UMLS:C0025202 - FACTA Search

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Query: UMLS:C0025202 (melanoma)
69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have suggested that differential expression and/or activation of integrins facilitates metastatic progression in murine and human melanoma. While recent data show that the integrin alphavbeta3 is involved in tumor angiogenesis and that tumor growth may be abrogated by alphavbeta3 inhibitors in vitro, the clinical significance of beta3 integrin expression in human malignant melanoma is not known. To assess the prognostic value of beta3 integrin expression, we examined primary cutaneous melanomas from 160 patients followed for a mean of 98 months or until death. We quantified the percentage of tumor area stained with beta3 integrin Ab CD-61 using an image analyzer. beta3 integrin expression was detected in 107/160 primary melanomas (69%). beta3-integrin-positive (beta3+) tumors were thicker (mean 2.98 +/- 0.3 mm) than beta3-integrin-negative (beta3-) melanomas (mean 1.64 +/- 0.2 mm) (P = 0.002). Patients with beta3+ melanomas were more likely to relapse (57/107, 53%) and to die from disease (45/107, 42%) than those with beta3- tumors (6/53, 11%; and 4/53, 8%, respectively) (P < 0.001). Overall survival was greater for beta3- than for beta3+ patients (mean 102 +/- 9 vs 69 +/- 6 months) (P = 0.001). These data show that beta3 integrin expression in primary cutaneous melanoma predicts subsequent metastatic progression. Further study of beta3 integrins in the development of melanoma metastases may yield new therapeutic strategies, as well as prognostic information, for the treatment of this cancer.
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PMID:Beta3 integrin expression in melanoma predicts subsequent metastasis. 866 Nov 92

Choroidal and ciliary body melanomas disseminate exclusively by a hematogenous route because there are no lymphatics inside the eye. Although angiogenesis is an absolute precondition for metastasis in this tumor system, not all morphologic expressions of tumor angiogenesis are associated with metastasis from choroidal and ciliary body melanomas. Specifically, the remodeling of the microcirculation to form vascular networks is very strongly associated with metastasis. Type VI collagen is upregulated in tissue remodeling and the generation of tissue patterns and is either not present in the normal choroid or present at very low levels. This study was designed to investigate the possible expression of type VI collagen in the stroma of choroidal and ciliary body melanomas. Type VI collagen was detected in tissue sections from five primary choroidal melanomas and three melanomas involving the choroid and ciliary body in the subendothelial compartment of the microcirculation and in avascular areas by immunohistochemistry. Melanoma cell lines were established from each of these tumors. Cultured melanoma cells invaded into type I collagen gels and expressed type VI collagen by immunohistochemistry. Using specific primers for human type VI collagen, the expected band size (413 base pairs) was isolated from one of the cell lines by reverse transcriptase PCR. The presence of type VI collagen in the melanoma tumor stroma reflects active remodeling of the uveal extracellular matrix microenvironment by the melanoma cells themselves. Before the formation of the microvasculature, the expression of type VI collagen and of the other matrix components, such as hyaluronan, to which it binds, may erect a scaffold permitting the formation of higher order stromal patterns such as vascular networks. These stromal patterns, which are markers of tumor progression, may be detectable clinically by a specialized form of ultrasonography that detects backscatterers of the same dimension as tissue compartments encircled by vascular loops in networks.
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PMID:Expression of type VI collagen in uveal melanoma: its role in pattern formation and tumor progression. 868 40

Tumor angiogenesis is associated with metastasis in several types of solid tumors, including melanoma, breast, prostate, lung, bladder, and oral-cavity tumors. The purpose of this study was to determine whether tumor angiogenesis could predict recurrence following curative surgery for colorectal cancer. Thirty-five patients were studied, including 13 patients with recurrent tumor and 22 without. Representative formalin-fixed, paraffin-embedded sections of invasive colorectal cancers from these patients were sectioned. The endothelial cells of microvessels within the tumors were highlighted by immunohistochemical staining for CD31. The most active areas were identified and the microvessels counted in a x 400 field (0.152 mm2) by two observers in a blinded fashion. Tumor microvessel count (p = 0.0062). Dukes' staging (p = 0.0004), vascular invasion (p = 0.0280), and tumor grade (p = 0.0559) were all significantly associated with tumor recurrence. Tumor microvessel counts > or = 65 per x 400 field were associated with tumor recurrence (p = 0.0035, relative risk [RR] = 11.3). Controlling for Dukes' stage, a multivariate logistic regression model revealed that a tumor microvessel count > or = 65 is an important predictor of tumor recurrence (p = 0.0783, RR = 6.0). A backwards elimination proportional hazards model revealed that a microvessel count > or = 65 shows a trend toward independent prediction of time to tumor recurrence (p = 0.1203, RR = 2.967) when controlled for Dukes' staging (p = 0.0029, RR = 9.089). Despite the small number of patients studied, these results suggest that the number of microvessels in sections of invasive colorectal adenocarcinoma immunohistochemically stained with CD31 may be an important independent predictor of tumor recurrence and time to recurrence.
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PMID:Tumor angiogenesis predicts recurrence in invasive colorectal cancer when controlled for Dukes staging. 882 33

