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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is considerable evidence that vascular endothelial growth factor is involved in the vascularization and growth of primary tumors and in the formation of metastases. The expression of vascular endothelial growth factor depends on activated oncogenes and inactivated tumor-suppressor genes as well as several other factors, e.g., growth factors, hypoxia, and tumor promoters. Substantial expression of vascular endothelial growth factor receptors is mainly restricted to tumor vessels. The causal involvement of this angiogenic factor in the progression of the disease has been successfully evaluated using monoclonal antibodies against vascular endothelial growth factor, dominant negative receptor mutants, and antisense oligonucleotides against the messenger RNA of vascular endothelial growth factor. Thus, the vascular endothelial growth factor-signaling system seems to be an appropriate target for inhibition of tumor angiogenesis and metastasis formation.
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PMID:Tumor angiogenesis: the pivotal role of vascular endothelial growth factor. 880 95

To elucidate the phenotype of the blood vessels and the expression of the growth factors involved in angiogenesis in metastatic liver cancers, we carried out an immunohistochemical study of 57 surgically resected livers with metastatic cancer. Blood vessels in the metastatic liver cancers frequently expressed von Willebrand factor (vWF), Ulex europaeus agglutinin I (UEA I)-binding sites, alpha-smooth muscle actin (alpha-SMA), type IV collagen and laminin. Sinusoidal endothelial cells around the metastatic liver cancers were positive for vWF in 33.3% of the specimens examined and for UEA I in 28.1%. alpha-SMA-positive perisinusoidal cells accumulated in the vicinity of the metastatic liver cancers in 68.4% of the specimens. Type IV collagen was detected in the perisinusoidal space close to the metastatic cancers as well as distant from them (91.2%). Laminin was detected in the perisinusoidal space in only one specimen (1.8%). Tumour cells of the metastatic liver cancers were positive for vascular endothelial growth factor, basic fibroblast growth factor (bFGF), and acidic fibroblast growth factor (aFGF) in 78.9%, 38.4% and 7.0% of the specimens, respectively. Hepatocytes close to the metastatic liver cancers expressed bFGF more strongly than those distant from the metastatic liver cancers, and their expression of bFGF was more intense than that in the tumour cells. These results suggest that: (1) tumour vessels in metastatic liver cancers consist of endothelium, basement membrane and pericytes, (2) the sinusoids adjacent to tumours undergo capillarization, and (3) vascular endothelial growth factor may contribute to angiogenesis in metastatic liver cancer. Basic fibroblast growth factor may be responsible for the sinusoidal capillarization and the peritumoral fibrosis.
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PMID:An immunohistochemical study of tumour vessels in metastatic liver cancers and the surrounding liver tissue. 881 92

Dominantly acting transforming oncogenes are generally considered to contribute to tumor development and progression by their direct effects on tumor cell proliferation and differentiation. However, the growth of solid tumors beyond 1-2 mm in diameter requires the induction and maintenance of a tumor blood vessel supply, which is attributed in large part to the production of angiogenesis promoting growth factors by tumor cells. The mechanisms which govern the expression of angiogenesis growth factors in tumor cells are largely unknown, but dominantly acting oncogenes may have a much greater impact than hitherto realized. An example of this is the induction of expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) by mutant H- or K-ras oncogenes, as well as v-src and v-raf, in transformed fibroblasts or epithelial cells. Besides VEGF/VPF, mutant ras genes are known to upregulate the expression of a variety of other growth factors thought to have direct or indirect stimulating effects on angiogenesis, e.g. TGF-beta and TGF-alpha. This effect may be mediated through the ras-raf-MAP kinase signal transduction pathway, resulting in activation of transcription factors such as AP1, which can then bind to relevant sites in the promoter regions of genes encoding angiogenesis growth factors. In principle, similar events could take place after activation or overexpression of many other oncogenes, especially those which can mediate their function through ras-dependent signal transduction pathways. The regulatory effect of oncogenes on mediators of angiogenesis has some potentially important therapeutic consequences. For example, it strengthens the rationale of pharmacologically targeting oncogene products, such as mutant RAS proteins, as an anti-tumor therapeutic strategy. Such drugs may attack the source of one or more angiogenic growth factors and by doing so, function, at least in part, as anti-angiogenic agents in vivo.
Cancer Metastasis Rev 1995 Dec
PMID:Oncogenes as inducers of tumor angiogenesis. 882 Oct 90

