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)

Tumour cell adhesion within the microvasculature of host organs, its stabilisation and cell invasion into the host organs, appear to be important steps in the formation of distant metastases. Intravital fluorescence-video microscopy was used to investigate the early steps in metastasis formation of colon carcinoma cells within the liver, which is the main target organ of colorectal carcinomas. The involvement of alphav-integrins was analysed in vivo using HT-29 cells after treatment with different function-blocking antibodies [pan-alphav (n=9 animals), specific alphavbeta3 (n=8 animals) and alphavbeta5 (n=8 animals)] or linear Arg-Gly-Asp (RGD)-containing peptides (RGD-peptides) (n=6 animals). Treatment with anti-alphav and anti-alphavbeta5 antibodies resulted in significantly (P<0.001) decreased tumour cell adhesion in vivo within the hepatic microvasculature. Cells treated with anti-alphavbeta3 antibodies or unspecific immunoglobulin-G (IgG) did not show significant changes in their adhesive properties. Furthermore, inhibition of cell adhesion was achieved by linear RGD-peptides in a dose-dependent manner. Relative numbers of migrated cells were not affected by any of the treatments. These results suggest that alphav-integrins, especially alphavbeta5, can influence the ability of circulating tumour cells to adhere within the hepatic microvessels. In contrast, migration of adherent cells into the liver parenchyma was not affected by alphav-integrin inhibition. Our findings support the hypothesis that specific interactions between circulating tumour cells and host organs are required for organ-specific tumour cell arrest.
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PMID:Alphavbeta5-integrins mediate early steps of metastasis formation. 1586 57

The present article refers to the mechanism of angiogenesis, a phenomenon which in certain cases is normal, however it usually accompanies the formation of solid cancerous tumors. During the process of angiogenesis, migration, differentiation and proliferation of endothelial cells occurs. In some pathological cases, the most important of which is cancer, the mechanism of angiogenesis is reinforced. It has been observed that a tumor cannot grow without the formation of new blood vessels in the surrounding tissues, which account for blood supply to the tumor. The process of angiogenesis is regulated by chemical signals of the organism, which function as an "angiogenesis switch" regulating the formation of new vasculature. A variety of anti-angiogenic agents which lead to angiogenesis inhibition are found in the clinical trial phase. Among these agents are: i) molecules which inhibit the action of Vascular Endothelial Growth Factors, VEGF, ii) molecules which obstruct migration, differentiation and proliferation of endothelial cells, via their binding to receptors of the alpha(nu)beta(3) integrins and iii) inhibitors of metalloproteinases (MMP). Certain molecules of the above mentioned categories, labeled with radionuclides which emit gamma- radiation or beta- particles or positrons, have been proposed and are being evaluated as possible radiopharmaceuticals, for the visualization of receptors involved in the mechanism of angiogenesis, aiming at the scintigraphic detection of primary or metastatic cancer at an early stage and possibly, aiming at its inhibition/treatment. Regarding the study of angiogenesis the following have been described: a. antibodies targeting VEGF, labeled with radionuclides emitting beta- and/or gamma-radiation, which can be applied for the diagnosis and possibly, for the treatment of cancer, b. peptide derivatives which contain the amino-acid sequence RGD (Arg-Gly-Asp) and compete for the alpha(nu)beta(3) integrins, with the proteins of the stroma. It has been found that these radiolabeled derivatives localize in tumors and can be used for the visualization and, possibly, for the tumor eradication of primary and metastatic cancer.
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PMID:[Angiogenesis in cancer and its detection with radiolabeled biomolecules]. 1588 45

