Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1658953 (tumor vasculature)
 2,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Localization of activated natural killer (A-NK) cells in the microvasculature of growing tumors is the result of recognition of the intracellular and vascular cell-adhesion molecules ICAM-1 and VCAM-1 on the tumor endothelium, mediated by lymphocyte function-associated protein LFA-1 and vascular lymphocyte function-associated protein VLA-4. In vitro and in vivo studies of A-NK cell adhesion to endothelial cells showed that vascular endothelial growth factor (VEGF) promotes adhesion, whereas basic fibroblast growth factor (bFGF) inhibits adhesion through the regulation of these molecules on tumor vasculature. Thus, some angiogenic factors may facilitate lymphocyte recognition of angiogenic vessels, whereas others may provide such vessels with a mechanism that protects them from cytotoxic lymphocytes.
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PMID:During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. 878 49

Tumor-derived vascular endothelial growth factor (VEGF)/ vascular permeability factor (VPF) plays an important role in neovascularization and the development of tumor stroma. Furthermore, VEGF receptors are over-expressed in the endothelial cells of tumor vasculature and almost non-detectable in the vascular endothelium of adjoining normal tissues. The differential expression of receptor offers a selective advantage for targeting cytotoxic toxin polypeptides. We have prepared a vascular targeting reagent by chemically linking recombinant VEGF to a truncated form of diphtheria toxin. The VEGF-toxin conjugate was selectively toxic to endothelial cell lines and inhibited experimental neovascularization of the chick chorioallantoic membrane. In the present study, we examined the effects of VEGF-toxin conjugate on solid tumor growth. Athymic nude mice with established subcutaneous tumors were treated with daily intraperitoneal injections of the VEGF-toxin conjugate or free toxin. When compared with control animals treated with the toxin polypeptide alone, the conjugate-treated animals displayed a significant inhibition of tumor growth. Histological analysis of tumors from conjugate-treated animals revealed hemorrhagic necrosis consistent with a vascular-mediated injury. In contrast, highly vascularized normal tissues from conjugate-treated animals demonstrated no evidence of hemorrhage or tissue injury. The conjugate was well tolerated without apparent toxicities. Our results illustrate the anti-tumor activity of a VEGF-toxin conjugate selectively targeting the tumor neovasculature.
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PMID:Targeting the tumor vasculature: inhibition of tumor growth by a vascular endothelial growth factor-toxin conjugate. 939 67

Based on their location and central role in solid tumor growth, tumor vascular endothelial cells may present an attractive target for the delivery of therapeutic drugs or cells. The potency of blocking the tumor blood supply in eradicating solid tumors was demonstrated recently in a mouse model of tumor vasculature targeting (Huang et al., Science 275: 547-550, 1997). For clinical application of such strategies, tumor endothelium specific target epitopes need to be identified. Recent studies on angiogenesis have identified angiogenesis-related molecules as potential target epitopes. Among these are vascular endothelial growth factor (VEGF)/VEGF-receptor complex, alpha(v) integrins, and Tie receptor tyrosine kinases. Besides blockade of their signalling cascades leading to inhibition of angiogenesis, these epitopes may also be instrumental in tumor vessel specific delivery of therapeutics. Data on the efficacy of therapeutic modalities aimed at these, mostly heterogeneously distributed tumor endothelial epitopes are scarce, and sophisticated experimentation is required to rationalize the development of new therapeutic strategies. Importantly, only detailed evaluations in cancer patients will provide the blueprint for the development of clinically effective tumor vascular targeted therapies.
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PMID:Tumor vasculature targeted therapies: getting the players organized. 971 13

