Mechanisms of normal and tumor-derived angiogenesis.
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Often those diseases most evasive to therapeutic intervention usurp the human body's own cellular machinery or deregulate normal physiological processes for propagation. Tumor-induced angiogenesis is a pathological condition that results from aberrant deployment of normal angiogenesis, an essential process in which the vascular tree is remodeled by the growth of new capillaries from preexisting vessels. Normal angiogenesis ensures that developing or healing tissues receive an adequate supply of nutrients. Within the confines of a tumor, the availability of nutrients is limited by competition among actively proliferating cells, and diffusion of metabolites is impeded by high interstitial pressure (Jain RK. Cancer Res 47: 3039-3051, 1987). As a result, tumor cells induce the formation of a new blood supply from the preexisting vasculature, and this affords tumor cells the ability to survive and propagate in a hostile environment. Because both normal and tumor-induced neovascularization fulfill the essential role of satisfying the metabolic demands of a tissue, the mechanisms by which cancer cells stimulate pathological neovascularization mimic those utilized by normal cells to foster physiological angiogenesis. This review investigates mechanisms of tumor-induced angiogenesis. The strategies used by cancer cells to develop their own blood supply are discussed in relation to those employed by normal cells during physiological angiogenesis. With an understanding of blood vessel growth in both normal and abnormal settings, we are better suited to design effective therapeutics for cancer. (+info)
Activation of the tie2 receptor by angiopoietin-1 enhances tumor vessel maturation and impairs squamous cell carcinoma growth.
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The distinct roles of angiopoietin (Ang)-1 and Ang2, counteracting ligands for the endothelium-specific Tie2 receptor, in tumor development and progression have remained poorly understood. We investigated the expression of Ang1 and Ang2 during multistep mouse skin carcinogenesis and in human squamous cell carcinoma (SCC) xenografts. Expression of Ang2, but not of Ang1, was up-regulated in angiogenic tumor vessels already in early stages of skin carcinogenesis and was also strongly increased in SCCs. Stable overexpression of Ang1 in human A431 SCCs resulted in a more than 70% inhibition of tumor growth, associated with enhanced Tie2 phosphorylation levels, as compared with low levels in control transfected tumors. No major changes in the vascular density, vascular endothelial growth factor mRNA and protein expression, and vascular endothelial growth factor receptor-2 phosphorylation levels were observed in Ang1-expressing tumors. However, the fraction of tumor blood vessels with coverage by alpha-smooth muscle actin-positive periendothelial cells was significantly increased, indicative of an increased vascular maturation status. These findings identify an inhibitory role of Ang1/Tie2 receptor-mediated vessel maturation in SCC growth and suggest that up-regulation of its antagonist, Ang2, during early-stage epithelial tumorigenesis contributes to the angiogenic switch by counteracting specific vessel-stabilizing effects of Ang1. (+info)
Minichromosome maintenance protein 2 expression in normal kidney and renal cell carcinomas: relationship to tumor dormancy and potential clinical utility.
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PURPOSE: A major problem in the management of patients with renal cell carcinoma is predicting tumor behavior. In the search for more accurate markers of prognosis, tumor cell proliferation has been investigated. These studies have mostly used antibodies directed against Ki-67 or proliferating cell nuclear antigen and have given conflicting results, findings that are likely because of a combination of specificity and methodological differences. Minichromosome maintenance (Mcm) proteins are a series of closely related proteins that are components of the prereplicative complex. The Mcm proteins are essential for initiating eukaryotic DNA replication and serve as useful markers of proliferating cells. EXPERIMENTAL DESIGN: The aims of this study were to determine the frequency and pattern of Mcm2 expression by immunohistochemistry in normal kidney (n = 10) and renal tumors [n = 56; clear cell n = 36; chromophil (papillary) n = 7; oncocytoma n = 5; and transitional cell carcinoma n = 8], compare its sensitivity to the established proliferation marker Ki-67, examine for differences in tumors derived from stable and labile epithelial cell populations in the kidney, and assess the relationship of Mcm2 proliferation to clinicopathological characteristics of kidney tumors. In addition, to additionally investigate the issue of tumor dormancy we wished to assess the relationship between Mcm2 labeling index (LI) and the angiogenic factors angiopoietin-1 (Ang) and Ang-2. RESULTS: In normal tissues, Mcm2 nuclear labeling was identified in both glomeruli (LI median 0.35%; range 0-1.7) and renal tubules (LI median 0.3%; range 0.1-2.9%). In tumors Mcm2 labeling was predominantly at the periphery with LIs ranging from 0.2-91.5%, which was significantly greater than Ki-67 LI (0.2-40.5%; P < 0.001). Mcm2 LI was also significantly higher in tumors derived from a labile epithelium (transitional cell carcinomas) than a stable epithelium (renal cell carcinomas; P = 0.013). A significant association was also demonstrated between Mcm2 LI and tumor grade (P = 0.0006), and angiogenic phenotype (defined by Ang expression; P = 0.03) but not with patient age (P = 0.84), patient sex (P = 0.25), tumor size (P = 0.74), or stage (P = 0.33). Furthermore, although not significant, a survival analysis demonstrated that 100% of patients with a low Mcm2 LI survived compared with 84% of those with a high Mcm2 LI over the follow-up period (up to 53.2 months; P = 0.14). CONCLUSIONS: This is the first study examining Mcm2 protein in normal and tumor kidney samples, and the first to perform histological subgroup analysis. It shows that Mcm2 is a superior marker to Ki-67 in the assessment of cell cycle entry in histological archival material and that normal kidney has a subset of cells within the glomerular and tubular compartments that are in cycle. It demonstrates that the frequency of cells in cycle in tumors formed from stable or labile epithelial populations mirrors that in the nonneoplastic epithelium. This study additionally demonstrates that the number of cells in cycle in tumors is limited by the angiogenic phenotype and supports animal models that show angiogenesis determines the likelihood of tumor dormancy. Additional study to confirm the clinical utility of Mcm2 as a prognostic marker is now indicated. (+info)
Tumor-specific regulation of angiogenic growth factors and their receptors during recovery from cytotoxic therapy.