We have shown that the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) inhibits the development of intrahepatic metastases of hepatocellular carcinoma CBO140C12, and EGFR transactivation by tumor necrosis factor-alpha is a possible target of gefitinib. In the present study, we focused on the fibronectin (FN)-dependent signaling pathway to further elucidate the antimetastatic activity of gefitinib in CBO140C12 cells. We initially observed that FN induced activation of extracellular signal-regulated kinase (ERK), p38 and Akt, as well as cell proliferation and CBO140C12 cell invasion. These responses were mediated by EGFR tyrosine kinase, because gefitinib inhibited these effects of FN. FN-induced ERK, p38 and Akt activation was partly blocked by the Arg-Gly-Asp (RGD)-pseudo-peptide FC-336, anti-alphav integrin antibody RMV-7, the broad-spectrum matrix metalloprotease inhibitor GM6001 and the broad spectrum a disintegrin and metalloprotease (ADAM) inhibitor TAPI-1. But these inhibitors had no effect on EGF-induced signaling pathways, suggesting that integrins and ADAM may be upstream components of EGFR in these responses. These results suggest that FN-induced activation of ERK, p38, Akt, cell proliferation and invasion was mediated, at least in part, via integrins, ADAM and EGFR, and that this FN-induced signaling pathway might be involved in the antimetastatic activity of gefitinib.
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PMID:Activation of MEK/ERK and PI3K/Akt pathways by fibronectin requires integrin alphav-mediated ADAM activity in hepatocellular carcinoma: a novel functional target for gefitinib. 1644 27

The treatment of metastatic colorectal cancer by chemotherapy alone was considered palliative and without the potential to cure patients unless patients were rendered resectable. We report two patients with metastatic colorectal cancer involving the liver who were considered inoperable and were treated with systemic chemotherapy using biomodulated 5-fluorouracil. Both patients received 5-fluorouracil and N-(phosphonoacetyl)-l-aspartic acid; one also received methotrexate, leucovorin, and triacetyluridine with the N-(phosphonoacetyl)-l-aspartic acid and 5-fluorouracil. Both patients had a complete remission with chemotherapy and are still alive with no evidence of cancer ten years after the diagnosis of unresectable metastatic disease. These patients provide evidence that prolonged survival can be achieved withsystemic chemotherapy without the use of surgery or other forms of local therapy. These patients also confirm the importance of continued investigation of fluorouracil modulating agents, which may further enhance the recent progress made with fluorouracil-based combination chemotherapy for colorectal cancer.
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PMID:Continued survival of more than ten years, without resection of metastatic disease, in patients with metastatic colorectal cancer treated with biomodulated fluorouracil: report of two cases. 1647 32

The potential preventive effect of the synthetic pineal peptide Epitalon (Ala-Glu-Asp-Gly) on spontaneous tumorigenesis in mice was studied. One-year-old female C3H/He mice were kept for 6.5 months under standard conditions. Epitalon was injected at a dose of 0.1 microg, 5 times a week. Long-term exposure to Epitalon in small doses did not show any toxic effect. Treatment with Epitalon decreased the number of tumor-bearing mice with malignant tumors and prevented the development of metastases. Spontaneous tumors of the reproductive organs (mammary glands and ovaries) were predominant in both groups of mice (control and experimental). The mammary gland tumors were different variants of invasive ductal carcinomas. In the ovaries, granulosa-cell tumors were found. Tumors were in the minority in other organs and had benign characteristics. In control mice, metastases were found in 3 out of 9 tumor-bearing mice, all of them being from tumors of the reproductive organs. Treatment with Epitalon slowed down the development of metastases from spontaneous tumors, and no metastases were found in the experimental mice. These data highlight the antimetastatic effect of Epitalon as part of its oncostatic properties.
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PMID:Effect of the synthetic pineal peptide epitalon on spontaneous carcinogenesis in female C3H/He mice. 1663 27

Although a primary route of breast cancer metastasis is believed to be via lymphatics, the molecular factors involved are poorly understood. We hypothesized that one such factor may be the integrin-binding protein osteopontin (OPN), and we investigated this clinically and experimentally. In breast cancer patients undergoing sentinel lymph node biopsy, OPN levels were significantly higher in lymph node metastases than in the primary tumor (P < 0.001). To test the functional contribution of OPN to lymphatic metastasis and to determine whether the RGD (Arg-Gly-Asp) integrin-binding sequence of OPN is important for this process, we transfected wild-type OPN or mutant OPN (lacking the RGD sequence) into MDA-MB-468 human breast cancer cells. In vitro, cells overexpressing OPN demonstrated increased anchorage-independent growth in soft agar (P = 0.001) and increased RGD-dependent adhesion (P = 0.045). Following mammary fat pad injection of nude mice, cells overexpressing OPN showed increased lymphovascular invasion, lymph node metastases, and lung micrometastases at earlier time points (P = 0.024). Loss of the RGD region partially abrogated this effect in the lymphatics (P = 0.038). These novel findings indicate that OPN is a key molecular player involved in lymphatic metastasis of breast cancer, potentially by affecting RGD-mediated adhesive interactions and by enhancing the establishment/persistence of tumor cells in the lymphatics.
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PMID:Role of the integrin-binding protein osteopontin in lymphatic metastasis of breast cancer. 1681 76