We have previously demonstrated that vascular endothelial growth factor-165 (VEGF), a tumor-secreted angiogenic factor, can acutely and chronically induce fenestrations in microvascular endothelium (Cancer Res 1997, 57:765-772). Because the morphology and function of microvascular endothelium differs from tissue to tissue, we undertook studies to examine whether the neovasculature in tumors also differed depending upon tumor location. Four tumor types implanted in the brain or subcutis in nude mice were studied: a murine rhabdomyosarcoma (M1S), a murine mammary carcinoma (EMT), and two human glioblastomas (U87 and U251). In addition, we studied Chinese hamster ovary cells stably transfected with human VEGF165. As previously reported, tumors grown in the subcutaneous space had a microvasculature that was fenestrated and had open endothelial gaps. The identical tumors when grown in the brain also had fenestrated endothelium and vessels with open endothelial gaps, but they were drastically reduced in occurrence. Open endothelial gaps were not seen in all tumors implanted in the brain (EMT and M1S), although fenestrated endothelium was always seen. VEGF and VEGF receptors were measured in tumors from both locations by immunoblotting and competitive polymerase chain reaction, respectively. VEGF amount was not significantly different between the tumor locations. Interestingly, total tumor vascular mRNA expression of both Flk-1 and Flt-1 was greater in tumor vessels derived from the brain compared with tumor vessels derived from subcutaneous tissues. These results demonstrate that the host microvascular environment determines the morphology and function of the tumor vasculature and that endothelia from different tissues vary in their ability to express the VEGF receptors given identical stimuli.
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PMID:Host microvasculature influence on tumor vascular morphology and endothelial gene expression. 977 55

Angiogenesis is a critical step in a benign tumor's evolution toward malignancy and metastasis. Tumor cells acquire such a phenotype by their ability to secrete angiogenic factors such as vascular endothelial growth factor (VEGF). VEGF receptors (VEGFRs) flt-1/VEGFR-1 and Flk-1/ KDR/VEGFR-2 are restricted to activated endothelial cells, with the highest expression being in the tumor vasculature. The present study was undertaken to target the VEGFRs. Targeted toxins were developed by recombinant methods by fusing VEGF165 or VEGF121 to the diphtheria toxin (DT) translocation and enzymatic domain (DT390-VEGF165 or DT390-VEGF121). Both fusion proteins were found to be highly toxic to proliferating endothelial cells but not to vascular smooth muscle cells. The fusion protein is also active in Kaposi's sarcoma, a tumor type that expresses high levels of VEGFRs. These fusion proteins completely inhibit the basic fibroblast growth factor-induced growth of new blood vessels in the chick chorioallantoic membrane assay. Furthermore, the fusion toxin substantially retards the growth of Kaposi's sarcoma tumors in mice. Because nearly all tumors induce local angiogenesis with high VEGFR expression, VEGF-derived toxins may have wide application in cancer therapy.
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PMID:Vascular endothelial growth factor chimeric toxin is highly active against endothelial cells. 989 5

Features that distinguish tumor vasculatures from normal blood vessels are sought to enable the destruction of preformed tumor vessels. We show that blood vessels in both a xenografted tumor and primary human tumors contain a sizable fraction of immature blood vessels that have not yet recruited periendothelial cells. These immature vessels are selectively obliterated as a consequence of vascular endothelial growth factor (VEGF) withdrawal. In a xenografted glioma, the selective vulnerability of immature vessels to VEGF loss was demonstrated by downregulating VEGF transgene expression using a tetracycline-regulated expression system. In human prostate cancer, the constitutive production of VEGF by the glandular epithelium was suppressed as a consequence of androgen-ablation therapy. VEGF loss led, in turn, to selective apoptosis of endothelial cells in vessels devoid of periendothelial cells. These results suggest that the unique dependence on VEGF of blood vessels lacking periendothelial cells can be exploited to reduce an existing tumor vasculature.
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PMID:Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. 991 26

Our analyses in several different tumor settings challenge the prevailing view that malignancies and metastases generally initiate as avascular masses that only belatedly induce vascular support. Instead, we find that malignant cells rapidly co-opt existing host vessels to form an initially well-vascularized tumor mass. Paradoxically, the co-opted vasculature does not undergo angiogenesis to support the growing tumor, but instead regresses (perhaps as part of a normal host defense mechanism) via a process that involves disruption of endothelial cell/smooth muscle cell interactions and endothelial cell apoptosis. This vessel regression in turn results in necrosis within the central part of the tumor. However, robust angiogenesis is initiated at the tumor margin, rescuing the surviving tumor and supporting further growth. The expression patterns of Angiopoietin-2 (the natural antagonist for the angiogenic Tie2 receptor) and vascular endothelial growth factor (VEGF) strongly implicate these factors in the above processes. Angiopoietin-2 is highly induced in co-opted vessels, prior to VEGF induction in the adjacent tumor cells, providing perhaps the earliest marker of tumor vasculature and apparently marking the co-opted vessels for regression. Subsequently, VEGF upregulation coincident with Angiopoietin-2 expression at the tumor periphery is associated with robust angiogenesis. Thus, in tumors, Angiopoietin-2 and VEGF seem to reprise the roles they play during vascular remodeling in normal tissues, acting to regulate the previously underappreciated balance between vascular regression and growth.
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PMID:New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. 1049 89

