Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heparanase is an endoglycosidase that degrades heparan sulfate (HS) in the extracellular matrix (ECM) and cell surfaces, and fulfills a significant role in cancer metastasis and angiogenesis. We evaluated the expression of heparanase and its possible association with the expression of angiogenic molecules in malignant mesothelioma (MM), and analyzed whether expression of these proteins is site-related (pleural vs peritoneal MM, solid lesions vs effusions). Sections from 80 MM (56 biopsies, 24 effusions) were analyzed for heparanase protein expression using immunohistochemistry (IHC). Sixty MM were of pleural origin, and 20 were peritoneal. Effusion specimens consisted of 6 peritoneal and 18 pleural effusions, while biopsies consisted of 14 peritoneal and 42 pleural lesions. Fifty-four specimens were additionally evaluated for expression of basic fibroblast growth factor (bFGF), interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) proteins using IHC. Microvessel density (MVD) was studied in 28 biopsies using an anti-CD31 antibody. mRNA expression of heparanase (HPSE-1), VEGF and the VEGF receptor KDR was analyzed in 23 effusions using RT-PCR. Heparanase protein expression was seen in 69/80 (86%) tumors. Of these, 35 showed combined membrane and cytoplasmic expression, 30 cytoplasmic expression, and four exclusively membrane expression. Both total (P = 0.001) and cytoplasmic (P = 0.002) expression was significantly higher in solid tumors compared to effusions. Protein expression of VEGF, IL-8 and bFGF was seen in 21/54 (39%), 22/54 (41%) and 44/54 (81%) specimens, respectively. Protein expression of bFGF was significantly higher in solid tumors (P < 0.001) and correlated with heparanase expression (P = 0.005). HPSE-1 and VEGF mRNA expression was detected in all 23 effusions using RT-PCR, while KDR mRNA was found in 12/23 MM. KDR mRNA expression correlated with that of both HPSE-1 (P = 0.005) and VEGF (P = 0.001). Our results document frequent expression of heparanase in MM, in agreement with the biological aggressiveness of this tumor. The co-expression of heparanase with bFGF is in agreement with the role of the former in releasing bFGF from the ECM. The concomitant reduction in protein expression of both molecules in effusions as compared to solid tumors, supports the hypothesis of a reduced need for pro-angiogenic stimuli in effusions, and may aid in defining tumor progression in this setting.
Clin Exp Metastasis 2004
PMID:Heparanase and basic fibroblast growth factor are co-expressed in malignant mesothelioma. 1567 72

Vascular endothelial growth factor A (VEGF-A) has two kinds of isoforms depending on cellular binding domains. VEGF189 is the largest molecule with the strongest cellular binding ability, and is thought to be most potent for vascularization in various cancers. This study aims to clear the clinicopathological characteristics of VEGF189 in the pulmonary adenocarcinoma. We finely and quantitatively examined the expression of VEGF-A isoforms (VEGF121, VEGF165 and VEGF189) by real-time polymerase chain reaction in a total of 100 pulmonary adenocarcinomas resected by surgical operation. The VEGF isoform expression status was analyzed on clinicopathological features including stromal vascularization, vascular involvement, distant metastasis, lymph nodal metastasis, postoperative relapse time and prognosis of long-term observation periods. All the pulmonary adenocarcinomas showed significant expression of VEGF-A. Twenty-two cases with the adenocarcinomas overexpressing VEGF-A significantly showed earlier postoperative relapse and poorer prognosis between 5- to 15-year periods (p = 0.0093 and p = 0.0240, Kaplan Meier, log-rank test). The expression levels of VEGF189 increased in 13% of the pulmonary adenocarcinoma. These 13 cases with increased VEGF189 expression significantly showed higher distant metastases, earlier postoperative relapse, and poorer prognosis (p = 0.0006, Fisher's test; p = 0.0016 and p = 0.0084, Kaplan Meier, log-rank test) than the other 87 cases. The 13 lung cancers with VEGF189 overexpression also showed increased vessel counts, areas (p = 0.0091 and p < 0.0001, Mann-Whitney U test) and enhanced venous involvement (p = 0.0056, Fisher's test). The cellular binding isoform VEGF189 confers pulmonary adenocarcinoma patients with poorer prognosis with distant metastasis via blood flow.
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PMID:Cell binding isoforms of vascular endothelial growth factor-A (VEGF189) contribute to blood flow-distant metastasis of pulmonary adenocarcinoma. 1587 Aug 64