Elevated vascular endothelial growth factor (VEGF) levels are required for ocular and tumor angiogenesis in animal models. Ischemic hypoxia is strongly correlated with increased VEGF expression in these systems and is considered a physiologically relevant stimulus. Because ischemic hypoxia is often followed by reperfusion and reactive oxygen intermediate (ROI) generation, we examined the potential role of ROI in the control of VEGF gene expression. Human retinal pigment epithelial cells exposed to superoxide or hydrogen peroxide rapidly increased VEGF mRNA levels. Superoxide-associated mRNA increases were dose dependent, blocked by antioxidants, and associated with elevated VEGF protein levels in conditioned media. Increases in VEGF mRNA levels were also observed in cultured human melanoma and rat glioblastoma cells with superoxide or hydrogen peroxide. Cycloheximide prevented the ROI-associated increases in VEGF mRNA. Transcriptional inhibition with actinomycin D revealed an inducible increase in VEGF mRNA half-life, but nuclear run-on experiments showed no increase in VEGF transcriptional rate. Reoxygenation of human retinal pigment epithelial cells in vitro and ocular reperfusion in vivo increased retinal VEGF mRNA levels. Antioxidants prevented the reperfusion-associated VEGF mRNA increases in retina. We conclude that ROIs increase VEGF gene expression in vitro and during the reperfusion of ischemic retina in vivo. The ROI-associated increases are mediated largely through increases in VEGF mRNA stability.
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PMID:Reactive oxygen intermediates increase vascular endothelial growth factor expression in vitro and in vivo. 883 17

Clinical and experimental evidence suggests that spreading of malignant cells from a localized tumor (metastasis) is directly related to the number of microvessels in the primary tumor. This tumor angiogenesis is thought to be mediated by tumor-cell-derived growth factors. However, most tumor cells express a multitude of candidate angiogenesis factors and it is difficult to decipher which of these are rate-limiting factors in vivo. Herein we use ribozyme targeting of pleiotrophin (PTN) in metastatic human melanoma cells to assess the significance of this secreted growth factor for angiogenesis and metastasis. As a model we used human melanoma cells (1205LU) that express high levels of PTN and metastasize from subcutaneous tumors to the lungs of experimental animals. In these melanoma cells, we reduced PTN mRNA and growth factor activity by transfection with PTN-targeted ribozymes and generated cell lines expressing different levels of PTN. We found that the reduction of PTN does not affect growth of the melanoma cells in vitro. In nude mice, however, tumor growth and angiogenesis were decreased in parallel with the reduced PTN levels and apoptosis in the tumors was increased. Concomitantly, the metastatic spread of the tumors from the subcutaneous site to the lungs was prevented. These studies support a direct link between tumor angiogenesis and metastasis through a secreted growth factor and identify PTN as a candidate factor that may be rate-limiting for human melanoma metastasis.
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PMID:Melanoma angiogenesis and metastasis modulated by ribozyme targeting of the secreted growth factor pleiotrophin. 896 27

The hyperpermeability of tumor vessels to macromolecules, compared with normal vessels, is presumably due to vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) released by neoplastic and/or host cells. In addition, VEGF/VPF is a potent angiogenic factor. Removal of this growth factor may reduce the permeability and inhibit tumor angiogenesis. To test these hypotheses, we transplanted a human glioblastoma (U87), a human colon adenocarcinoma (LS174T), and a human melanoma (P-MEL) into two locations in immunodeficient mice: the cranial window and the dorsal skinfold chamber. The mice bearing vascularized tumors were treated with a bolus (0.2 ml) of either a neutralizing antibody (A4.6.1) (492 micrograms/ml) against VEGF/VPF or PBS (control). We found that tumor vascular permeability to albumin in antibody-treated groups was lower than in the matched controls and that the effect of the antibody was time-dependent and influenced by the mode of injection. Tumor vascular permeability did not respond to i.p. injection of the antibody until 4 days posttreatment. However, the permeability was reduced within 6 h after i.v. injection of the same amount of antibody. In addition to the reduction in vascular permeability, the tumor vessels became smaller in diameter and less tortuous after antibody injections and eventually disappeared from the surface after four consecutive treatments in U87 tumors. These results demonstrate that tumor vascular permeability can be reduced by neutralization of endogenous VEGF/ VPF and suggest that angiogenesis and the maintenance of integrity of tumor vessels require the presence of VEGF/VPF in the tissue microenvironment. The latter finding reveals a new mechanism of tumor vessel regression-i.e., blocking the interactions between VEFG/VPF and endothelial cells or inhibiting VEGF/VPF synthesis in solid tumors causes dramatic reduction in vessel diameter, which may block the passage of blood elements and thus lead to vascular regression.
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PMID:Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. 896 29

