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)

Accumulating evidence indicates that the formation of tumor cell platelet emboli complexes in the blood stream is a very important step during metastases and that the anti-metastasis effects of heparin are partially due to a blockade of P-selectin on platelets. In this study, heparin and chemically modified heparins were tested as inhibitors of three human colon carcinoma cell lines (COLO320, LS174T, and CW-2) binding to P-selectin, adhering to CHO cells expressing a transfected human P-selectin cDNA, and adhering to surface-anchored platelets expressing P-selectin under static and flow conditions. The aim was to screen for heparin derivatives with high anti-adhesion activity but negligible anticoagulant activity. In this study, four modified heparins with high anti-adhesion activity were identified including RO-heparin, CR-heparin, 2/3ODS-heparin, and N/2/3DS-heparin. NMR analysis proved the reliability of structure of the four modified heparins. Our findings suggested that the 6-O-sulfate group of glucosamine units in heparin is critical for the inhibition of P-selectin-mediated tumor cell adhesion. Heparan sulfate-like proteoglycans on these tumor cell surfaces are implicated in adhesion of the tumor cells to P-selectin. Some chemically modified heparins with low anticoagulant activities, such as 2/3ODS-heparin, may have potential value as therapeutic agents that block P-selectin-mediated cell adhesion and prevent tumor metastasis.
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PMID:Modified heparin inhibits P-selectin-mediated cell adhesion of human colon carcinoma cells to immobilized platelets under dynamic flow conditions. 1513 30

The increased risk of thromboembolism in cancer may be related to a prothrombotic or hypercoagulable state, with abnormalities of haemostasis and platelet activation. To further investigate the role of platelets in this disease, we developed and applied a new assay to detect and quantify platelet adhesion to the well-defined subendothelial substrate, fibrinogen. Platelet-rich plasma was obtained from 31 females with breast cancer (13 metastatic, 18 benign), and 30 healthy female controls, re-suspended to 2 x 10(8) cells/ml and 100 microl and incubated for 1 h in microtitre plates pre-coated with fibrinogen (5 mg/ml). The supernatant was carefully aspirated, lysed with Triton X-100 and stored at -70 degrees C as supernatant-platelet lysate. The microtitre wells were carefully washed with saline, bound platelets lysed with Triton, and the lysate stored at -70 degrees C as bound-platelet lysate. P-selectin was determined in supernatant-platelet lysate and bound-platelet lysate for each patient by enzyme-linked immunosorbent assay. Interpreting differences in P-selectin in different lysates as reflective of adhesion, patients with cancer had increased platelet adhesion (absolute and percentage, both P < 0.001) compared with healthy controls. There was also more adhesion (P < 0.001) in metastatic disease compared with non-metastatic disease. Patients with breast carcinomas, and, in particular, those with metastatic disease, have a higher degree of platelet adhesion, which may by quantified by a novel method based on cell lysis. This increase in platelet adhesiveness may be related to an increased risk of thromboembolism in these patients.
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PMID:Platelet adhesion in breast cancer: development and application of a novel assay. 1531 Nov 62

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

Expression of sialyl Lewis(x) (sLe(x)) and sLe(a) on tumor cells is thought to facilitate metastasis by promoting cell adhesion to selectins on vascular endothelial cells. Experiments supporting this concept usually bypass the early steps of the metastatic process by employing tumor cells that are injected directly into the blood. We investigated the relative role of sLe(x) oligosaccharide in the dissemination of breast carcinoma, employing a spontaneous murine metastasis model. An sLe(x) deficient subpopulation of the 4T1 mammary carcinoma cell line was produced by negative selection using the sLe(x)-reactive KM93 MAb. This subpopulation was negative for E-selectin binding but retained P-selectin binding. Both sLe(x)-negative and -positive cells grew at the same rate; however, sLe(x)-negative cells spread more efficiently on plates and had greater motility in wound-scratch assays. Mice inoculated in the mammary fat pad with sLe(x)-negative and -positive variants produced lung metastases. However, the number of lung metastases was significantly increased in the group inoculated with the sLe(x)-negative variant (p = 0.0031), indicating that negative selection for the sLe(x) epitope resulted in enrichment for a subpopulation of cells with a high metastatic phenotype. Cell variants demonstrated significant differences in cellular morphology and pattern of tumor growth in primary and secondary tumor sites. These results strongly suggest that loss of sLe(x) may facilitate the metastatic process by contributing to escape from the primary tumor mass.
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PMID:Deficiency in surface expression of E-selectin ligand promotes lung colonization in a mouse model of breast cancer. 1590 60