Our group has developed a new molecular tool based on the use of a regioselectively addressable, functionalized template (RAFT) scaffold, where four cyclic (Arg-Gly-Asp) (cRGD) peptide motifs were grafted. The aim of this study was to determine whether RAFT-c(-RGDfK-)4 combined with optical imaging could allow noninvasive detection of deep ovarian metastases. Human ovarian adenocarcinoma IGROV1 cells expressing low levels of integrin alphaVbeta3 (the main receptor for the cRGD peptide) were used for in vitro and in vivo assays in combination with Cy5-labeled RAFT-c(-RGDfK-)4, cRGD, or RAFT-c(-RbetaADfK-)4. In vivo fluorescence imaging was performed on subcutaneous (SC) tumors and intraperitoneal IGROV1 metastases in nude mice. The accumulation of RGD-Cy5 conjugates in cultured cells or in tumor tissues was examined using confocal laser scanning microscopy. RAFT-c(-RGDfK-)4 exhibited stronger staining in vitro, enhanced tumor-to-background ratio for sc tumors, and allowed early detection of 1- to 5-mm large intraabdominal nodules using noninvasive optical imaging. Histological study revealed that RAFT-c(-RGDfK-)4 accumulated into tumor neovasculature but also into tumor cells. Our data demonstrate that a Cy5-labeled RAFT-c(-RGDfK-)4 is an efficient optical probe for early and noninvasive tumor detection.
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PMID:Noninvasive optical imaging of ovarian metastases using Cy5-labeled RAFT-c(-RGDfK-)4. 1695 34

An arginine-glycine-aspartic acid (RGD) containing model peptide was conjugated to the surface of poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) micelles as a ligand that can recognize adhesion molecules overexpressed on the surface of metastatic cancer cells, that is, integrins, and that can enhance the micellar delivery of encapsulated hydrophobic drug into a tumor cell. Toward this goal, PEO-b-PCL copolymers bearing acetal groups on the PEO end were synthesized, characterized, and assembled to polymeric micelles. The acetal group on the surface of the PEO-b-PCL micelles was converted to reactive aldehyde under acidic condition at room temperature. An RGD-containing linear peptide, GRGDS, was conjugated on the surface of the aldehyde-decorated PEO-b-PCL micelles by incubation at room temperature. A hydrophobic fluorescent probe, that is, DiI, was physically loaded in prepared polymeric micelles to imitate hydrophobic drugs loaded in micellar carrier. The cellular uptake of DiI loaded GRGDS-modified micelles by melanoma B16-F10 cells was investigated at 4 and 37 degrees C by fluorescent spectroscopy and confocal microscopy techniques and was compared to the uptake of DiI loaded valine-PEO-b-PCL micelles (as the irrelevant ligand decorated micelles) and free DiI. GRGDS conjugation to polymeric micelles significantly facilitated the cellular uptake of encapsulated hydrophobic DiI most probably by intergrin-mediated cell attachment and endocytosis. The results indicate that acetal-terminated PEO-b-PCL micelles are amenable for introducing targeting moieties on the surface of polymeric micelles and that RGD-peptide conjugated PEO-b-PCL micelles are promising ligand-targeted carriers for enhanced drug delivery to metastatic tumor cells.
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PMID:Conjugation of arginine-glycine-aspartic acid peptides to poly(ethylene oxide)-b-poly(epsilon-caprolactone) micelles for enhanced intracellular drug delivery to metastatic tumor cells. 1731 46

