Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the process of tumor cell invasion and metastasis, tumor cells are known to interact with extracellular matrix proteins, endothelial cells, platelets and other organ-specific structures. Integrins are cell surface molecules which mediate cell-matrix and cell-cell interactions and are likely to be important for tumor cell survival and dissemination. The purpose of this study was to characterize the integrin and proteolytic enzyme repertoire from low (A375P), medium (A375M) and high metastatic (A375SM) human melanoma cell lines. These cell lines are also invasive through human amniotic membranes in vitro and their invasiveness parallels the reported metastatic phenotype. The types and levels of expression of the various integrin receptors were analysed by quantitative immunoprecipitation using a panel of monoclonal antibodies directed to known integrin subunits. In addition, cDNA probes to the integrin subunits were used in quantitative northern blot analysis. These data show that the integrin alpha v beta 3 increases 50- to 100-fold as these cells progress to a more metastatic phenotype. alpha 4 beta 1 levels also appeared to increase several fold, while other beta 1 integrins did not differ in their expression levels. The increased alpha v beta 3 expression in the more metastatic cells resulted in an increased adhesion to vitronectin and fibrinogen substrates in cell attachment assays. However, alpha v- and beta 3-specific antibodies did not inhibit A375 cell invasion through the amnion. Each cell line was found to release similar quantities of a 72-kDa gelatinase/type IV collagenase and tissue type plasminogen activator. These results suggest that during the progression of these tumor cells from a low to high metastatic phenotype, marked changes in integrin expression occurred which may facilitate interactions with platelets, endothelial cells and specific extracellular matrix proteins to promote metastasis.
Clin Exp Metastasis 1992 Mar
PMID:Integrin expression in human melanoma cells with differing invasive and metastatic properties. 131 Dec 25

Human melanoma originates in the skin and can lead to wide-spread metastatic disease. Analysis of melanoma biopsy material has shown that the vitronectin receptor, integrin alpha v beta 3, is a specific marker of the most malignant cells, i.e., vertically invasive primary lesions or distant metastases (Albelda, S. M., S. A. Mette, D. E. Elder, R. Stewart, L. Damjanovich, M. Herlyn, and C. A. Buck. 1990. Cancer Res. 50:6757-6764), suggesting a role for this adhesion receptor in the malignant growth of human melanoma tumors. A cell model was established to analyze the role of alpha v integrins on the tumorigenicity of human melanoma. From M21 human melanoma cells, stable variants were selected that lack alpha v gene expression and thus fail to express integrin alpha v beta 3 (M21-L cells). These cells not only lost the ability to attach to vitronectin but showed a dramatic reduction in tumorigenicity when transplanted into athymic nude mice, compared with M21 cells, even though both cell types showed identical beta 1 integrin expression and growth properties in vitro. M21-L cells were stably transfected with a cDNA-encoding alpha v. This resulted in the functional expression of integrin alpha v beta 3 on these cells and completely restored their tumorigenicity. Thus, integrin alpha v gene expression and the resulting adhesive phenotype are directly involved in the proliferation of human melanoma in vivo.
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PMID:Involvement of integrin alpha V gene expression in human melanoma tumorigenicity. 137 31

Human melanoma is a highly metastatic cancer and the regional lymph nodes are generally the first site of metastasis. Adhesion to cryostat sections of human lymph nodes was therefore studied using two human melanoma models established from lymph node metastases, namely, MeWo cell lines of diverse metastatic potentials and a highly metastatic cell line of recent origin designated MIM/8. We found a good correlation between the metastatic potentials of the melanoma cells as measured in nude mice and their ability to adhere to cryostat sections of human lymph nodes. When adhesion to immobilized extracellular matrix proteins was measured, a significant increase in adhesion, which correlated with increased metastasis, was seen mainly on vitronectin and to a lesser extent on fibronectin. The adhesion to vitronectin and to the frozen sections were specifically blocked by an RGD-containing peptide, mAb 661 to vitronectin and mAb LM609 to integrin alpha v beta 3. FACS analysis revealed a significant and specific increase in cell surface expression of alpha v beta 3 on the metastatic cells as compared to the parent line. Together these results suggest that the adhesion of melanoma cells to lymph node vitronectin via the alpha v beta 3 receptor plays a role in the process of lymphatic dissemination.
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PMID:Human melanoma cells derived from lymphatic metastases use integrin alpha v beta 3 to adhere to lymph node vitronectin. 138 72