Formation of tumor cell-platelet aggregates facilitates hematogenous metastases. However, molecular mechanisms implicated in tumor cell-induced platelet aggregation (TCIPA) in colon cancer are unclear. To investigate mechanisms of TCIPA induced by colon adenocarcinoma cells in vitro, human Caco-2 cells were used to study their interactions with platelets using aggregometry, zymography, phase-contrast microscopy, and flow cytometry. Caco-2-induced platelet aggregation in a concentration-dependent manner. This aggregation resulted in the release of matrix metalloproteinase (MMP)-2, as measured by zymography. In addition, flow cytometry showed a significant up-regulation of activated GpIIb/IIIa, total GpIIb/IIIa, GpIb, and P-selectin receptors on platelets. Inhibition of MMP-2 by phenantroline and degradation of ADP by APT102, respectively, resulted in inhibition of TCIPA. Furthermore, both phenantroline and APT102 significantly down-regulated the surface abundance of platelet receptors. Caco-2 cells aggregate platelets, at least in part, via releasing MMP-2 and ADP. Modulation of MMP-2 and ADP actions could have therapeutic value in colonic cancer.
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PMID:Platelet aggregation-induced by caco-2 cells: regulation by matrix metalloproteinase-2 and adenosine diphosphate. 1642 48

Hematogenous carcinoma metastasis is supported by aggregated platelets and leukocytes, forming tumor cell emboli. Early tumor cell-platelet interactions can be mediated by P-selectin binding to tumor cell surface ligands and this process is blocked by heparin. We previously showed that L-selectin deficiency also attenuates experimental metastasis. However, the mechanisms and timing of L-selectin action remained unknown. Here, we study how L-selectin facilitates establishment of pulmonary metastatic foci in syngeneic mice by using experimental metastasis to time events following entry of tumor cells into the bloodstream. Although L-selectin deficiency did not affect platelet aggregation or initial tumor cell embolization, the association of leukocytes with tumor cells was reduced and tumor cell survival was diminished 24 hours later. Temporal inhibition of L-selectin by a function-blocking antibody reduced metastasis. Moreover, although selectin blockade by heparin 6 to 18 hours after tumor cell injection was synergistic with P-selectin deficiency in reducing metastasis, there was no further effect in L-selectin-deficient animals. Thus, heparin apparently works at these time points primarily by blocking L-selectin. Endogenous L-selectin ligands were concomitantly induced adjacent to established intravascular tumor cell emboli in a similar time window when leukocytes were also present. Metastasis was attenuated in mice missing these induced endogenous L-selectin ligands due to fucosyltransferase-7 deficiency. Thus, L-selectin facilitation of metastasis progression involves leukocyte-endothelial interactions at sites of intravascular arrest supported by local induction of L-selectin ligands via fucosyltransferase-7. These data provide the first explanation for how leukocyte L-selectin facilitates tumor metastasis.
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PMID:L-selectin facilitation of metastasis involves temporal induction of Fut7-dependent ligands at sites of tumor cell arrest. 1645 10

Breast cancer cells frequently metastasize to the ends of long bones, ribs and vertebrae, structures which contain a rich microvasculature that is closely juxtaposed to metabolically active trabecular bone surfaces. This study focuses on the effects of osteoblast secretions on the surface presentation of adhesive proteins on skeletal vascular endothelial cells. Vascular endothelial cells were isolated from trabecular bone regions of the long bones of 7-week-old Swiss Webster mice and also from the central marrow cavity where trabecular bone is absent. Both types of endothelial cells were placed in culture for 7 days, then exposed 24 h to conditioned media from MC3T3-E1 osteoblasts. Conditioned medium (CM) from two different stages of osteoblast development were tested: (1) from immature MC3T3-E1 cells cultured for 5-7 days and (2) from mature MC3T3-E1 cells cultured for 28-30 days. The immature osteoblasts were in a stage of rapid proliferation; the mature osteoblasts formed a matrix that mineralized. Following exposure to the conditioned media, the vascular cells were exposed to anti-P-selectin, anti-E-selectin, anti-ICAM-1, and anti-VCAM-1 to detect the corresponding adhesive proteins on their surfaces. Breast cancer cells are known to bind to these adhesive proteins. Of the four proteins evaluated, E-selectin was consistently found on more cell surfaces (approximately 30%) of bone-derived vascular endothelial cells (BVECs) when exposed to the immature CM whereas vascular endothelial cells from marrow (MVECs) did not show this response to either immature CM or mature CM. These studies suggest that the BVEC blood vessels near immature bone cells express more surface adhesive protein that could enhance entrapment and extravasation of breast cancer cells. Once cancer cells have undergone extravasation into marrow adjacent to bone, they could be readily attracted to nearby bone surfaces.
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PMID:Osteoblast-conditioned media influence the expression of E-selectin on bone-derived vascular endothelial cells. 1651 47

