Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 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

Kaposi sarcoma (KS) is the most common tumor associated with HIV-1 infection and develops in nearly 30% of cases. The principal features of this tumor are abnormal vascularization and the proliferation of endothelial cells and spindle (tumor) cells. KS-derived spindle cells induce vascular lesions and display enhanced vascular permeability when inoculated subcutaneously in the nude mouse. This finding suggests that angiogenesis and capillary permeability play a central role in the development and progression of KS. In this study, we show that AIDS-KS cell lines express higher levels of vascular endothelial growth factor/vascular permeability factor (VEGF/VGF) than either human umbilical vein endothelial cells or human aortic smooth muscle cells. AIDS-KS cells and primary tumor tissues also expressed high levels of Flt-1 and KDR, the receptors for VEGF, while the normal skin of the same patients did not show any expression. We further demonstrate that VEGF antisense oligonucleotides AS-1 and AS-3 specifically block VEGF mRNA and protein production and inhibit KS cell growth in a dose-dependent manner. Furthermore, growth of KS cells in nude mice was specifically inhibited by VEGF antisense oligonucleotides. These results show that VEGF is an autocrine growth factor for AIDS-KS cells. To our knowledge, this is the first report that shows that VEGF acts as a growth stimulator in a human tumor. Inhibitors of VEGF or its cognate receptors may thus be candidates for therapeutic intervention.
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PMID:Vascular endothelial growth factor/vascular permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma. 902 68

The generation of vascular stroma is essential for solid tumor growth and involves stimulatory and inhibiting factors as well as stromal components that regulate functions such as cellular adhesion, migration, and gene expression. In an effort to obtain a more integrated understanding of vascular stroma formation in breast carcinoma, we examined expression of the angiogenic factor vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF); the VPF/VEGF receptors flt-1 and KDR; thrombospondin-1, which has been reported to inhibit angiogenesis; and the stromal components collagen type I, total fibronectin, ED-A+ fibronectin, versican, and decorin by mRNA in situ hybridization on frozen sections of 113 blocks of breast tissue from 68 patients including 28 sections of breast tissue without malignancy, 18 with in situ carcinomas, 56 with invasive carcinomas, and 8 with metastatic carcinomas. A characteristic expression profile emerged that was remarkably similar in invasive carcinoma, carcinoma in situ, and metastatic carcinoma, with the following characteristics: strong tumor cell expression of VPF/VEGF; strong endothelial cell expression of VPF/VEGF receptors; strong expression of thrombospondin-1 by stromal cells and occasionally by tumor cells; and strong stromal cell expression of collagen type I, total fibronectin, ED-A+ fibronectin, versican, and decorin. The formation of vascular stroma preceded invasion, raising the possibility that tumor cells invade not into normal breast stroma but rather into a richly vascular stroma that they have induced. Similarly, tumor cells at sites of metastasis appear to induce the vascular stroma in which they grow. We conclude that a distinct pattern of mRNA expression characterizes the generation of vascular stroma in breast cancer and that the formation of vascular stroma may play a role not only in growth of the primary tumor but also in invasion and metastasis.
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PMID:Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast. 1035 37

Early stage primary human cutaneous melanoma is known to remain relatively avascular and dormant for up to a decade, after which it may give rise to more rapidly growing, vascular and metastatically- competent primary tumor. Clinical dormancy of early stage human melanomas can be recapitulated experimentally by injection of cell lines established from such tumors into nude mice. For example, WM1341B cells, which were isolated from a thin vertical growth phase (VGP) human melanoma, are non-tumorigenic in nude mice even though some of the cells remain viable for at least three weeks at the site of orthotopic injection. These cells produce little or no vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), a potent stimulator of angiogenesis. In order to determine whether their in vivo dormant behaviour may therefore be related to an inability to induce tumor angiogenesis, subpopulations of WM1341B cells were engineered to constitutively overexpress the VEGF/VPF121 isoform. This apparently single modification was sufficient to induce overt and progressively growing tumors by several independent VEGF/VPF121 producing clones, which could be largely blocked by systemic treatment of mice with a monoclonal anti-VEGF neutralizing antibody (A 4.6.1). No evidence for an autocrine mechanism of growth stimulation by VEGF was found. Taken together, these results support the notion that defective angiogenesis may, at least in part, account for dormant phenotype of some early stage primary melanomas. Since the induction of an overt tumorigenic phenotype in several VEGF/VPF transfected WM1341B clones appears to depend exclusively on their expression of VEGF/VPF, such sublines should be useful for screening the activity of known or potential VEGF/VPF ligand or VEGF/VPF receptor antagonists in an in vivo context.
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PMID:The dormant in vivo phenotype of early stage primary human melanoma: termination by overexpression of vascular endothelial growth factor. 1451 61

