UMLS:C0178874 - FACTA Search

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental evidence has shown, both in vitro and in animal models, that neoplastic growth and subsequent metastasis formation depend on the tumor's ability to induce an angiogenic switch. This requires a change in the balance of angiogenic stimulators and inhibitors. To assess the potential role of angiogenesis factors in human thyroid tumor growth and spread, we analyzed their expression by semiquantitative RT-PCR and immunohistochemistry in normal thyroid tissues, benign lesions, and different thyroid carcinomas. Compared to normal tissues, in thyroid neoplasias we observed a consistent increase in vascular endothelial growth factor (VEGF), VEGF-C, and angiopoietin-2 and in their tyrosine kinase receptors KDR, Flt-4, and Tek. In particular, we report the overexpression of angiopoietin-2 and VEGF in thyroid tumor progression from a prevascular to a vascular phase. In fact, we found a strong association between tumor size and high levels of VEGF and angiopoietin-2. Furthermore, our results show an increased expression of VEGF-C in lymph node invasive thyroid tumors and, on the other hand, a decrease of thrombospondin-1, an angioinhibitory factor, in thyroid malignancies capable of hematic spread. These results suggest that, in human thyroid tumors, angiogenesis factors seem involved in neoplastic growth and aggressiveness. Moreover, our findings are in keeping with a recent hypothesis that in the presence of VEGF, angiopoietin-2 may collaborate at the front of invading vascular sprouts, serving as an initial angiogenic signal that accompanies tumor growth.
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PMID:Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features. 1059 26

Vascular changes in gliomas were analyzed by implanting fluorescent-labeled glioma 261 cells in the brains of 28 mice. Seven animals were killed each week for 4 weeks. We investigated the expression of angiopoietin-2 (Ang-2) by in situ hybridization and compared it with the distribution of apoptotic cells identified by DNA strand breaks (using the terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labeling [TUNEL] method) and transmission electron microscopy (TEM). As early as 1 week after implantation, tumor cells accumulated around vessels, which expressed Ang-2 and were TUNEL negative. TEM showed tumor cells adjacent to the vascular cells "lifting up" the normal astrocytic feet processes away from the endothelial cells and disrupting normal pericytic cuffing. After 2 weeks the number of perivascular glioma cells had increased. No increase in the number of blood vessels was detected at this time. Vascular cells remained positive for Ang-2 and rare ones were TUNEL positive. TEM showed closely packed proliferating perivascular tumor cells. After 3 weeks, there was vascular involution with scant zones of tumor necrosis. Ang-2 was still detected in vascular cells, but now numerous vascular cells were TUNEL positive. In addition, TEM showed apoptotic vascular cells. After 4 weeks, there were extensive areas of tumor necrosis with pseudopalisading and adjacent angiogenesis. Ang-2 was detected in vascular cells at the edge of the tumors in the invaded brain and in vessels surrounded by tumor cells. At both 3 and 4 weeks, most of the TUNEL-positive tumor cells lacked morphological features characteristic of apoptosis and displayed features consistent with necrotic cell death as determined by TEM. Only rare tumor cells appeared truly apoptotic. In contrast, the TUNEL-positive endothelial cells and pericytes were round and shrunken, with condensed nuclear chromatin by TEM, suggesting that vascular cells were undergoing an apoptotic cell death. These results suggest that vascular cell apoptosis and involution preceded tumor necrosis and that angiogenesis is a later event in tumor progression in experimental gliomas. Moreover, Ang-2 is detected prior to the onset of apoptosis in vascular cells and could be linked to vascular involution.
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PMID:Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis. 1087 35