Physiologically, angiogenesis in adults is a controlled process which plays a role, for example, in wound healing. Pathological angiogenesis is observed in tumor formation and represents a multifactorial process, in which specific angiogenic factors, as well as growth factors, extracellular matrix proteins and cell adhesion molecules are involved. Tumor growth is characterized by an imbalance in favor of angiogenic over angiogenesis-inhibiting factors. Some of the most frequently examined angiogenic factors are vascular endothelial growth factor, acidic/basic fibroblast growth factors and the platelet-derived endothelial cell growth factor. The most important angiogenesis inhibitors are angiostatin and thrombospondin. To date, the clinical relevance of tumor angiogenesis has been shown for several human tumors. For most urological tumors, the grade of tumor vessel formation, measured as microvessel density, has been associated with metastases, tumor growth and clinical course. The prognostic value of this feature of malignant growth seems to be higher than that of most of the classical and newer prognostic factors. Systematic investigations of tumor angiogenesis are becoming increasingly relevant for diagnostic and therapeutic strategies and offer opportunities for the development of new specific therapeutic approaches in clinical oncology.
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PMID:[Angiogenesis--principles and significance in urologic tumors]. 899 26

In situ hybridization analysis provides a means to qualitatively study the heterogeneity of primary tumors and metastases based on the types of genes transcribed. In this study, we have tested some parameters for quantitative analysis of in situ hybridizations with paraffin-embedded human breast tumors and measured mRNA levels for the angiogenic protein, vascular endothelial growth factor (VEGF). VEGF mRNAs were highly tumor specific, with the highest levels near necrotic regions within the tissues (0.1 to 2.7 dpm/mm2). Normal cells within the tissue sections did not have detectable levels of VEGF mRNA. For comparison, tumor levels of c-myc (4 to 46 dpm/mm2) and glyceraldehyde-3-phosphate dehydrogenase mRNAs (48 to 214 dpm/mm2) were measured. The mRNAs for both of these genes were more broadly expressed across the tissue sections. The hybridization pattern for VEGF mRNAs was consistent with hypoxia-induced VEGF mRNA steady-state levels and supports the hypothesis that oxidative stress regulates VEGF expression in breast tumors.
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PMID:Quantitation of vascular endothelial growth factor mRNA levels in human breast tumors and metastatic lymph nodes. 920 8

The concentration of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) was determined in the serum of 90 untreated and 42 treated metastatic cancer patients, including patients with colorectal, breast, ovarian and renal carcinomas, with an enzyme-linked immunosorbent assay (ELISA). Levels higher than the 95th percentile of the concentrations of a control group, i.e. 7.5 pg ml(-1) for bFGF and 500 pg ml(-1) for VEGF, were identified as 'elevated'. One measurement during follow-up was included into the analysis per patient. For 19 treated patients, consecutive serum samples were analysed. Fifty-seven per cent of all untreated patients had elevated serum levels of one or both angiogenic factors. The fraction of patients with elevated serum levels of bFGF and/or VEGF was similar in the different tumour types. Agreement of bFGF levels and VEGF levels, classified in relation to their respective cut-off values, was present in 67% of all patients. Fifty-eight per cent of the patients with progressive disease during treatment compared with 15% of the patients showing response to treatment (chi-squared test P < 0.05) had elevated bFGF and/or VEGF serum levels. When consecutive serum samples were analysed, two-thirds of the patients showing progressive disease had increasing serum levels of the angiogenic factors compared with less than one-tenth of the patients showing response (chi-squared test P < 0.05). The lack of association between the serum bFGF and VEGF levels and the tumour type may suggest an aspecific host reaction responsible for solid tumour-related angiogenesis. The main determinants of the serum bFGF and VEGF concentration are the progression kinetics of the metastatic carcinomas.
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PMID:Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients. 923 25

Tumor growth and progression result from complex controls that appear to be facilitated by the growth factors (GFs) which emerge from the tumor and find responsive targets both within the tumor and in the surrounding host. For example, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are both angiogenic signals which appear to emerge from upregulated genetic messages in the proliferating rim of a solid tumor in response to tumor-wide hypoxia. If these signals are generated in response to unfavorable environmental conditions, i.e. a tumor-wide decrease in oxygen tension, then the tumor may be playing a role in manipulating its own environment. Two questions are raised in this paper: (1) How does the host respond to such signals? (2) Is there a linkage between the host's response and the ultimate growth of the tumor? To answer these questions, we have idealized these adaptive signals within a mathematical model of tumor growth. The host response is characterized by a function which represents the host's carrying capacity for the tumor. If the function is constant, then environmental control is strictly limited to tumor shape and mitogenic signal processing. However, if we assume that the response of the local stroma to these signals is an increase in the host's ability to support an ever larger tumor, then the model describes a positive feedback controller. In this paper, we summarize our previous results and ask the question: What form of host response is reasonable, and how will it affect ultimate tumor growth? We examine some specific candidate response functions, and analyze them for system stability. In this model, unstable states correspond to 'infinite' tumor growth. We will also discuss countervailing negative feedback signals and their roles in maintaining tumor stability.
Invasion Metastasis 1996
PMID:Host response in tumor growth and progression. 931 88