Glucocorticoid hormones, retinoids, and vitamin D3 display anti-angiogenic activity in tumor-bearing animals. However, despite their in vivo effect on the tumor vasculature little is known about their mechanism of action. Here we show that the synthetic glucocorticoid dexamethasone (Dex) and retinoic acid (RA) inhibit the activation of c-Jun N-terminal kinase (JNK) and extracellular-regulated kinase (ERK) signalling pathways by the pro-angiogenic agents tumor necrosis factor and vascular endothelial growth factor in endothelial cells. In contrast, Dex and RA failed to inhibit the activation of the p38 mitogen-activated protein kinase cascade. As a number of pro-angiogenic factors activate AP-1 transcription factor via the JNK and ERK pathways, our results suggest that the antagonism with AP-1 may underlie at least partially the anti-angiogenic effect of glucocorticoids and retinoids.
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PMID:Hormone-activated nuclear receptors inhibit the stimulation of the JNK and ERK signalling pathways in endothelial cells. 1051 34

The growth and metastases of many solid tumors are dependent on the recruitment of new blood vessels. Tumor angiogenesis is most likely initiated by paracrine release of growth factors that bind to their corresponding endothelial cell surface receptors. To determine whether angiogenesis and growth factor receptor expression are consistent findings in malignant melanoma, primary human melanomas were examined for mRNA expression of receptors for fibroblast growth factors (FGFR-1, FGFR-2), vascular endothelial growth factor (VEGFR-1, VEGFR-2), and the receptors Tiel and Tie2. Charts were reviewed and archival formalin-fixed, paraffin-embedded primary tumors were obtained from patients with thin (<1 mm; n = 10), intermediate (1 to 4 mm; n = 10), or thick malignant melanoma (>4 mm; n = 8). Also examined was whether melanoma cell lines could induce endothelial growth factor receptor synthesis by metabolic labeling. It was found that tumor vascularity did not correlate with clinical stage, melanoma thickness, or clinical outcome. It was also found that melanoma cell lines were not capable of directly regulating endothelial cell synthesis of growth factor receptors. However, expression of Tiel and VEGFR-2 mRNA by the tumor vasculature in select stage IA-IIB patients, and FGFR-1 mRNA expression by the tumor cells in the same clinical stages was found. The expression of these growth factor receptors did not correlate with clinical outcome. These data suggest that angiogenesis is not a prominent characteristic of primary malignant melanoma lesions and that the endothelial cell expression of Tiel and VEGFR-2 in vivo is probably not directly induced by the tumor.
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PMID:Angiogenesis and vascular growth factor receptor expression in malignant melanoma. 1094 63

We assessed the association of vascular endothelial growth factor (VEGF) on the formation of carcinomatosa pleuritis in orthotopic model systems. Immune-deficient rats were inoculated with PC-14 cells into i) a subpleural space of the parietal pleura after pneumonectomy or ii) into the thoracic cavity directly. The rats bearing tumor cells were randomly separated into two groups: non-treatment and treatment with anti-VEGF neutralizing antibody groups. At the time of the autopsy, all rats developed gross pleural dissemination with/without malignant effusions. In the first model, despite no significant difference in the mean volume of the subpleural tumors between the groups, the degree of dissemination was suppressed in the treatment group with less tumor vasculature and with reduced expression of autocrine motility factor receptor (AMFR) in tumor cells. In the second model, although the inhibitory effect on dissemination was not clear, the formation of pleural effusion was inhibited in the treatment group. In addition to the ability of vascular permeability, the results demonstrated here showed the possible association of VEGF with the development of pleural dissemination/metastasis in the context of blood/lymphatic routes and cancer cell motility affected by AMFR.
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PMID:Biological characteristics of carcinomatosa pleuritis in orthotopic model systems using immune-deficient rats. 1117 78


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