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After cytotoxic treatment, up-regulation of vascular growth factors and their receptors may be crucial for tumor relapse or progression. To determine how cytotoxic therapy (radioimmunotherapy) alters expression of angiogenic growth factors and receptors, athymic mice bearing LoVo, GW-39, HT-29, or Calu3 human tumor xenografts were treated with one dose (240 microCi) of (131)I-MN-14 anti-CEA IgG or (295 microCi) (131)I-RS-7-3G11 anti-EGP-1 IgG. Tumors removed at 1-week intervals up to week 6 were probed by immunohistochemistry (n = 3-11 samples) for vascular endothelial growth factor (VEGF), placental growth factor (PlGF), flk-1 and flt-1, angiopoietin-1 and -2, and Tie-1 and -2. Tumor extracts were also assayed for VEGF by immunoblot and for PlGF by comparative reverse transcription-PCR. During weeks 2-5 after radioimmunotherapy, significantly up-regulated tumor cell VEGF was only detected in HT-29 (immunohistochemistry; 2-fold; week 4; P < 0.05). The increased VEGF of HT-29 was paralleled by a 2-fold (week 4) rise in VEGF receptor flk-1 on vessels as well as increased ang-2/Tie-2. HT-29, GW-39, and Calu-3 increased tumor cell expression of PlGF by week 2 (HT-29 and Calu-3, P < 0.05). In Calu-3, PlGF mRNA increased 8-fold at week 5. PlGF was detected in hypoxic areas at week 2. Vascular expression of orphan receptor Tie-1 increased in all four of the tumors by week 2 (LoVo, GW-39, and Calu-3, P < 0.05). Regulation of angiogenic factors and angiogenesis after tumoricidal therapy may be tumor-specific. Antiangiogenic therapy may require a tumor-specific combination of inhibitors for PlGF, the angiopoietins, or their receptors, in addition to VEGF/flk-1. (+info)
Expression of angiopoietin-2 and vascular endothelial growth factor in mice cerebral cortex after permanent focal cerebral ischemia.
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AIM: To study the expressions of vascular endothelial growth factor (VEG F), angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), Tie-1, and Tie-2 in C57BL/6 mouse brain after permanent focal cerebral ischemia. METHODS: The mRNA levels of VEGF, Ang-1, Ang-2, Tie-1, and Tie-2 were measured by semiquantitative reverse transcription polymerase chain reaction (RT-PCR). The protein express ions of VEGF and Ang-2 were determined by immunohistochemistry. RESULTS: Low mRNA levels of VEGF, Ang-1, Ang-2, Tie-1, and Tie-2 were constitutively expressed in the normal cortex of mouse. After middle cerebral artery occlusion (MCAO), the expressions of VEGF, Ang-2, and Tie-2 mRNA were dramatically increased in the infarcted cortex and the elevation was remained through 7 d of ischemia. However, the levels of Ang-1 and Tie-1 mRNA were unchanged in the infarcted cortex. Immunoreactivities of Ang-2 or VEGF were hardly observed in the normal cortex. Ang-2 protein was evidently detected in the infarct core 8 h after MCAO and in t he perifocal area 1 d after MCAO. Expression of VEGF protein was elevated in the infarct core 2 h after MCAO and in the perifocal area 1 d after MCAO. Immunoreaction was restricted to endothelial cells and glial-like cells within the infarct core and perifocal area. CONCLUSION: The expressions of An g-2 and VEGF are induced after focal cerebral ischemia, which may contribute to the angiogenic response in the cortex of ischemic brain. (+info)
Biomedical significance of endothelial cell specific growth factor, angiopoietin.
