Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Tie-1 is a transmembrane receptor expressed in vascular endothelium during angiogenic events and during embryonal growth in most mammalian species. The monoclonal antibodies (mAbs) used here are generated against the extracellular part of the Tie-1 receptor protein. We analyzed the specific binding of (125)I-labeled Tie-1 mAbs in the metastatic tumor model in mouse and in human serum samples to determine the possible use of the Tie-1 mAbs in detecting malignant growth. The in vivo biodistribution of (125)I-Tie-1 mAbs (IgG1) was evaluated in the mouse model. The same Tie-1 mAbs were used to analyze Tie-1 in patient serum samples. A high accumulation of two (125)I-Tie-1 mAbs, clones 10f11g6 and 3c4c7, was detected in the lung metastases of mouse tumor model. The uptake in the metastases is 12% injected dose/gram (ID/g; 10f11g6) and 7.8% ID/g (3c4c7) at 96 h after the injections of (125)I-Tie-1 mAbs, and the accumulation to the blood is 7% and 5% ID/g with the two mAbs, respectively. The finding directed us to analyze serum samples from lung, ovarian, and breast cancer patients. High levels of Tie-1 were detected in samples related to new pelvic or thoracic metastases in patients. Here we connect the Tie-1 levels in serum to tumor progression. The results suggest that Tie-1 mAbs can be used as a surrogate marker of progressive disease.
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PMID:The new Tie-1 monoclonal antibodies detect angiogenesis in metastatic malignancies. 1450 79

Limited options for the treatment of prostate cancer have spurred the search for new therapies. One innovative approach is the use of targeted alpha therapy (TAT) to inhibit cancer growth, using an alpha particle emitting radioisotope such as (213)Bi. Because of its short range and high linear energy transfer (LET), alpha-particles may be particularly effective in the treatment of cancer, especially in inhibiting the development of metastatic tumors from micro-metastases. Prostate-specific membrane antigen (PSMA) is expressed in prostate cancer cells and the neovasculature of a wide variety of malignant neoplasms including lung, colon, breast and others, but not in normal vascular endothelium. The expression is further increased in higher-grade cancers, metastatic disease and hormone-refractory prostate cancer (PCA). J591 is one of several monoclonal antibodies (mabs) to the extracellular domain of PSMA. Chelation of J591 mab with (213)Bi forms the alpha-radioimmunoconjugate (AIC). The objective of this preclinical study was to design an injectable AIC to treat human prostate tumors growing subcutaneously in mice. The anti-proliferative effects of AIC against prostate cancer were tested in vitro using the MTS assay and in vivo with the nude mice model. Apoptosis was documented using terminal deoxynucleotidyl transferase [TdT]-mediated deoxyuridinetriphosphate [dUTP] nick end-labeling (TUNEL) assay, while proliferative index was assessed using the Ki-67 marker. We show that a very high density of PSMA is expressed in an androgen-dependent human PCA cell line (LNCaP-LN3) and in tumor xenografts from nude mice. We also demonstrate that the AIC extensively inhibits the growth of LN3 cells in vitro in a concentration-dependent fashion, causing the cells to undergo apoptosis. Our in vivo studies showed that a local AIC injection of 50 microCi at 2 days post-cell inoculation gave complete inhibition of tumor growth, whereas results for a non-specific AIC were similar to those for untreated mice. Further, after 1 and 3 weeks post-tumor appearance, a single (100 microCi/100 microl) intra-lesional injection of AIC can inhibit the growth of LN3 tumor xenografts (volume<100 mm(3)) in nude mice. Tumors treated with AIC decreased in volume from a mean 46+/-14 mm(3) in the first week or 71+/-15 mm(3) in the third week to non-palpable, while in control mice treated with a non-specific AIC using the same dose, tumor volume increased from 42 to 590 mm(3). There were no observed side effects of the treatment. Because of its in vitro cytotoxicity and these anti-proliferative properties in vivo, the (213)Bi-J591 conjugate has considerable potential as a new therapeutic agent for the treatment of prostate cancer.
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PMID:In vitro and preclinical targeted alpha therapy of human prostate cancer with Bi-213 labeled J591 antibody against the prostate specific membrane antigen. 1519 29