Fumagillin is an inhibitor of type 2 methionine aminopeptidase that can block blood vessel formation, but its molecular mechanism and therapeutic value in colon cancer still remain to be elucidated. In this study, male severe combined immunodeficiency (SCID) mice were injected with colon cancer cells in the subcutis and then treated with Fumagillin and Cyclo (Arg-Gly-Asp-D-Phe-Val), an integrin alphavbeta(3) antagonist. The tumor weight, microvessel density (MVD), and number of pulmonary metastatic foci were examined. Gene expression profiles were examined by microarray analysis of human umbilical endothelial cells (HUVEC). The Fumagillin-treated mice had smaller tumor mass, fewer pulmonary metastases, and lower MVD-CD105 levels than control animals. In vitro proliferation and tube formation of HUVEC was also significantly decreased by Fumagillin. Microarray analysis of Fumagillin-treated HUVEC showed upregulation of 71 genes and downregulation of 143 genes. Expression changes were involved in cell proliferation, migration, adhesion, and gene transcription. Quantitative real-time-polymerase chain reaction and western blotting showed decreased expression of cyclin E2, activated leukocyte cell adhesion molecule (ALCAM), and intercellular adhesion molecule-1 (ICAM-1) genes in the presence of Fumagillin. This downregulation by Fumagillin may be involved in the anti-angiogenesis by Fumagillin. In conclusion, Fumagillin was found to suppress colorectal cancer growth and metastasis by suppressing angiogenesis.
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PMID:Fumagillin inhibits colorectal cancer growth and metastasis in mice: in vivo and in vitro study of anti-angiogenesis. 1956 8

The purpose of this study was to examine the melanoma imaging properties of a novel 67Ga-labeled lactam bridge-cyclized alpha-melanocyte stimulating hormone (alpha-MSH) peptide. A lactam bridge-cyclized alpha-MSH peptide, DOTA-GlyGlu-CycMSH {DOTA-Gly-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Asp]}, was synthesized and radiolabeled with 67Ga. The melanoma targeting and pharmacokinetic properties of 67Ga-DOTA-GlyGlu-CycMSH were determined in B16/F1 flank primary melanoma-bearing and B16/F10 pulmonary metastatic melanoma-bearing C57 mice. Flank primary melanoma and pulmonary metastatic melanoma imaging were performed by small animal single photon emission computed tomography (SPECT)/CT using 67Ga-DOTA-GlyGlu-CycMSH as an imaging probe. 67Ga-DOTA-GlyGlu-CycMSH was readily prepared with greater than 95% radiolabeling yield. 67Ga-DOTA-GlyGlu-CycMSH exhibited substantial tumor uptake (12.93 +/- 1.63%ID/g at 2 h postinjection) and prolonged tumor retention (5.02 +/- 1.35%ID/g at 24 h postinjection) in B16/F1 melanoma-bearing C57 mice. The uptake values for nontarget organs were generally low (<0.30%ID/g) except for the kidneys at 2, 4, and 24 h postinjection. 67Ga-DOTA-GlyGlu-CycMSH exhibited significantly (p < 0.05) higher uptakes (1.44 +/- 0.75%ID/g at 2 h postinjection and 1.49 +/- 0.69%ID/g at 4 h postinjection) in metastatic melanoma-bearing lung than those in normal lung (0.15 +/- 0.10%ID/g and 0.17 +/- 0.11%ID/g at 2 and 4 h postinjection, respectively). Both flank primary B16/F1 melanoma and B16/F10 pulmonary melanoma metastases were clearly visualized by SPECT/CT using 67Ga-DOTA-GlyGlu-CycMSH as an imaging probe 2 h postinjection. 67Ga-DOTA-GlyGlu-CycMSH exhibited favorable melanoma targeting and imaging properties, highlighting its potential as an effective imaging probe for early detection of primary and metastatic melanoma.
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PMID:Gallium-67-labeled lactam bridge-cyclized alpha-melanocyte stimulating hormone peptide for primary and metastatic melanoma imaging. 1991 57


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