Growth and metastasis of solid tumors depend on the formation of new blood vessels which originate from the existing vascular system. These blood vessels grow into the tumor and thus provide the necessary nutrients and growth factors for tumor progression. At the same time, the newly formed blood vessels allow tumor cells to disseminate and form metastases in distant organs. Normally, vascular homeostasis is regulated by a balance of angiogenic and antiangiogenic mechanisms. Tumor-induced angiogenesis is mainly sustained by the production and secretion of angiogenic factors originating from tumor and stroma cells. The most prominent angiogenic factor is the vascular endothelial growth factor (VEGF). Recently, additional angiogenic factors and their respective receptors have been identified and related to tumor angiogenesis. Among these, the angiopoietins and their receptor TIE-2 have been investigated to some detail. Angiopoietin-1 which binds to and activates TIE-2 is obviously responsible for the stabilization of vessels under homeostatic conditions. Angiopoietin-2 binds to the same receptor as angiopoietin-1 but is antagonistic with respect to angiopoietin-1. It destabilizes blood vessels and, under appropriate conditions, induces complete regression. In the similar situation angiopoietin-2 induces the destabilization of blood vessels, and the angiogenic factor VEGF produced by the tumor induces the massive formation of new vessels. When human melanoma cells A375 are stably transfected to produce the soluble variant of the angiopoietin receptor TIE-2 (sTIE-2), they show a substantial inhibition of tumor growth on nude mice. Similar effects have been seen with the soluble variant of the VEGF receptor FLT-1 (sFLT-1). In both cases, the vessel density of the tumors is significantly reduced. These experiments show that the inhibition of the angiopoietin/TIE-2 system, similar to the inhibition of the VEGF/VEGF receptor system, has an antitumoral effect, most probably due to the inhibition of tumor angiogenesis. Thus, inhibition of both signalling systems seem to be a valid strategy for the development of novel antiangiogenic therapies. Recently, the inhibition of the VEGF receptor tyrosine kinase by the compound PTK787/ZK222584 has been shown to substantially inhibit tumor growth and metastases formation. This compound has now entered clinical trials at the Tumor Biology Center in Freiburg i.Br. A preliminary evaluation of phase I study shows a very promising clinical outcome.
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PMID:[Tumor angiogenesis: new approaches to cancer therapy]. 1144 5

We had demonstrated previously a functional bridge between altered homebox (HOX) gene expression and tumor progression through HOXB7 transactivation of basic fibroblast growth factor. Here, we have studied whether HOXB7, in addition to basic fibroblast growth factor, may induce other genes directly or indirectly related to neoangiogenesis and tumor invasion. Parental, beta-galactosidase-transduced, and HOXB7-transduced SkBr3 cell lines were examined for the expression of several growth factors and growth factor receptors involved in the proliferative and angiogenic processes. Vascular endothelial growth factor, melanoma growth-stimulatory activity/growth-related oncogenene alpha, interleukin-8, and angiopoietin-2 were up-regulated by HOXB7 transduction. The exception was angiopoietin-1 expression that was abrogated. Additional analyses included the expression levels of enzymes such as matrix metalloprotease (MMP)-2 and MMP-9 and heparanase, capable of proteolytic degradation of extracellular matrix and basement membranes. Results showed an induction of only MMP-9. The functional implication of such a finding was tested using an in vitro coculture assay in a three-dimensional matrix. A delay of differentiation with persistent nests of proliferating cells was found in endothelial cells cocultured with HOXB7-transduced SkBr3 cells. Tumorigenicity of these cells has been evaluated in vivo. Xenograft into athymic nude mice showed that SkBr3/HOXB7 cells developed tumors in mice, either irradiated or not, whereas parental SkBr3 cells did not show any tumor take unless mice were sublethally irradiated. Comparison of tumor nodules for vascularization by CD-31 and CD-34 immunostaining revealed an increased number of blood vessels in tumors expressing HOXB7. Together, the results indicate HOXB7 as a key factor up-regulating a variety of proangiogenic stimuli. Thus, HOXB7 gene or protein is a target to aim at to inhibit tumor-associated neoangiogenesis, considering the number and the redundancy of proangiogenic molecules that should be targeted one by one to theoretically achieve the same effect.
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PMID:HOXB7: a key factor for tumor-associated angiogenic switch. 1152 51