Adhesion of tumor cells to endothelium via cell-adhesion molecules constitutes a crucial step in metastasis, which is largely responsible for the poor prognosis of small-cell lung carcinoma (SCLC). Patients with SCLC were reported to have elevated levels of intercellular adhesion molecule-1 (ICAM-1). The present study therefore focusses on endothelial ICAM-1 in tumor-cell adhesion. We found that the adherence of SCLC cells (cell lines H24, H69, H82) to cultured vascular endothelium in stasis and flow depends on the expression of ICAM-1. After blocking endothelial ICAM-1 with monoclonal antibodies, adhesion was significantly reduced. These results pinpoint ICAM-1 for the first time as a molecule crucially involved in SCLC cell-endothelial adhesion.
Clin Exp Metastasis 2004
PMID:ICAM-1 supports adhesion of human small-cell lung carcinoma to endothelial cells. 1538 68

Expression of N-acetylglucosaminyltransferase V (GnT-V) in colon cancer has been shown to be related to hematogenous metastasis and poor prognosis. To investigate the mechanism by which cancer cells expressing GnT-V metastasize to distant organs, we established GnT-V-overexpressing DLD-1 and WiDr cells (human colon cancer cell lines) by transfecting them with a GnT-V expression vector. Attachment to endothelial cells expressing E-selectin was studied, and expression of the E-selectin ligand, sialyl Lewis x, in colon cancer cells was investigated. Both of the cell lines showed reduced adhesion to fibronectin as compared with mock transfectants. In contrast, attachment to human umbilical vein endothelial cells expressing E-selectin was significantly enhanced by GnT-V expression (p < 0.01). Sialyl Lewis x is a ligand for E-selectin and a marker for poor prognosis of colon cancer. Its synthesis in cells has been shown to involve GnT-V. We demonstrated that expression of sialyl Lewis x in colon cancer cells was induced by GnT-V expression. These results suggest that GnT-V induces sialyl Lewis x expression and leads colon cancer cells to metastasize by enhancing their ability to attach to vascular endothelium in distant organs, such as liver or lung. Inhibition of GnT-V activity may prevent metastasis in colon cancer patients with high sialyl Lewis x expression.
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PMID:Attachment of human colon cancer cells to vascular endothelium is enhanced by N-acetylglucosaminyltransferase V. 1545 79

VEGF is unique among angiogenic growth factors because it disrupts endothelial barrier function. Therefore, we considered whether this property of VEGF might contribute to tumor cell extravasation and metastasis. To test this, mice lacking the Src family kinases Src or Yes, which maintain endothelial barrier function in the presence of VEGF, were injected intravenously with VEGF-expressing tumor cells. We found a dramatic reduction in tumor cell extravasation in lungs or livers of mice lacking Src or Yes. At the molecular level, VEGF compromises the endothelial barrier by disrupting a VE-cadherin-beta-catenin complex in lung endothelium from wild-type, but not Yes-deficient, mice. Disrupting the endothelial barrier directly with anti-VE-cadherin both amplifies metastasis in normal mice and overcomes the genetic resistance in Yes-deficient mice. Pharmacological blockade of VEGF, VEGFR-2, or Src stabilizes endothelial barrier function and suppresses tumor cell extravasation in vivo. Therefore, disrupting Src signaling preserves host endothelial barrier function providing a novel host-targeted approach to control metastatic disease.
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PMID:Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. 1550 9