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Until recently, vascular endothelial growth factor (VEGF) was the only growth factor proven to be specific and critical for blood vessel formation. Other long-known factors, such as the fibroblast growth factors (FGFs), platelet-derived growth factor, or transforming growth factor-beta, had profound effects in endothelial cells. But such factors were nonspecific, in that they could act on many other cells, and it seemed unlikely that these growth factors would be effective targets for treatment of endothelial cell diseases. A recently discovered endothelial cell specific growth factor, angiopoietin, has greatly contributed to our understanding of the development, physiology, and pathology of endothelial cells (Davis et al., 1996; Yancopoulos et al., 2000). The recent studies that identified and characterized the physiological and pathological roles of angiopoietin have allowed us to widen and deepen our knowledge about blood vessel formation and vascular endothelial function. Therefore, in this review, we describe the biomedical significance of these endothelial cell growth factors, the angiopoietins, in the vascular system under normal and pathological states. (+info)
Inhibition of infiltration and angiogenesis by thrombospondin-1 in papillary thyroid carcinoma.
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PURPOSE: Angiogenesis is essential for tumor growth and is controlled by the balance between angiogenic and antiangiogenic factors. We studied the expression of angiogenic factors and antiangiogenic factors in papillary thyroid carcinoma. EXPERIMENTAL DESIGN: We investigated immunohistochemically the expression patterns and levels of antiangiogenic factor and its receptor, thrombospondin-1 (TSP-1) and CD36, and four angiogenic factors, vascular endothelial growth factor (VEGF), VEGF-C, angiopoietin-2 (Ang-2), and Tie-2, in the primary tumors of 75 papillary thyroid carcinoma patients. We also examined the microvessel count (MVC), using CD31 staining. RESULTS: VEGF expression strongly correlated with other angiogenic factors. The cytoplasm of cancer cells stained positive for all factors. Tie-2 and TSP-1 receptor also appeared in endothelia of microvessels. TSP-1 inversely correlated with the degree of invasion of the primary tumor to other adjacent organs and with MVC. A higher MVC correlated with poorer survival. To clarify the balance between angiogenic and antiangiogenic factors in the same tumor, we calculated the ratio of each angiogenic factor against TSP-1 as the antiangiogenic factor. The ratios VEGF/TSP-1, VEGF-C/TSP-1, and Ang-2/TSP-1 significantly correlated with a higher MVC. Furthermore, the ratios VEGF/TSP-1 and Ang-2/TSP-1 significantly correlated with the degree of infiltration. CONCLUSIONS: To the best of our knowledge, this is the first report demonstrating that the balance between angiogenic and antiangiogenic factors correlates with distinct invasion to other organs and neovascularization of papillary thyroid carcinoma. (+info)
Differential expression of the angiogenic Tie receptor family in arthritic and normal synovial tissue.
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Angiopoietins (Ang) are vascular endothelial cell-specific growth factors that play important roles principally during the later stages of angiogenesis. We have compared the distribution of the receptor tyrosine kinase (Tie) and the Ang ligands in synovial tissues from normal subjects and those with rheumatoid arthritis (RA) and osteoarthritis (OA). Immunohistochemical analysis was used to determine the expression of Ang-1, Ang-2, Tie1 and Tie2 in synovial tissue of normal subjects and those with RA and OA. Ang-1, Ang-2, Tie1 and Tie2 mRNA and protein expression were quantified in synovial tissues and RA synovial tissue fibroblasts with real-time reverse transcription polymerase chain reaction and western blot analysis. In RA, Ang-1 positive immunostaining on lining cells, macrophages and endothelial cells was significantly higher than in OA and normal synovial tissue. The expression pattern of Ang-2 in synovial tissue was similar in RA and OA, whereas the Ang-2 expression was low in normal tissue. Synovial tissue from subjects with RA and OA showed a significant upregulation of Tie1 on lining cells, macrophages and endothelial cells compared to that from normal subjects. Tie2 was significantly upregulated in the RA and OA synovial tissue lining cells, macrophages and smooth muscle cells compared to normal synovial tissue. Generally Ang-1, Ang-2, Tie1 and Tie2 mRNA levels were higher in RA synovial tissue compared to normal and OA synovial tissues, and RA synovial tissue fibroblasts. Western blot analysis also demonstrated greater Tie1 and Tie2 protein expression in RA and OA synovial tissue compared to RA synovial tissue fibroblasts. In conclusion, the dominance of Ang-1 mRNA and protein expression over Ang-2 is in agreement with an active neovascularization in RA synovial tissue. (+info)