Angiogenesis is a process by which new blood vessels are formed from preexisting vessels. New blood vessel formation by angiogenesis involves the degradation of extra-cellular matrix combined with sprouting and migration of endothelial cells from preexisting capillaries. Solid tumors consist of several components, including normal and stromal cells, extracellular matrix, and vasculature. To grow and metastasize, tumors must stimulate the development of new vasculature through angiogenesis. Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide with biologic effects that include regulation of hematopoietic stem cell development, extracellular matrix remodeling, and inflammatory cytokine regeneration. VEGF is both a vascular growth factor and a vascular permeability factor. Its expression can upregulate several proangiogenic and prometa-static molecules. As a central mediator of angiogenesis, VEGF has emerged as an important target for antiangiogenic therapy. In this review, the authors describe the essential characteristics of VEGF and the VEGF family of ligands and their receptors. They also provide an overview of the central role of VEGF in physiologic and pathologic angiogenesis, directly or indirectly. This review sheds light on the importance of VEGF-targeted antiangiogenic therapy based on the monoclonal antibodies against VEGF, small interfering RNA, and therapy directed against VEGF-VEGFR kinase. It also gives a brief overview of the natural products or dietary compounds that could be used as antiangiogenic agents. Therapeutic inhibition of vessel formation could be best suited to preventive strategies aimed at the suppression of angiogenesis in primary tumors in subjects at risk or of micrometastases after surgical removal of primary tumor.
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PMID:Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in tumor angiogenesis and malignancies. 1628 8

Both vascular endothelial growth factor A (VEGF) and osteopontin (OPN) can directly induce tumor angiogenesis, which is essential for the growth and metastasis of solid tumors. Here we engineered a bispecific antibody (VEGF/OPN-BsAb) using the anti-VEGF-A antibody bevacizumab and the anti-OPN antibody hu1A12. Compared with hu1A12 alone and bevacizumab alone, VEGF/OPN-BsAb was significantly more effective in inhibiting tumor angiogenesis in a highly metastatic human hepatocellular carcinoma nude mouse model. Further study demonstrated that VEGF/OPN-BsAb could effectively suppress primary tumor growth and metastasis to lungs, suggesting that it might be a promising therapeutic agent for treatment of metastatic cancer.
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PMID:A bispecific antibody effectively inhibits tumor growth and metastasis by simultaneous blocking vascular endothelial growth factor A and osteopontin. 2082 49

The development of metastases has been shown to be associated with the microvascular density of the primary tumor in some clinical studies and with the extent of hypoxia in others. The aim of this study was to investigate the validity of these apparently inconsistent observations and to reveal possible links between them. Xenografted tumors of nine melanoma cell lines established from patients with diseases differing in aggressiveness were studied. The aggressiveness of the cell lines was assessed by measuring their lung colonization potential, invasiveness, angiogenic potential, and tumorigenicity. Spontaneous metastasis was assessed in untreated mice and mice treated with neutralizing antibody against vascular endothelial growth factor A (VEGF-A) or interleukin 8 (IL-8). Microvascular density was scored in histologic preparations. Hypoxic fractions were measured by using a radiobiologic assay and a pimonidazole-based immunohistochemical assay. The aggressiveness of the melanoma lines reflected the aggressiveness of the donor patients' tumors. The metastatic propensity was associated with the microvascular density but not with the hypoxic fraction. Anti-VEGF-A and anti-IL-8 treatments resulted in decreased microvascular density and reduced incidence of metastases in all lines. Large hypoxic fractions were not a secondary effect of high cellular aggressiveness, whereas the microvascular density was associated with the cellular aggressiveness. The metastatic propensity was governed by the angiogenic potential of the tumor cells. The differences in microvascular density among the lines were most likely a consequence of differences in the constitutive angiogenic potential rather than differences in hypoxia-induced angiogenesis. VEGF-A and IL-8 may be important therapeutic targets for melanoma.
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PMID:Metastasis in melanoma xenografts is associated with tumor microvascular density rather than extent of hypoxia. 2107 14