Metastasis, the main reason for high mortality of cancer, is a multistep process. One important step in this process is the adhesion of tumor cells to vascular endothelium at sites distant from primary tumors during hematogenous dissemination. In order to investigate and quantify the adhesion of tumor cells to endothelial cells we developed an in vitro model using MCF-7 breast cancer cells and monolayers of human umbilical vein endothelial cells (HUVEC). The tumor cells were specifically labeled with a fluorescent dye for quantification; for increasing the amount of adherent cells, HUVEC monolayers were stimulated with phorbol ester before the addition of the tumor cells. Due to previous reports that products of several P450 enzymes contribute to the progression of certain kinds of cancer, inhibitors of CYP5 (thromboxane A(2) synthase), CYP17 (17alpha-hydroxylase-C17, 20-lyase), and CYP19 (aromatase) were tested in this in vitro model for their potency to reduce cancer cell adhesion. Within each series of P450 inhibitors, compounds with high inhibitory activity on tumor cell adhesion were identified. At an initial concentration of 100 microM, BW26, a potent inhibitor of CYP5, reduced tumor cell adhesion of MCF-7 to HUVECs to 15%, BW40 (CYP17) to 29%, and SU5a (CYP19) to 11% of the corresponding controls (no inhibitor). Reduction of tumor cell adhesion was shown to occur in a concentration-dependent manner. In addition to these inhibitors of CYP5, CYP17, and CYP19, liarozole, known to be a potent inhibitor of CYP26 (retinoic acid-4-hydroxylase) and ATRA (all-trans-retinoic acid) metabolism, was able to reduce tumor cell adhesion to 51% of the initial rate. Experiments elucidating the mode of action of these compounds revealed that inhibition of the mentioned CYP enzymes is not responsible for their ability to reduce tumor cell adhesion.
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PMID:Discovery of inhibitors of MCF-7 tumor cell adhesion to endothelial cells and investigation on their mode of action. 1559 2

Adhesion of inflammatory cells to vascular endothelium is mediated by specific cell adhesion receptors on both leukocytes and endothelial cells. One of the adhesion molecules on the endothelium is P-selectin. Decreased vascular P-selectin expression has been associated with tumor progression in melanoma patients. We now report on the expression of endothelial P-selectin in colorectal cancer (CRC). We studied a colorectal tissue specimen series ranging from normal colorectal tissue via unmetastasized primary tumors to tumors with the same depth of invasion at the primary site but with liver metastases. Moreover, P-selectin expression levels in liver metastases were determined. The number of P-selectin positive vessels as a fraction of the total number of vessels, both intra- and peritumorally, was determined by staining for CD62P and CD34, respectively. Furthermore, by immunostaining for leukocytes (CD45) and macrophages (CD68), it was evaluated whether levels of P-selectin expression influenced infiltrate density and composition. The results showed that levels of peritumoral P-selectin expression were reciprocal to the degree of progression in CRC. This relation was even more pronounced intratumorally: in metastasized primary tumors and in the metastatic lesions, P-selectin expression was virtually absent. This distribution pattern was reflected in the numbers of leukocytes that accumulated in the various tissues, since in the primary tumors with metastases, and in the metastatic lesions, hardly any infiltrating cells were observed. In these lesions, leukocytes were present in the peritumoral zone, but seemed unable to enter the tumor tissue. In primary tumors without metastasis, the intratumoral leukocyte infiltration density was significantly higher. Recruitment levels of macrophages remained constant throughout the different tissues. We suggest that downregulation of endothelial P-selectin expression is a mechanism by which CRC lesions evade inflammatory regression and, thereby, progress to a more advanced stage of malignancy.
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PMID:Progressive loss of endothelial P-selectin expression with increasing malignancy in colorectal cancer. 1564 Aug 34