Tumour progression is dependent on the formation of new vessels in tumour tissue. Tumour cells produce a variety of factors that influence vessel growth and maintenance both in tumour and tumour-adjacent tissues. Angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and their tyrosine kinase receptor Tie-2 have been shown to play an important role in the processes of growth and remodelling of normal as well as tumour vessels. We studied gene expression of the angiogenic factors Ang-1 and Ang-2 and of their tyrosine kinase receptor Tie-2 in the tumour and non-tumour tissues of mice bearing the experimental melanoma B16. Using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR we measured Ang-1, Ang-2 and Tie-2 mRNA levels in the tumour, bone marrow, liver and spleen. Melanoma tissue overexpressed Ang-2 mRNA compared with spleen, liver and bone marrow of normal mice, suggesting its role during melanoma progression. On the other hand, there was a significant decrease in Ang-2 mRNA level in bone marrow cells collected on days 5 and 10 of tumour growth compared with the expression of Ang-2 mRNA in the bone marrow of normal mice and those collected on days 15 and 20 of tumour growth. These data demonstrate, for the first time, an ectopic effect of the tumour on the gene coding for an angiogenic factor, and also suggest that tumour growth may influence angiogenesis and/or vasculogenesis in distant organs.
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PMID:Angiopoietin-1, angiopoietin-2 and Tie-2 in tumour and non-tumour tissues during growth of experimental melanoma. 1172 11

Cancer therapies based on the inhibition of angiogenesis by endostatin have recently been developed. We demonstrate that a mutated form of human endostatin (P125A) can inhibit the angiogenic switch in the C3(1)/Tag mammary cancer model. P125A has a stronger growth-inhibitory effect on endothelial cell proliferation than wild-type endostatin. We characterize the angiogenic switch, which occurs during the transition from preinvasive lesions to invasive carcinoma in this model, and which is accompanied by a significant increase in total protein levels of vascular endothelial growth factor (VEGF) and an invasion of blood vessels. Expression of the VEGF(188) mRNA isoform, however, is suppressed in invasive carcinomas. The VEGF receptors fetal liver kinase-1 (Flk-1) and Fms-like tyrosine kinase-1 (Flt-1) become highly expressed in epithelial tumor and endothelial cells in the mammary carcinomas, suggesting a potential autocrine effect for VEGF on tumor cell growth. Angiopoietin-2 mRNA levels are also increased during tumor progression. CD-31 (platelet-endothelial cell adhesion molecule [PECAM]) staining revealed that blood vessels developed in tumors larger than 1 mm The administration of P125A human endostatin in C3(1)/Tag females resulted in a significant delay in tumor onset, decreased tumor multiplicity and tumor burden and prolonged survival of the animals. Endostatin treatment did not reduce the number of preinvasive lesions, proliferation rates or apoptotic index, compared with controls. However, mRNA levels of a variety of proangiogenic factors (VEGF, VEGF receptors Flk-1 and Flt-1, angiopoietin-2, Tie-1, cadherin-5 and PECAM) were significantly decreased in the endostatin-treated group compared with controls. These results demonstrate that P125A endostatin inhibits the angiogenic switch during mammary gland adenocarcinoma tumor progression in the C3(1)/Tag transgenic model.
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PMID:Inhibition of the mammary carcinoma angiogenic switch in C3(1)/SV40 transgenic mice by a mutated form of human endostatin. 1220 72

In vivo progression to malignancy is characterized by the switch to an angiogenic phenotype. The angiogenic switch is a critical control point for tumor expansion. The ability of a tumor to become neovascularized permits rapid expansion of tumor growth and increases the likelihood of metastases. The genetic alterations that accompany the switch to the angiogenic phenotype are unknown. Discoveries of such genes lead to comprehension of molecular mechanisms of the tumor progression, as well as development of novel therapeutic tools. We have isolated a novel "angiogenic switch molecule," angiopoietin-2, upregulated specifically in hypervascular hepatocellular carcinoma (HCC). Angiopoietin family proteins have been originally identified as ligands of the vascular endothelial receptor of tyrosine kinase Tie2. Ectopic expression of angiopoietin-2 promotes the rapid development of human HCCs and produces hemorrhage within tumors in nude mice. These results suggest a role for angiopoietin-2 in the neovascularization of HCC. In vitro expression of a dominant-negative construct, containing a soluble Tie2 ectodomain (sTie2), led to Angiopoietin protein interaction, inhibition of endogenous Tie2 phosphorylation in vascular endothelial cells. Tumorigenicity with angiogenesis was suppressed by in vivo gene transfer and sTie2 expression in a murine HCC model, suggesting a possible role for angiopoietin/Tie2 signaling in the induction of HCC neovascularization and disease progression. More important, inhibition of the angiopoietin/Tie2 signal transduction cascade is a promising approach for HCC treatment.
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PMID:Angiogenic switch as a molecular target of malignant tumors. 1269 80