The NPXY sequence is highly conserved among integrin beta subunit cytoplasmic tails, suggesting that it plays a fundamental role in regulating integrin-mediated function. Evidence is provided that the NPXY structural motif within the beta 3 subunit, comprising residues 744-747, is essential for cell morphological and migratory responses mediated by integrin alpha v beta 3 in vitro and in vivo. Transfection of CS-1 melanoma cells with a cDNA encoding the wild-type integrin beta 3 subunit, results in de novo alpha v beta 3 expression and cell attachment, spreading, and migration on vitronectin. CS-1 cells expressing alpha v beta 3 with mutations that disrupt the NPXY sequence interact with soluble vitronectin or an RGD peptide, yet fail to attach, spread, or migrate on immobilized ligand. The biological consequences of these observations are underscored by the finding that CS-1 cells expressing wild-type alpha v beta 3 acquire the capacity to form spontaneous pulmonary metastases in the chick embryo when grown on the chorioallantoic membrane. However, migration-deficient CS-1 cells expressing alpha v beta 3 with mutations in the NPXY sequence lose this ability to metastasize. These findings demonstrate that the NPXY motif within the integrin beta 3 cytoplasmic tail is essential for alpha v beta 3-dependent post-ligand binding events involved in cell migration and the metastatic phenotype of melanoma cells.
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PMID:Requirement of the NPXY motif in the integrin beta 3 subunit cytoplasmic tail for melanoma cell migration in vitro and in vivo. 754 48

Osteopontin (OPN) is a secreted phosphoglycoprotein abundant in secretory luminal epithelia (Brown et al., 1992) and in bone (Reinholt et al., 1990). It contains a functional gly-arg-gly-asp-ser (GRGDS) integrin binding domain (Oldberg et al., 1986), promotes the adhesion of a variety of cell types (Somerman et al., 1989; Brown et al., 1992) and is a ligand for the vitronectin binding integrin alpha v beta 3 (Miyauchi et al., 1991). Elevated expression of OPN correlates with tumorigenic transformation in a great variety of stromal and epithelial cell lines (Senger et al., 1980, 1983, 1989; Craig et al., 1988; Chambers et al., 1992; Chang & Prince, 1993). The protein is also present in excess in the blood of patients with metastatic disease (Senger et al., 1988). To find whether OPN contributes significantly to the tumorigenic phenotype, we expressed antisense mRNA to OPN in high OPN producing malignant B77-Rat1 fibroblasts. This caused a reduction in their OPN secretion and reduced their ability to form both lung tumors in nude mice after intravenous injection, and colonies in soft agar. Antisense transfectants also showed increased spreading on vitronectin. These observations suggest that OPN overproduction is advantageous to the metastatic phenotype, possibly by altering adhesion via, or signal transduction from, vitronectin receptors.
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PMID:Specific reduction in osteopontin synthesis by antisense RNA inhibits the tumorigenicity of transformed Rat1 fibroblasts. 803 14

Metastasis is the primary cause of death in human breast cancer. Metastasis to bone, lungs, liver, and brain involves dissemination of breast cancer cells via the bloodstream and requires adhesion within the vasculature. Blood cell adhesion within the vasculature depends on integrins, a family of transmembrane adhesion receptors, and is regulated by integrin activation. Here we show that integrin alpha v beta 3 supports breast cancer cell attachment under blood flow conditions in an activation-dependent manner. Integrin alpha v beta 3 was found in two distinct functional states in human breast cancer cells. The activated, but not the nonactivated, state supported tumor cell arrest during blood flow through interaction with platelets. Importantly, activated alpha v beta 3 was expressed by freshly isolated metastatic human breast cancer cells and variants of the MDA-MB 435 human breast cancer cell line, derived from mammary fat pad tumors or distant metastases in severe combined immunodeficient mice. Expression of constitutively activated mutant alpha v beta 3(D723R), but not alpha v beta 3(WT), in MDA-MB 435 cells strongly promoted metastasis in the mouse model. Thus breast cancer cells can exhibit a platelet-interactive and metastatic phenotype that is controlled by the activation of integrin alpha v beta 3. Consequently, alterations within tumors that lead to the aberrant control of integrin activation are expected to adversely affect the course of human breast cancer.
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PMID:Integrin activation controls metastasis in human breast cancer. 1117 40