Metastasis of circulating tumor cells requires a multistep cascade of events initiated by adhesion of tumor cells to the vascular endothelium of involved tissues. This process occurs under the forces of blood flow and is promoted by adhesion molecules specialized to interact under shear conditions. The endothelial molecule E-selectin is a major mediator of these adhesive events, and there is strong evidence that E-selectin receptor-ligand interactions contribute to the formation of metastasis. However, little is known about the identity of E-selectin ligand(s) expressed on cancer cells. To address this issue, we did SDS-PAGE analysis of membrane proteins, metabolic inhibition studies, and blot rolling assays of LS174T, a colon carcinoma cell line known to interact with E-selectin under physiologic flow conditions. Our studies show that LS174T cells express the hematopoietic cell E/L-selectin (HCELL) glycoform of CD44, which functions as a high-affinity E-selectin glycoprotein ligand on these cells. However, in contrast to the HCELL glycoform on human hematopoietic progenitor cells, which expresses carbohydrate-binding determinant(s) for E-selectin primarily on N-glycans of standard CD44, the relevant determinant(s) on LS174T cells is expressed on O-glycans and is predominantly found on variant isoforms of CD44 (CD44v). Our finding that tumor-associated CD44 splice variant(s) express E-selectin ligand activity provides novel perspectives on the biology of CD44 in cancer metastasis.
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PMID:CD44 on LS174T colon carcinoma cells possesses E-selectin ligand activity. 1599 57

Endothelial cells express two dependent intercellular adhesion molecules: vascular endothelial (VE)-cadherin, specific for endothelial cells, and N-cadherin, also present in neuronal, lens, skeletal and heart muscle cells, osteoblasts, pericytes and fibroblasts. While there exists a vast amount of evidence that VE-cadherin promotes angiogenesis, the role of N-cadherin still remains to be elucidated. We found that a soluble 90-kDa fragment N-cadherin promotes angiogenesis in the rabbit cornea assay and in the chorioallantoic assay when cleaved enzymatically from the extracellular domain of N-cadherin. Soluble N-cadherin stimulates migration of endothelial cells in the wound healing assay and stimulates phosphorylation of extracellular regulated kinase. In vitro experiments with PD173074 and knock-down of N-cadherin and fibroblast growth factor (FGF)-receptor, showed that the pro-angiogenic effect of soluble N-cadherin is N-cadherin- and FGF-receptor-dependent. Our results suggest that soluble N-cadherin stimulates migration of endothelial cells through the FGF-receptor.
Clin Exp Metastasis 2006
PMID:Soluble N-cadherin fragment promotes angiogenesis. 1702 23

Metastases of adenocarcinomas from the pancreas, liver, and gastrointestinal tract are difficult to distinguish from each other because of their similar morphological and immunohistochemical features. So far, no specific marker for pancreatic ductal adenocarcinomas has been described. Podocalyxin-like protein 1 (PODXL-1) is expressed on vascular endothelium, hematopoietic precursor cells, and renal podocytes. We found that 44% (71/160) of pancreatic ductal adenocarcinomas expressed PODXL-1 in a membranous pattern. There was no expression in intrahepatic cholangiocarcinomas (0/18, P < .001), rarely in adenocarcinomas of the extrahepatic bile ducts (1/13, P = .009), and none in duodenal adenocarcinomas (0/5, P = .070). PODXL-1 expression was seen in only 9% of hepatocellular carcinomas (5/56, P < .001), 9% (4/47, P < .001) of gastric carcinomas, 10% of esophageal adenocarcinomas (2/20, P = .003), and 6% of colonic adenocarcinomas (1/17, P = .001). When used as a differential diagnostic marker, ampullary carcinoma needs to be excluded, as 30% (6/20, P = .24) of ampullary carcinomas stain positive, especially those of the signet-ring type (3/3). Adenocarcinomas of the lung and prostate, and liver metastases of colorectal carcinomas lacked PODXL-1 expression. It is concluded that immunoreactivity for PODXL-1 favors a pancreatic origin if ampullary carcinoma is excluded.
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PMID:Podocalyxin-like protein 1 expression is useful to differentiate pancreatic ductal adenocarcinomas from adenocarcinomas of the biliary and gastrointestinal tracts. 1713 15


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