Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1519670 (tumor angiogenesis)
 6,052 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This article reviews actual advances in the development and application of three-dimensional (3-D) cell culture systems. Recent therapeutically oriented studies include characterization of multicellular-mediated drug resistance, novel ways of quantifying hypoxia, and new approaches to more efficient immunotherapy. Recent progress toward understanding the development of necrosis in tumor spheroids has been made using novel spheroid models. 3-D cultures have been used for studies on molecular mechanisms involved in invasion and metastasis, with a major focus on the role of E-cadherin. Similarly, tumor angiogenesis and the significance of vascular endothelial growth factor have been investigated in a variety of 3-D culture systems. There are many ongoing developments in tissue modeling or remodeling that promise significant progress toward the development of bioartificial liver support and artificial blood. Perhaps one of the most interesting areas of basic research with 3-D cultures is the characterization of embryoid bodies obtained from stable embryonic stem cells. These models have greatly increased the understanding of embryonic development, in particular through the notable exceptional advances in cardiogenesis.
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PMID:Three-dimensional cell cultures: from molecular mechanisms to clinical applications. 935 53

Although all carcinoids are potentially malignant, their biologic behavior is quite variable. Currently there are no reliable morphological criteria to predict metastatic potential. Cell adhesion molecules, such as CD44 and E-cadherin, are considered important in regulating invasion and metastasis of tumors. Also, angiogenesis has been shown to be associated with tumor growth and progression. In this study, we examined 51 carcinoids, including 13 carcinoids with known lymph node and/or visceral metastasis, for expression of CD44s (the standard form of CD44) and E-cadherin by immunohistochemistry. We found that 55% and 37% of carcinoids were negative for CD44s and E-cadherin, respectively. Carcinoids with lymph node and/or visceral metastasis were significantly more frequently negative for CD44s than were those without demonstrated metastasis (P =.030). Ten of 11 tumors with lymph node metastasis lacked CD44s (P =.022), whereas E-cadherin was negative in only 3 (P =.975). Additionally, we analyzed microvessel density to evaluate the role of tumor angiogenesis in the tumor behavior. Carcinoid tumors in general demonstrated high microvessel density (160 +/- 82/five 200x fields), irrespective of location and with and without metastasis. These results suggest that loss of CD44s, but not E-cadherin, may be a useful predictor of metastatic potential of carcinoid tumors.
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PMID:Expression of cell adhesion molecules, CD44s and E-cadherin, and microvessel density in carcinoid tumors. 1248 Oct 15

An in vivo melanoma spontaneous metastases model was adopted to study the molecular mechanisms of the anti-metastatic effect of Taxol. The morphology of melanoma cells in the melanoma tissue lesions was examined by hematoxylin/eosin (H&E) staining and electron microscopy. The in situ programmed cell death was tested by TUNEL analysis. Vascular endothelial growth factor (VEGF) and E-cadherin expression were detected by immunohistochemistry. The metastases suppressor gene nm23 mRNA expression level was analyzed by in situ hybridization. The results showed that i.p. injection of Taxol at 5 mg/kg per day for three weeks significantly inhibited metastases formation in the pulmonary of mice. Taxol induced melanogenesis and apoptosis in the melanoma cells, inhibited angiogenesis in melanoma tissue lesions, and reduced the expression of VEGF. Conversely, Taxol increased the expression of E-cadherin and nm23. In conclusion, administration of Taxol in the early stage of melanoma metastases can significantly inhibit melanoma metastases. This effect was possibly related to apoptosis induction, tumor angiogenesis inhibition, and restoration of the metastasis suppression ability.
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PMID:Taxol inhibits melanoma metastases through apoptosis induction, angiogenesis inhibition, and restoration of E-cadherin and nm23 expression. 1457 88

Tumor angiogenesis plays an important role in tumor growth, maintenance and metastatic potential. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and a potent inducer of vessel permeability and angiogenesis in vivo. The aims of this study were to determine the value of VEGF expression in non-small cell lung cancer (NSCLC) and its association with vascularity, E-cadherin expression and clinicopathological variables. The expression of VEGF and E-cadherin was studied immunohistochemically in 88 NSCLC (48 squamous cell carcinomas, 30 adenocarcinomas, 10 large cell carcinomas). Vascularity was measured by the average number of CD31-positive cells (MVC: microvessel count). A high expression of VEGF (> or = 25% of cells) was observed in 75% and 73.34% of squamous cell carcinomas and adenocarcinomas, respectively, and in all cases of large cell carcinomas. High vascularity was associated with high VEGF expression. VEGF and MVC were correlated with low tumor differentiation (p < 0.001). Reduced E-cadherin expression (< 50% of cells) was noted in 61.36% of tumors and was associated with poor differentiation (p < 0.0001). The simultaneous high expression of VEGF and reduced expression of E-cadherin was correlated with tumor dedifferentiation (p < 0.001). In conclusion, the intratumoral VEGF expression correlates with tumor angiogenesis and histological differentiation. Reduced expression of E-cadherin is associated with poor tumor differentiation. Combined evaluation of VEGF and E-cadherin may become a useful indicator of NSCLC biological behavior and provide clinically important evidence on which to base treatment.
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PMID:Expression of vascular endothelial growth factor and the adhesion molecule E-cadherin in non-small cell lung cancer. 1498 18