The angiogenic response of a progressing malignancy is characterized by a shift in the balance of stimulatory and inhibiting factors of angiogenesis. Recognition of the regulated steps in tumor angiogenesis provides unique targets for developing anti-tumor therapy. Vitaxin is a humanized monoclonal antibody, which has specificity for the integrin alpha v beta 3 (vitronectin receptor). This antibody can impair the vascular response of endothelial cell growth factors in vitro and inhibit tumor cell mediated angiogenesis in pre-clinical animal models. Patients with metastatic cancer who failed standard therapy received intravenous doses of 10, 50 or 200 mg in cohorts of three patients. The unlabeled dose of Vitaxin was infused on days 0 and 21 of a treatment cycle. All patients received a pre-therapy imaging dose of 1 mg of Tc-99m Vitaxin with gamma camera imaging studies. There was no significant toxicity noted in these three dose levels. There were no objective anti-tumor responses. Three patients received two cycles of therapy and had stable disease at day 85 when taken off study. Radioimaging of tumor vasculature was unsuccessful although one patient with alpha v beta 3 positive melanoma had imaging of tumor sites. There was no immune response to Vitaxin in any patient. Patients receiving 10 mg doses of Vitaxin had poor plasma recovery of injected doses and brief circulation in plasma. Doses of 50 and 200 mg had plasma recovery that better approximated the predicted levels in plasma and circulation half-lives of approximately 7 days. This data suggests that an every three-week schedule of Vitaxin at doses of 200 mg (2.5-3.5 mg/kg) can maintain circulating levels of antibody with little or no toxicity. Future studies will be challenged to define anti-tumor activity in malignancy or appropriate surrogates of anti-tumor effect and explore escalating doses and alternate schedules of administration.
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PMID:A pilot trial of Vitaxin, a humanized anti-vitronectin receptor (anti alpha v beta 3) antibody in patients with metastatic cancer. 1138 59

Early metastasis is the primary cause of death in melanoma patients. The adhesion receptor integrin alpha v beta 3 contributes to tumor cell functions that are potentially involved in melanoma growth and metastasis. We tested whether integrin alpha v beta 3 supports metastasis of human melanoma cells when injected into the bloodstream of immune deficient mice. Comparing variants of the same melanoma cell type that expressed either alpha v beta 3, alpha IIb beta 3 or no beta 3 integrin, we found that only alpha v beta 3 strongly supported metastasis. Inhibition of tumor cell alpha v beta 3 function reduced melanoma metastasis significantly and prolonged animal survival. To understand mechanisms that allow alpha v beta 3, but not alpha IIb beta 3 to support melanoma metastasis, we analyzed proteolytic and migratory activities of the melanoma cell variants. Melanoma cells expressing alpha v beta 3, but not those expressing alpha IIb beta 3 or no beta 3 integrin, produced the active form of metalloproteinase MMP-2 and expressed elevated mRNA levels of MT1-MMP and TIMP-2. This indicates an association between alpha v beta 3 expression and protease processing. Furthermore, alpha v beta 3 expression was required for efficient melanoma cell migration toward the matrix proteins fibronectin and vitronectin. The results suggest that expression of integrin alpha v beta 3 promotes the metastatic phenotype in human melanoma by supporting specific adhesive, invasive and migratory properties of the tumor cells and that the related integrin alpha IIb beta 3 cannot substitute for alpha v beta 3 in this respect.
Clin Exp Metastasis 2002
PMID:Involvement of tumor cell integrin alpha v beta 3 in hematogenous metastasis of human melanoma cells. 1219 71

A series of radiolabeled cyclic arginine-glycine-aspartic acid (RGD) peptide ligands for cell adhesion molecule integrin alpha v beta 3-targeted tumor angiogenesis targeting are being developed in our laboratory. In this study, this effort continues by applying a positron emitter 64Cu-labeled PEGylated dimeric RGD peptide radiotracer 64Cu-DOTA-PEG-E[c(RGDyK)]2 for lung cancer imaging. The PEGylated RGD peptide indicated integrin alpha v beta 3 avidity, but the PEGylation reduced the receptor binding affinity of this ligand compared to the unmodified RGD dimer. The radiotracer revealed rapid blood clearance and predominant renal clearance route. The minimum nonspecific activity accumulation in normal lung tissue and heart rendered high-quality orthotopic lung cancer tumor images, enabling clear demarcation of both the primary tumor at the upper lobe of the left lung, as well as metastases in the mediastinum, contralateral lung, and diaphragm. As a comparison, fluorodeoxyglucose (FDG) scans on the same mice were only able to identify the primary tumor, with the metastatic lesions masked by intense cardiac uptake and high lung background. 64Cu-DOTA-PEG-E[c(RGDyK)]2 is an excellent position emission tomography (PET) tracer for integrin-positive tumor imaging. Further studies to improve the receptor binding affinity of the tracer and subsequently to increase the magnitude of tumor uptake without comprising the favorable in vivo kinetics are currently in progress.
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PMID:Integrin alpha v beta 3-targeted imaging of lung cancer. 1579 27