P-selectin belongs to the family of selectin adhesion molecules, and is expressed by platelets and endothelial cells on stimulation. This pattern of expression may indicate an involvement of this molecule in inflammation and coagulation. Data from mice lacking P-selectin expression confirmed this assumption. In addition, a key role of P-selectin in the formation of tumour metastases has been established. Apparently unrelated, clinical experience has pointed towards a detrimental interaction of inflammation and cancer with thromboembolic diseases and vice versa. Therefore, targeting molecules such as P-selectin contributing to coagulation, inflammation and metastasis may offer novel therapeutic strategies to treat chronic inflammatory diseases and metastatic cancer. The authors aim to critically evaluate the contribution of P-selectin in these diseases, and discuss the value of therapeutic inhibition of P-selectin functions in coagulation, inflammation and metastasis.
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PMID:P-selectin: a common therapeutic target for cardiovascular disorders, inflammation and tumour metastasis. 1766 81

Cell rolling is an important physiological and pathological process that is used to recruit specific cells in the bloodstream to a target tissue. This process may be exploited for biomedical applications to capture and separate specific cell types. One of the most commonly studied proteins that regulate cell rolling is P-selectin. By coating surfaces with this protein, biofunctional surfaces that induce cell rolling can be prepared. Although most immobilization methods have relied on physisorption, chemical immobilization has obvious advantages, including longer functional stability and better control over ligand density and orientation. Here we describe chemical methods to immobilize P-selectin covalently on glass substrates. The chemistry was categorized on the basis of the functional groups on modified glass substrates: amine, aldehyde, and epoxy. The prepared surfaces were first tested in a flow chamber by flowing microspheres functionalized with a cell surface carbohydrate (sialyl Lewis(x)) that binds to P-selectin. Adhesion bonds between P-selectin and sialyl Lewis(x) dissociate readily under shear forces, leading to cell rolling. P-selectin immobilized on the epoxy glass surfaces exhibited enhanced long-term stability of the function and better homogeneity as compared to that for surfaces prepared by other methods and physisorbed controls. The microsphere rolling results were confirmed in vitro with isolated human neutrophils. This work is essential for the future development of devices for isolating specific cell types based on cell rolling, which may be useful for hematologic cancers and certain metastatic cancer cells that are responsive to immobilized selectins.
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PMID:Covalent immobilization of p-selectin enhances cell rolling. 1794 12

Morphogenesis of malignant tumors is characterized by proliferation, invasive growth and metastasis. Although these properties are determined mainly by genetic derangements, their biological behavior within tissues is strictly regulated by tumor microenvironment, which consists of extracellular matrix, proteinases, soluble factors (cytokines/growth factors/chemokines), stromal cells and blood vessels. Thus, modulation of the microenvironment is implicated in morphogenesis in tumorigenesis. ADAMs (a disintegrin and metalloproteinases) are a new gene family of membrane-anchored and secreted proteins that have proteolytic and/or adhesive properties. They are involved in biological events including cell adhesion, cell fusion, membrane protein shedding and proteolysis. We examined the expression of the proteinase-type ADAMs in the invasive breast and lung carcinoma tissues, and found that membrane-anchored ADAM28m and secreted ADAM28s are selectively overexpressed in activated forms by carcinoma cells. The mRNA expression levels directly correlated with the proliferative activity of the carcinoma cells in both carcinomas, and with lymph node metastasis in the lung carcinomas. Our experimental studies showed that ADAM28 plays a key role in cancer cell proliferation through enhancing bioavailability of insulin-like growth factor-I (IGF-I) released from the IGF-I/IGF-binding protein 3 (IGFBP-3) complex by selective cleavage of IGFBP-3. We also identified P-selectin glycoprotein ligand-1 (PSGL-1) as a binding protein to ADAM28 by yeast two-hybrid system, and demonstrated that ADAM28s promotes PSGL-1/P-selectin-mediated HL-60 cell rolling adhesion to endothelial cells and subsequent transendothelial migration into tissue spaces. Altogether, our data suggest the possibility that ADAM28 expressed by cancer cells is involved in cancer cell proliferation and metastases in human cancers through modulation of tumor microenvironment and cell adhesion.
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PMID:Modulation of the microenvironment and adhesion of cancer cells by ADAMs (a disintegrin and metalloproteinase). 1831 93


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