Lipocalin 2 is an iron-binding secreted protein that converts embryonic kidney mesenchyme to epithelia. Previously, we reported that lipocalin 2 could revert 4T1-ras-transformed mesenchymal tumor cells to a more epithelial phenotype, increase E-cadherin expression, and suppress cell invasiveness in vitro and in vivo, indicating that lipocalin 2 is a metastasis suppressor. Here, we show that lipocalin 2 can suppress the ras-induced expression of vascular endothelial growth factor in 4T1 cells via down-regulation of ras mitogen-activated protein kinase and ras phosphatidylinositol-3-kinase signaling. In addition, the expression of thrombospondin-1 (an antiangiogenic molecule) was increased in tumors formed by 4T1-ras cells into which lipocalin 2 was stably introduced. Tumor angiogenesis, assessed via an intradermal tumor angiogenesis assay, was also suppressed by lipocalin 2. We also show that caveolin-1 is a critical mediator of this activity. These data provide new insights into the action of lipocalin 2 and raise the possibility that the administration of lipocalin 2 may be useful for inhibiting tumor angiogenesis, in addition to suppressing tumor metastasis, in cancers which show ras activation.
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PMID:Lipocalin 2 antagonizes the proangiogenic action of ras in transformed cells. 1711 40

The conversion from E-cadherin to N-cadherin has been observed in several human cancer types, including prostate cancer, with more homogenous expression of N-cadherin detected in high-grade prostate tumors. N-cadherin, in vitro, has been shown to promote cell mobility, migration and invasion of several cancer cell lines, indicating the possibility of N-cadherin as a molecular target of cancer therapy. Herein, we examined the potential of an N-cadherin inhibitor, ADH1, in reducing tumor angiogenesis ex vivo and delaying tumor progression in vivo. Our data demonstrate that ADH1, at the dosages evaluated, does not display either antiangiogenic activity in a rat aortic ring assay or antitumor potential in a PC3 subcutaneous xenograft tumor model. We detected cytotoxic activity in human umbilical vein endothelial cells, PC3, and Tsu-Pr1 cells, when ADH1 exposure was evaluated at 500 micromol/l or above.
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PMID:ADH1, an N-cadherin inhibitor, evaluated in preclinical models of angiogenesis and androgen-independent prostate cancer. 1741 25

Squamous cell carcinoma of the head and neck (SCCHN) metastasizes to the lymph nodes and lungs. We have generated previously an orthotopic mouse model for head and neck metastasis and did in vivo selection of SCCHN cells through four rounds of serial metastases. A subpopulation of 686LN cells with high metastatic potential (686LN-Ms) was isolated. When the highly metastatic cells were compared with their low metastatic parental cells (686LN-Ps), we found that CXC chemokine receptor-4 (CXCR4) mRNA levels were significantly higher in the 686LN-Ms cells than the 686LN-Ps cells. Interestingly, the metastatic subclones had lost epithelial morphology and acquired mesenchymal features, which were maintained during cell expansion in vitro. This was featured by decreased E-cadherin and involucrin and increased vimentin and integrin beta(1). These results imply that CXCR4 and epithelial-mesenchymal transition markers can be potential biomarkers to identify the subpopulation of cells with high metastatic potential. Using the orthotopic SCCHN animal model, we showed that anti-CXCR4 treatment suppressed primary tumor growth by inhibiting tumor angiogenesis and prevented lung metastasis. Because the reduction of metastasis seen in the treated group could have resulted from 2-fold reduction in primary tumor size compared with that in the control group, we examined the effects of the CXCR4 antagonist in an experimental metastatic animal model in which 686LN-Ms cells were i.v. injected. 686LN-Ms cells failed to metastasize in the CXCR4 antagonist-treated group, whereas they metastasized to the lungs in the control group. Our data indicate that CXCR4 is an important target to inhibit tumor progression in SCCHN.
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PMID:CXC chemokine receptor-4 antagonist blocks both growth of primary tumor and metastasis of head and neck cancer in xenograft mouse models. 1767 Dec 23