The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Understanding the mechanisms regulating VEGF expression in neuroblastoma cells provides additional therapeutic options to control neuroblastoma tumor growth. VEGF mRNA is controlled by growth factors and hypoxia via the transcription factor hypoxia-inducible factor (HIF-1alpha). HIF-1alpha protein levels are regulated by the von Hippel Lindau tumor suppressor gene, VHL, which targets HIF-1alpha degradation. To determine whether the levels of VEGF in neuroblastomas are due to mutations in VHL, we evaluated genomic DNA from 15 neuroblastoma cell lines using PCR. We found no mutations in exons 1, 2, or 3 of the VHL gene. VEGF mRNA levels in neuroblastoma cells cultured in serum-free medium increased after 8 to 16 hours in serum, insulin-like growth factor-I (IGF-I), epidermal growth factor, or platelet-derived growth factor. Serum/IGF-I induced increases in HIF-1alpha protein that temporally paralleled increases in VEGF mRNA, whereas HIF-1beta levels were unaffected. VEGF and HIF-1alpha levels were blocked by inhibitors of phosphatidylinositol 3-kinase and mammalian target of rapamycin. Furthermore, we confirmed that HIF-1alpha mediates approximately 40% of the growth factor activity stimulating VEGF protein expression. Topotecan blocked the IGF-I-stimulated increase in HIF-1alpha but not HIF-1beta, and this resulted in a decrease in VEGF in four neuroblastoma cell lines tested. These data indicate that growth factors in an autocrine or paracrine manner play a major role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to phosphatidylinositol 3-kinase, mammalian target of rapamycin, and/or HIF-1alpha have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth.
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PMID:Topotecan blocks hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression induced by insulin-like growth factor-I in neuroblastoma cells. 1593 Feb 97

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

The VEGF/VPF (vascular endothelial growth factor/vascular permeability factor) ligands and receptors are crucial regulators of vasculogenesis, angiogenesis, lymphangiogenesis and vascular permeability in vertebrates. VEGF-A, the prototype VEGF ligand, binds and activates two tyrosine kinase receptors: VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). VEGFR1, which occurs in transmembrane and soluble forms, negatively regulates vasculogenesis and angiogenesis during early embryogenesis, but it also acts as a positive regulator of angiogenesis and inflammatory responses, playing a role in several human diseases such as rheumatoid arthritis and cancer. The soluble VEGFR1 is overexpressed in placenta in preeclampsia patients. VEGFR2 has critical functions in physiological and pathological angiogenesis through distinct signal transduction pathways regulating proliferation and migration of endothelial cells. VEGFR3, a receptor for the lymphatic growth factors VEGF-C and VEGF-D, but not for VEGF-A, regulates vascular and lymphatic endothelial cell function during embryogenesis. Loss-of-function variants of VEGFR3 have been identified in lymphedema. Formation of tumor lymphatics may be stimulated by tumor-produced VEGF-C, allowing increased spread of tumor metastases through the lymphatics. Mapping the signaling system of these important receptors may provide the knowledge necessary to suppress specific signaling pathways in major human diseases.
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PMID:Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. 1633 62

Vascular endothelial growth factor (VEGF) is an essential peptide in new vessel growth in physiology (endometrial growth, embryonic development); pathological conditions (diabetic retinopathy, rheumatoid arthritis); as well as in tumor cell growth, particularly distant metastases. This study focused on VEGF structure, receptors, and angiogensis in tumors, especially their roles in thyroid cancer. The VEGF mRNA undergoes alternative splicing events that generate four homodimeric isoforms, including VEGF121, VEGF165, VEGF189, or VEGF206. Using VEGF purified from a culture medium conditioned by A-431 human epidermoid carcinoma cells, VEGF-binding site complexes of 230, 170, and 125 kDa were detected on human umbilical vein endothelial cells. The VEGF specifically induced the tyrosine phosphorylation of a 190-kDa polypeptide, which had similar mass to the largest binding site detected through affinity cross-linking. A transmembrane receptor belongs to the tyrosine kinase family, fms-like tyrosine kinase (FLT). These receptor tyrosine kinases encoded by the FLT gene family have distinct functions in regulating blood vessel growth and differentiation. Regulation of VEGF is a complex, multistep mechanism in various kinds of cells and tissues. Hypoxia-dependent and -independent mechanisms are illustrated in different cancer tissues. Hypoxic tumor cells may switch to a proangiogenic phenotype, which increases VEGF transcription. Clinical applications of VEGF in cancer have included diagnosis, prediction of prognosis, and treatment in different solid tumors, including thyroid tumors. Studies involving thyroid cancer cell lines, serum level determination, immunohistocytochemical staining, molecular biological studies, and gene therapy to the in vivo clinical trials, have shown that antiangiogensis therapy can provide another treatment modality for thyroid cancer. Future studies focused on recombinant human anti-VEGF research involving patients with advanced thyroid cancer, and investigation of the protection of high-risk patients by using novel antiangiogenic vaccines, are warranted.
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PMID:Vascular endothelial growth factor in thyroid cancers. 1639 17