Judah Folkman recognized that new blood vessel formation is important for tumor growth and proposed antiangiogenesis as a novel approach to cancer therapy. Discovery of vascular permeability factor VEGF-A as the primary tumor angiogenesis factor prompted the development of a number of drugs that targeted it or its receptors. These agents have often been successful in halting tumor angiogenesis and in regressing rapidly growing mouse tumors. However, results in human cancer have been less impressive. A number of reasons have been offered for the lack of greater success, and, here, we call attention to the heterogeneity of the tumor vasculature as an important issue. Human and mouse tumors are supplied by at least 6 well-defined blood vessel types that arise by both angiogenesis and arterio-venogenesis. All 6 types can be generated in mouse tissues by an adenoviral vector expressing VEGF-A(164). Once formed, 4 of the 6 types lose their VEGF-A dependency, and so their responsiveness to anti-VEGF/VEGF receptor therapy. If therapies directed against the vasculature are to have a greater impact on human cancer, targets other than VEGF and its receptors will need to be identified on these resistant tumor vessels.
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PMID:Anti-VEGF/VEGFR therapy for cancer: reassessing the target. 2250 95

High microvascular density (MVD) in the primary tumor has been shown to be associated with increased incidence of lymph node metastases and poor clinical outcome. Other investigations have revealed that a large fraction of hypoxic tissue in the primary tumor is associated with metastatic disease and impaired survival. These data are apparently incompatible because tumor hypoxia is primarily a consequence of poor oxygen supply caused by an inadequate vasculature with increased intervessel distances. Here, we provide an explanation of these observations. Human melanoma xenografts were used as preclinical cancer models. Tumors that metastasized to lymph nodes showed higher interstitial fluid pressure (IFP) than those that did not metastasize, and compared with tumors with low IFP, tumors with high IFP showed large hypoxic fractions centrally, high MVD in the periphery, high peritumoral density of lymphatics, and elevated expression of vascular endothelial growth factor A (VEGF-A) and VEGF-C. Significant correlations were found between peripheral MVD and central hypoxia, and lymph node metastasis was associated with high values of both parameters. These findings suggest that the outcome of cancer may be associated with both high MVD and extensive hypoxia in the primary tumor. We propose that proangiogenic factors are upregulated in the tumor center and that the outward interstitial fluid flow caused by the elevated IFP transports these factors to the tumor surface where they evoke hemangiogenesis and lymphangiogenesis, and consequently, that the IFP serves as a link between tumor hypoxia, peripheral tumor hemangiogenesis, peritumoral lymphangiogenesis, and lymph node metastasis.
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PMID:Tumor interstitial fluid pressure-a link between tumor hypoxia, microvascular density, and lymph node metastasis. 2511 80

The present study aimed to investigate the roles of the vascular endothelial cell growth factor (VEGF) and micro (mi)RNA-210 in the metastasis of primary medulloblastoma (MB) tumors. A total of 86 adult patients diagnosed with cerebellar MB were enrolled in the present study, of which 11 patients had metastatic MB in the subarachnoid space. The following samples were collected: MB primary tumor tissue, MB secondary tumor tissue, tumor adjacent tissues and cerebrospinal fluid (CSF). Immunohistochemical analyses of the tissue samples were conducted in order to detect patterns of VEGF expression. In addition, the expression levels of VEGF mRNA and miRNA-210 were analyzed using reverse transcription-quantititative polymerase chain reaction, and western blot analyses were used to investigate VEGF protein expression levels. The positive expression rate of VEGF was significantly higher in MB tumor tissue, as compared with adjacent tissues (P<0.01). In addition, VEGF mRNA and protein expression levels in MB primary and secondary tumor tissues, and in the CSF of patients with metastatic MB, were significantly upregulated, as compared with tumor adjacent tissues and the CSF of patients with non-metastatic MB, respectively (P<0.01). miRNA-210 expression levels were significantly upregulated in MB tumor tissues, the CSF of patients with metastatic MB and in tumor tissues of metastatic MB (P<0.01). In the present study, the expression levels of VEGF and miRNA-210 were upregulated in patients with MB and metastatic MB; thus suggesting that miRNA-210 may promote the metastasis of MB primary tumors by regulating the expression of VEGF.
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PMID:Expression levels of vascular endothelial cell growth factor and microRNA-210 are increased in medulloblastoma and metastatic medulloblastoma. 2666 6


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