We put forward an algorithm describing the three principal interconnected sub-processes that influence tumor and vasculature dynamics: (i) tumor cell proliferation (ii) angiogenesis, that is, the formation and regression of immature vessels (IV), and (iii) maturation, i.e., the formation and destabilization of mature vessels (MV). This algorithm takes account of the crucial quantitative interactions of these sub-processes, occurring across the molecular, cellular and organ levels. Implementing this complex algorithm in a computer model, one can evaluate the correlations between various factors influencing angiogenesis and their influence on tumor progression at any given moment. Moreover, the computer simulations enable analysis of the versatile effects of drugs on the growth and decay of both the tumor and the immature and mature blood vessels, as well as on the induction of an array of relevant growth factors such as angiopoietin-1 (Ang1), angiopoietin-2 (Ang2), vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). Simulation results suggest that vessel maturation and destabilization of MV drive the otherwise non-linearly growing system into a very dynamic region, having irregular, scale-invariant, fluctuations, around certain asymptotic values of all the involved quantities. Destabilization itself adequately explains the experimentally observed eventual decrease of tumor growth, with no need to implicate additional assumptions, such as a new tumor growth inhibitory, or anti-angiogenic, factors. Our results further suggest that mono-therapy alone can slow tumor growth, but is not capable of eliminating it altogether. In contrast, the combined treatment of anti-angiogenic and anti-maturation drugs causes prolonged suppression of tumor growth and a significant linear decrease in average tumor size. Laboratory experiments are warranted for validating our predictions and for providing in vivo evaluated parameters.
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PMID:A computer algorithm describing the process of vessel formation and maturation, and its use for predicting the effects of anti-angiogenic and anti-maturation therapy on vascular tumor growth. 1283 Oct 61

Chromatin remodeling agents such as histone deacetylase inhibitors have been shown to modulate gene expression in tumor cells and inhibit tumor growth and angiogenesis. Vascular endothelial growth factor (VEGF) and VEGF receptors represent critical molecular targets for antiangiogenesis therapy. In this study, we investigated the biological effect of the histone deacetylase inhibitor NVP-LAQ824 in combination with the VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on tumor growth and angiogenesis. We report that treatment with NVP-LAQ824 affected tumor and endothelial cells and was associated with increased histone acetylation, p21 up-regulation, and growth inhibition. In addition, NVP-LAQ824 treatment inhibited the expression of angiogenesis-related genes such as angiopoietin-2, Tie-2, and survivin in endothelial cells and down-regulated hypoxia-inducible factor 1-alpha and VEGF expression in tumor cells. Combination treatment with NVP-LAQ824 and PTK787/ZK222584 was more effective than single agents in inhibiting in vitro and in vivo VEGF-induced angiogenesis. Endothelial cell proliferation, tube formation, and invasion into the Matrigel plugs were reduced. In mouse models with established subcutaneous prostate (PC3) and orthotopic breast tumors (MDA-MB321), this combination treatment induced 80 to 85% inhibition of tumor growth without overt toxicity. These results suggest that the combination of histone deacetylase inhibitors and VEGF receptor inhibitors may target multiple pathways in tumor progression and angiogenesis and represents a novel therapeutic approach in cancer treatment.
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PMID:The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584. 1537 77

Angiogenesis is a critical process in the transition of tumors from a localized, primary site to a distant site of metastases. Hypoxic conditions within the tumor mass lead to the activation of signalling pathways which initiate tumor cell invasion, migration, adhesion and subsequent angiogenesis. Several key molecular players in hypoxia-induced tumor progression are well-described, e.g., hypoxia-inducible factor-1 (HIF-1) and angiopoietin-2; however, drug development aimed at suppressing individual members of this signalling cascade has proven to be challenging. The article by Erler et al. published in Nature (Vol. 440, April 2006) identifies lysyl oxidase (LOX) as an essential enzyme for hypoxia-induced metastases. This Journal Club reviews the findings presented by Erler and colleagues and briefly discusses the implications of LOX in cancer.
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PMID:Lysyl oxidase (LOX) and hypoxia-induced metastases. 1696 95

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