Hepatocellular carcinoma (HCC) is a highly invasive tumor characterized by vigorous neovascularization. The purpose of this study is to examine the expression of Twist, a highly conserved bHLH transcription factor that is known to promote EMT, and evaluate its effect on tumor angiogenesis and metastasis of HCC. The mRNA expression of Twist, VEGF, E-cadherin, and N-cadherin was determined by Real-Time RT-PCR in 30 pairs of hepatocellular carcinomas and matched non-cancerous tissues. Immunohistochemistry was carried out to analyze the protein expression of Twist, VEGF, E-cadherin, and N-cadherin in 40 hepatocellular carcinoma cases. The staining of endothelial cells for CD34 was used to evaluate the MVD. We found that Twist mRNA and protein were both increased in HCC as compared to non-cancerous tissues. The HCC specimens showing positive Twist expression had a higher microvessel density than those without Twist expression. And up-regulated Twist protein was significantly associated with intrahepatic and extrahepatic metastasis (p=0.048 and P=0.039 respectively). In addition, patients with Twist expression had poor prognosis. We also found that the expression of Twist positively correlated with up-regulation of VEGF and N-cadherin (P=0.002 and p=0.016 respectively), but not with downregulation of E-cadherin in HCC. Our results demonstrate that Twist may play an important role in the angiogenesis and metastasis of HCC. Twist expression may become a potential novel prognostic factor for the disease survival of HCC.
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PMID:Up-regulation of Twist induces angiogenesis and correlates with metastasis in hepatocellular carcinoma. 1798 1

Hepatocellular carcinoma (HCC) is one of most malignant and aggressive human tumors. Transforming growth factor-beta1 (TGF-beta1) and its coreceptor CD105 have been shown to contribute to HCC malignant progression. TGF-beta1 and CD105 have also been implicated in angiogenesis, but their role in the vascularization of HCC has not been investigated. To fill this gap, we studied the effect of TGF-beta1 and CD105 on HCC-derived endothelium. By using immunomagnetic beads, we isolated and cultured endothelial cells (ECs) from HCC (HCC-EC) and adjacent nonneoplastic tissue (nNL-ECs) obtained from 24 liver biopsies. HCC and nNL biopsies were also analyzed by immunohistochemistry for the expression of CD105, TGF-beta1, Ve-cadherin (Ve-cad), CD44, beta-catenin, and E-cadherin. Compared with nNL-ECs, HCC-ECs had higher expression of CD105, enhanced spontaneous motility, and greater capacity to migrate in response to TGF-beta1 (5 ng/mL), particularly in the presence of a fibronectin matrix. The chemotactic effect of TGF-beta1 was blocked by anti-CD105 antibodies and correlated with the grade of HCC malignancy. Histologic examination of HCC biopsies showed that HCCs with the worse malignant features had the highest expression of TGF-beta1, CD105, and angiogenic markers (Ve-cad and CD44). Because CD105 was highly expressed in microvessels at the tumor periphery and TGF-beta1 staining was only found in neoplastic hepatocytes, we conclude that HCC-derived TGF-beta1 may act as a chemoattractant for CD105-expressing ECs and as a promoter of tumor angiogenesis. Thus, drugs that selectively target the TGF-beta1/CD105 axis may interfere with HCC-related angiogenesis and HCC progression.
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PMID:Transforming growth factor-beta1 and CD105 promote the migration of hepatocellular carcinoma-derived endothelium. 1892 39

It was proposed that increased level of mitochondrial reactive oxygen species (ROS), mediating execution of the aging program of an organism, could also be critical for neoplastic transformation and tumorigenesis. This proposal was addressed using new mitochondria-targeted antioxidant SkQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) that scavenges ROS in mitochondria at nanomolar concentrations. We found that diet supplementation with SkQ1 (5 nmol/kg per day) suppressed spontaneous development of tumors (predominantly lymphomas) in p53(-/-) mice. The same dose of SkQ1 inhibited the growth of human colon carcinoma HCT116/p53(-/-) xenografts in athymic mice. Growth of tumor xenografts of human HPV-16-associated cervical carcinoma SiHa was affected by SkQ1 only slightly, but survival of tumor-bearing animals was increased. It was also shown that SkQ1 inhibited the tumor cell proliferation, which was demonstrated for HCT116 p53(-/-) and SiHa cells in culture. Moreover, SkQ1 induced differentiation of various tumor cells in vitro. Coordinated SkQ1-initiated changes in cell shape, cytoskeleton organization, and E-cadherin-positive intercellular contacts were observed in epithelial tumor cells. In Ras- and SV40-transformed fibroblasts, SkQ1 was found to initiate reversal of morphological transformation of a malignant type, restoring actin stress fibers and focal adhesion contacts. SkQ1 suppressed angiogenesis in Matrigel implants, indicating that mitochondrial ROS could be important for tumor angiogenesis. This effect, however, was less pronounced in HCT116/p53(-/-) tumor xenografts. We have also shown that SkQ1 and related positively charged antioxidants are substrates of the P-glycoprotein multidrug resistance pump. The lower anti-tumor effect and decreased intracellular accumulation of SkQ1, found in the case of HCT116 xenografts bearing mutant forms of p53, could be related to a higher level of P-glycoprotein. The effects of traditional antioxidant N-acetyl-L-cysteine (NAC) on tumor growth and tumor cell phenotype were similar to the effects of SkQ1 but more than 1,000,000 times higher doses of NAC than those of SkQ1 were required. Extremely high efficiency of SkQ1, related to its accumulation in the mitochondrial membrane, indicates that mitochondrial ROS production is critical for tumorigenesis at least in some animal models.
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PMID:Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 3. Inhibitory effect of SkQ1 on tumor development from p53-deficient cells. 1912 16


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