it potently increases microvascular permeability to plasma proteins, thereby modifying the tumor extracellular matrix to promote the ingrowth of fibroblasts and new blood vessels, and (2) it is a selective EC mitogen. VPF/VEGF is also involved in several other nonmalignant processes with a pathogenesis analogous to that of tumor stroma generation, including wound healing and rheumatoid arthritis.
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PMID:Vascular permeability factor, tumor angiogenesis and stroma generation. 754 75

The growth of solid tumors in vivo beyond 1-2 mm in diameter requires induction and maintenance of an angiogenic response. This can occur through the release of various angiogenic growth factors from tumor cells. One such factor is vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), a secreted and specific mitogen for vascular endothelial cells. We show that one of the most commonly encountered genetic changes detected in human cancer, i.e., expression of mutant ras oncogenes, is associated with marked up-regulation of VEGF/VPF in transformed epithelial cells. Thus, elevation of the levels of both VEGF/VPF mRNA and secreted functional protein were detected in human and rodent tumor cell lines expressing mutant K-ras or H-ras oncogenes, respectively. Genetic disruption of the mutant K-ras allele in human colon carcinoma cells was associated with a reduction in VEGF/VPF activity. Furthermore, pharmacological disruption of mutant RAS protein function in H-ras transformed rat intestinal epithelial cells by treatment with L-739,749 (a protein farnesyltransferase inhibitor) caused a significant suppression of VEGF/VPF. The results suggest that dominantly acting ras oncogenes may contribute to the growth of solid tumors in vivo not only by a direct effect on tumor cell proliferation but also indirectly, i.e., by facilitating tumor angiogenesis. Hence, pharmacologically targeting mutant ras oncogenes could conceivably suppress solid tumor growth in vivo, in part, by inhibiting tumor-induced angiogenesis.
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PMID:Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. 755 32

We elucidated the relationship between vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), which is a potent angiogenic factor, and the growth of primary and metastatic tumors using an immunoneutralizing monoclonal antibody against human VEGF/VPF121. The monoclonal antibody, MV303, suppressed the growth of human umbilical vein endothelial cells (HUVEC) induced by VEGF/VPF121 or VEGF/VPF165 but did not inhibit its growth induced by basic fibroblast growth factor. MV303 inhibited the binding of 125I-VEGF/VPF121 to HUVEC. We examined the effects of MV303 on tumor angiogenesis using a membrane chamber packed with the human fibrosarcoma cell line HT-1080 and implanted s.c. into BALB/c mice. The neovascularization induced by HT-1080 was inhibited by the i.v. injection of MV303 at a dose of 100 micrograms/mouse. Furthermore, the growth of solid tumors of s.c. implanted HT-1080 in BALB/c nude mice was almost completely inhibited by the i.v. and s.c. administration of MV303 ten times from day 1 at a dose of 100 micrograms/mouse (T/C values of tumor volume at day 18 were 0.20 and 0.18, respectively). Tumor growth was suppressed when MV303 was administered, even from eight days after tumor inoculation. MV303 suppressed the increase in lung weight caused by experimental metastasis with i.v. inoculation of cultured HT-1080 cells to BALB/c nude mice. The life spans of the mice treated with MV303 were significantly prolonged. These results indicated that VEGF/VPF played an important role in both primary and metastatic tumor growth as a tumor angiogenesis factor. MV303, an immunoneutralizing monoclonal antibody against VEGF/VPF, potently inhibited both primary and metastatic tumor growth with no marked side effects.
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PMID:Inhibition of tumor growth and metastasis by an immunoneutralizing monoclonal antibody to human vascular endothelial growth factor/vascular permeability factor121. 758 91

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is an endothelial cell-specific mitogen that is structurally related to platelet-derived growth factor (PDGF). Vascular endothelial growth factor/vascular permeability factor induces angiogenesis in vivo and may play a critical role in tumor angiogenesis. Using immunohistochemical analysis, the authors demonstrated the presence of VEGF/VPF protein in surgical specimens of glioblastoma multiforme and cultured glioma cells. By means of an enzyme-linked immunosorbent assay (ELISA) of cell supernatants, the authors showed that VEGF/VPF is variably secreted by all nine cultured human malignant glioma cell lines (CH-235MG, D-37MG, D-54MG, D-65MG, U-87MG, U-105MG, U-138MG, U-251MG, U-373MG) and by a single meningioma cell line (CH-157MN). An immunocytochemical survey of these cell lines revealed a cytoplasmic and cell-surface distribution of VEGF/VPF. In the U-105MG glioma cell line, VEGF/VPF secretion was induced with physiological concentrations of epidermal growth factor, PDGF-BB, or basic fibroblast growth factor, but not with PDGF-AA. Moreover, it was observed that activation of convergent growth factor signaling pathways led to increased glioma VEGF secretion. Similar results were obtained using these growth factor combinations in the D-54MG glioma cell line. The data obtained suggest a potential role for VEGF/VPF in tumor hypervascularity and peritumoral edema. These observations may lead to development of new therapeutic strategies.
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PMID:Vascular endothelial growth factor in human glioma cell lines: induced secretion by EGF, PDGF-BB, and bFGF. 771 13


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