There is a worldwide increase in the incidence of melanoma. Without treatment, melanomas can progress to metastatic disease and result in death. It is now accepted that for a tumor to grow, non-tumorous host tissue must form blood vessels in and around the tumor. Tumor cells and blood vessels must form a highly regulated system whereby endothelial cells can be switched from a resting state to one of rapid growth. Tumor cells have been shown to produce diffusible angiogenic regulatory molecules. Nitric oxide [NO] and polyamines [PA] have been implicated in the angiogenic process. This paper hypothesizes that NO and PA regulate melanoma angiogenesis differently. During early stages of malignant melanoma an increase in PA synthesis is expected to promote endothelial cell proliferation and therefore angiogenesis. NO is expected to be maintained at low levels. During the vascular stage of malignant melanoma, NO synthesis is hypothesized to be elevated which will decrease endothelial cell proliferation and maintain a vasodilator tone in and around the tumor. PA concentrations are expected to be lower. A regulatory link between NO and PA may be involved in the maintenance of tumor homeostasis. The regulation of L-arginine metabolism in tumor angiogenesis requires investigation as it may lead to novel selective therapeutic interventions in cancer therapy.
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PMID:The importance of L-arginine metabolism in melanoma: an hypothesis for the role of nitric oxide and polyamines in tumor angiogenesis. 898 Oct 51

The regulation of tumor growth by cytokine-induced alterations in host effector cell recruitment and activation is intimately associated with leukocyte adhesion and angiogenic modulation. In the present study, we have developed a novel tumor model to investigate this complex series of events in response to cytokine administration. Gelatin sponges containing recombinant human basic fibroblast growth factor (rhFGFb) and B16F10 melanoma cells were implanted onto the serosal surface of the left lateral hepatic lobe in syngeneic C57BL/6 mice. The tumor model was characterized by progressive tumor growth initially localized within the sponge and the subsequent development of peritoneal carcinomatosis. Microscopic examination of the sponge matrix revealed well developed tumor-associated vascular structures and areas of endothelial cell activation as evidenced by leukocyte margination. Treatment of mice 3 days after sponge implantation with a therapeutic regimen consisting of pulse recombinant human interleukin-2 (rhIL-2) combined with recombinant murine interleukin-12 (rmIL-12) resulted in a marked hepatic mononuclear infiltrate and inhibition of tumor growth. In contrast to the control group, sponges from mice treated with rhIL-2/rmIL-12 demonstrated an overall lack of cellularity and vascular structure. The regimen of rhIL-2 in combination with rmIL-12 was equally effective against gelatin sponge implants of rhFGFb/B16F10 melanoma in SCID mice treated with anti-asialo-GM1 in the absence of a mononuclear infiltration, suggesting that T, B, and/or NK cells were not the principal mediators of the anti-tumor response in this tumor model. The absence of vascularity within the sponge after treatment suggests that a potential mechanism of rhIL-2/rmIL-12 anti-tumor activity is the inhibition of neovascular growth associated with the establishment of tumor lesions. This potential mechanism could be dissociated from the known activities of these two cytokines to induce the recruitment and activation of host effector cells. Moreover, this model provides a unique opportunity to study the cellular and molecular mechanism(s) underlying both tumor angiogenesis and leukocyte recruitment to metastatic lesions.
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PMID:Regulation of local host-mediated anti-tumor mechanisms by cytokines: direct and indirect effects on leukocyte recruitment and angiogenesis. 913 9

Administration of tumor necrosis factor (TNF) and gamma interferon (IFN-gamma) to melanoma patients causes selective disruption of the tumor vasculature but the mechanism of this disruption is unknown. Here we report that exposure of human endothelial cells to TNF and IFN-gamma results in a reduced activation of integrin alphaVbeta3, an adhesion receptor that plays a key role in tumor angiogenesis, leading to a decreased alphaVbeta3-dependent endothelial cell adhesion and survival. Detachment and apoptosis of angiogenic endothelial cells was demonstrated in vivo in melanoma metastases of patients treated with TNF and IFN-gamma. These results implicate integrin alphaVbeta3 in the anti-vascular activity of TNF and IFN-gamma and demonstrate a new mechanism by which cytokines control cell adhesion.
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PMID:Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. 954 82

Angiogenesis, the formation of new blood vessels, is a requirement for malignant tumor growth and metastasis. In the absence of angiogenesis, local tumor expansion is suppressed at a few millimeters and cells lack routes for distant hematogenous spread. Clinical studies have demonstrated that the degree of angiogenesis is correlated with the malignant potential of several cancers, including breast cancer and malignant melanoma. Moreover, the expression of a specific angiogenesis marker, the endothelial integrin alphaVbeta3, has been shown to correlate with tumor grade. However, studies of tumor angiogenesis such as these have generally relied on invasive procedures, adequate tissue sampling and meticulous estimation of histologic microvessel density. In the present report, we describe a novel approach to detecting angiogenesis in vivo using magnetic resonance imaging (MRI) and a paramagnetic contrast agent targeted to endothelial alphaVbeta3 via the LM609 monoclonal antibody. This approach provided enhanced and detailed imaging of rabbit carcinomas by directly targeting paramagnetic agents to the angiogenic vasculature. In addition, angiogenic 'hot spots' not seen by standard MRI were detected. Our strategy for MR imaging of alphaVbeta3 thus represents a non-invasive means to assess the growth and malignant phenotype of tumors.
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PMID:Detection of tumor angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging. 958 40

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