The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Recently, we have shown that insulin-like growth factor-I and serum-derived growth factors stimulate VEGF expression in neuroblastoma cells via induction of hypoxia-inducible factor-1alpha (HIF-1alpha). Because another marker of poor prognosis in neuroblastoma tumors is high expression of brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor, TrkB, we sought to evaluate the involvement of BDNF and TrkB in the regulation of VEGF expression. VEGF mRNA levels in neuroblastoma cells cultured in serum-free media increased after 8 to 16 hours in BDNF. BDNF induced increases in VEGF and HIF-1alpha protein, whereas HIF-1beta levels were unaffected. BDNF induced a 2- to 4-fold increase in VEGF promoter activity, which could be abrogated if the hypoxia response element in the VEGF promoter was mutated. Transfection of HIF-1alpha small interfering RNA blocked BDNF-stimulated increases in VEGF promoter activity and VEGF protein expression. The BDNF-stimulated increases in HIF-1alpha and VEGF expression required TrkB tyrosine kinase activity and were completely blocked by inhibitors of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) pathways. These data indicate that BDNF plays a role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to BDNF/TrkB, PI3K, mTOR signal transduction pathways, and/or HIF-1alpha have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth.
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PMID:Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. 1661 48

Lung cancer is the leading cause of cancer death worldwide, and most patients die of metastatic disease. Angiogenesis, namely, neovascularization from preexisting vasculature, is necessary for tumor growth in both primary and distant organs to supply oxygen and nutrition. Angiogenesis consists of sprouting and nonsprouting (the enlargement, splitting, and fusion of preexisting vessels) processes, and both can occur concurrently. The growth of non-small cell lung cancer (NSCLC), which accounts for more than 80% of all lung cancers, is usually dependent on angiogenesis, which is regulated by complex mechanisms in the presence of various angiogenesis-related molecules. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is one of the most potent angiogenic molecules, while also regulating both angiogenesis and vascular permeability and hence promoting tumor progression and the development of malignant pleural effusions in NSCLC. Recent clinical trials showed that the anti-VEGF antibody bevacizumab, combined with standard first-line chemotherapy, provided a statistically and clinically significant survival advantage with tolerable toxicity. In addition, the combined use of the anti-VEGF antibody with an inhibitor of epidermal growth factor receptor (EGFR) has also shown favorable antitumor efficiency. These successes proved the validity of an antivasculature strategy for NSCLC. Furthermore, a large number of antivasculature agents have been shown to be effective against multiple targets. The efficiency of these compounds is currently being investigated in clinical trials for NSCLC.
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PMID:Current status and perspective of angiogenesis and antivascular therapeutic strategy: non-small cell lung cancer. 1662 42

This review advances the hypothesis that the function of vascular endothelial growth factor (VEGF) in breast cancer is not limited to angiogenesis, and that VEGF signaling in breast carcinoma cells is important for the ability of these cells to evade apoptosis and progress towards invasive and metastatic disease. In other terms, VEGF signaling provides a selective advantage for the survival and dissemination of breast carcinoma cells that may be independent of angiogenesis. The key component of this hypothesis is that breast carcinoma cells express specific VEGF receptors and that these receptors respond to autocrine VEGF, resulting in the activation of signaling pathways that impede apoptosis and promote cell migration. A related hypothesis, which is developed in this review, is that the alpha6beta4 integrin, which has been implicated in the survival and motility of breast cancer cells, can stimulate the translation of VEGF mRNA and, consequently, autocrine VEGF signaling. These findings imply that VEGF and VEGF receptor-based therapeutics, in addition to targeting angiogenesis, may also target tumor cells directly.
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PMID:Non-angiogenic functions of VEGF in breast cancer. 1692 71

Because metastasis contributes significantly to cancer mortality, understanding its mechanisms is crucial to developing effective therapy. Metastasis is facilitated by lymphangiogenesis, the growth of new intratumoral or peritumoral lymphatic vessels from pre-existing vessels. Vascular endothelial growth factor A (VEGF-A) is a well-known angiogenic factor. Increasing evidence implicates VEGF-A in lymphangiogenesis, although the mechanism of its pro-lymphangiogenic effect is poorly understood. We examined the effect of the anti-VEGF-A neutralizing antibody 2C3 on tumor lymphangiogenesis and metastasis in an orthotopic breast carcinoma model using MDA-MB-231 cells and its luciferase-tagged derivative, 231-Luc(+) cells. Anti-VEGF-A antibody therapy reduced blood and lymphatic vessel densities by 70% and 80%, respectively, compared with the control antibody. Treatment with 2C3 antibody also decreased incidence of lymphatic and pulmonary metastases by 3.2- and 4.5-fold, respectively. Macrophage infiltration was reduced in 2C3-treated tumors by 32%, but VEGF-C expression was unchanged. In contrast, neoplastic cells and blood vessels in tumors from 2C3-treated mice expressed significantly less angiopoietin-2 (Ang-2) than tumors from control mice. The reduction in Ang-2 was associated with inhibition of VEGFR-3 expression in intratumoral lymphatic endothelial cells. Both VEGF-A and Ang-2 upregulated the expression of VEGFR-3 in cultured lymphatic endothelial cells. VEGF-A induced proliferation of lymphatic endothelial cells was reduced by 50% by soluble Tie-2, suggesting that Ang-2 is an intermediary of the pro-lymphangiogenic VEGF-A effect. These results suggest a novel mechanism by which anti-VEGF-A therapy may suppress tumor lymphangiogenesis and subsequent metastasis supporting the use of anti-VEGF-A therapy to control metastasis clinically.
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PMID:Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model. 1759 3


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