Effects on the liver of the antiangiogenesis agent O-(chloroacetyl-carbamoyl) fumagillol (TNP-470) on hematogenous metastasis of a human pancreatic carcinoma cell line were examined. One million PCI-43 cells, a human pancreas carcinoma cell line, were injected into the spleen of SCID beige mice, then TNP-470 at 30 mg/kg was administered subcutaneously every other day. The mice were killed 6 or 10 weeks thereafter and metastatic nodules in the liver were counted and measured microscopically. Metastases were inhibited and an approximately 10% loss of weight was evident in the TNP-470-administered mice. There was no suppression in maximal size of metastatic colonies in mice given the agent for 6 weeks, while inhibition was apparent in mice given the drug for 10 weeks. Suppression of proliferation and an increase in apoptosis were evident in metastatic nodules in the TNP-470-administered groups, following stainings for proliferative cell nuclear antigen and terminal deoxytransferase-mediated dUTP-biotin nick end-labeling, respectively. TNP-470 inhibited the proliferation of human umbilical vein endothelial cells but not PCI-43 in vitro. TNP-470 did not suppress production of vascular endothelial growth factor by PCI-43 cells. Neovascularization in vivo induced by PCI-43 cells was suppressed in the TNP-470-administered mice, using a diffusion chamber placed in subcutaneous tissues of SCID beige mice. These observations suggest that inhibition of angiogenesis is effective in suppressing establishment and subsequent growth of hematogenous micrometastases of pancreatic adenocarcinoma to the liver.
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PMID:Inhibitory effects of the antiangiogenic agent TNP-470 on establishment and growth of hematogenous metastasis of human pancreatic carcinoma in SCID beige mice in vivo. 933 88

Recent studies have demonstrated that the p53 tumor suppressor gene plays an important role in controlling tumor angiogenesis. We examined the expression of p53 and vascular endothelial growth factor (VEGF), a well-characterized angiogenic inducer, together with microvessel density to investigate the role of p53 in the regulation of angiogenesis and its clinical significance in human colorectal carcinoma. Surgically resected specimens of 163 colorectal carcinomas were studied by immunohistochemical staining for p53 protein, VEGF and factor VIII-related antigen. Positive p53 protein accumulation and VEGF expression was found in 41.7% and 49.1% of tumors, respectively. p53 and VEGF staining status was identical in 65.6% of tumors. The incidence of p53- or VEGF-positive tumors was significantly higher in patients with venous invasion and liver metastases than in those without. The microvessel count (MVC) in p53- or VEGF-positive tumors was significantly higher than that in negative tumors, and MVC in both p53- and VEGF-positive tumors was significantly higher than that in the other subgroups. Neither synchronous nor metachronous hepatic metastases were found in patients with p53- and VEGF-negative tumors, while 52.2% of patients with both-positive tumors had liver metastases and had a poorer prognosis than those with both-negative tumors. Our findings suggest the presence of a p53-VEGF pathway regulating tumor angiogenesis in human colorectal carcinoma. Combined analysis of p53 and VEGF expression might be useful for predicting the occurrence of liver metastasis in patients with this disease.
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PMID:Combined analysis of p53 and vascular endothelial growth factor expression in colorectal carcinoma for determination of tumor vascularity and liver metastasis. 935 71

The relationship between vascular endothelial growth factor (VEGF) and lymph node metastasis was studied in 90 cases of primary lung cancer without distant metastasis. As a result of quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis, the VEGF121 mRNA expression levels in lung cancer tissues with nodal metastasis (n = 35) were higher than in those without nodal metastasis (n = 55). However, no significant difference could be found in VEGF121 mRNA expression levels as stratified by tumour size (T1N0M0 vs T2N0M0). Simultaneously, ten lymph nodes (four node positive and six node negative) together with the corresponding primary lung tumours and adjacent normal lung tissue, were studied for VEGF expression. The VEGF mRNA expression in metastatic lymph nodes was intense in three out of the four cases examined. Further, while VEGF expression levels in metastatic lymph nodes were conspicuously higher than those for the primary site, all its expression levels in non-metastatic nodes were inferior to those of the primary tumours. Except for macrophages, the VEGF antigen was identified mainly in the cytoplasm of metastatic cancer cells and the endothelial cells of blood or lymphatic vessels in lymph nodes. Although the detailed mechanisms and the significance of strong VEGF expressions in metastatic lymph nodes are still unknown, these data are consistent with a model whereby VEGF increases the opportunity for nodal metastasis through neoblood and lymphatic vessels.
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PMID:Vascular endothelial growth factor and lymph node metastasis in primary lung cancer. 968 8


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