UMLS:C0178874 - FACTA Search

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

E-, P-, and L-selectin support the adhesion of leukocytes to the vessel wall through the recognition of specific carbohydrate ligands, which often contain sialylated, fucosylated lactosamines such as sialyl Lewis x [sLex; Neu5Ac alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc-]. E-selectin expressed by activated endothelium has been shown to support the adhesion of sLex-bearing colon cancer cells. In the present study, we examine the interactions of multiple colon cancer cell lines with all three selectins. Three colon cancer cell lines (LS 180, T84, and COLO 205) bound to recombinant purified E-, P-, and L-selectin. The colon cancer line COLO 320 bound to P- and L-selectin but not E-selectin; conversely, HT-29 cells bound E-selectin but not P- and L-selectin. Caco-2 showed little or no interaction with any of the three selectins. Treatment of the cells with O-sialoglycoprotease from Pasteurella haemolytica, an enzyme that selectively cleaves mucin-type O-linked glycoproteins, reduced binding to purified P- and L-selectin in all cases. In addition, recombinant soluble P- and L-selectin bound to affinity-purified mucins from all adherent tumor cell lines. Of the four tumor cell lines that interacted with E-selectin, O-glycoprotease treatment substantially diminished adhesion of LS 180 and T84, had little effect on COLO 205, and failed to inhibit the binding of HT-29. As predicted by these data, E-selectin showed substantial binding only to mucins purified from LS 180 and T84. These findings suggest that L- and P-selectin interact primarily with mucin-type ligands on colon cancers, whereas E-selectin can recognize both mucin and nonmucin ligands. Binding of the colon cancer lines to purified selectins correlates with their adhesion to activated endothelial cells (E-selectin-dependent), platelets (P-selectin-dependent), and neutrophils (L-selectin-dependent). These differential tumor cell-selectin interactions may influence metastatic spread and may also contribute to the observed variability in host response to tumor progression.
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PMID:Differential colon cancer cell adhesion to E-, P-, and L-selectin: role of mucin-type glycoproteins. 754 41

Aberrant glycosylation expressed in glycosphingolipids and glycoproteins in tumor cells has been implicated as an essential mechanism in defining stage, direction, and fate of tumor progression. This general concept is supported by results from three lines of study: (a) Numerous clinicopathological studies have shown a clear correlation between aberrant glycosylation status of primary tumor and invasive/metastatic potential of human cancer as reflected by 5- or 10-year survival rates of patients. (b) Carbohydrates expressed in tumor cells are either adhesion molecules per se or modulate adhesion receptor function. Some are directly involved in cell adhesion. They are recognized by selectins or other carbohydrate-binding proteins or by complementary carbohydrates (through carbohydrate-carbohydrate interaction). N- or O-glycosylation of functionally important membrane components may alter tumor cell adhesion or motility in a direction that either promotes or inhibits invasion and metastasis. Examples of such receptors are E-cadherin, integrins, immunoglobulin family receptors (e.g., CD44), and lysosome-associated membrane protein. (c) Gangliosides and sphingolipids modulate transmembrane signaling essential for tumor cell growth, invasion, and metastasis. The transducer molecules susceptible to gangliosides and sphingolipids include integrin receptors, tyrosine kinase-linked growth factor receptors, protein kinase C, and G-protein-linked receptor affecting protein kinase A. Some glycosphingolipids (e.g., Gb3Cer, Le(y), ceramide, and sphingosine induce tumor cell differentiation and subsequent apoptosis. Shedded gangliosides may block immunogenicity of tumor cells, providing conditions favorable for "escape" from immunological suppression of tumor growth by the host. Various reagents that block carbohydrate-mediated tumor cell adhesion or block glycosylation processing have been shown to inhibit tumor cell metastasis. This provides the basis for further development of "anti-adhesion therapy." Ganglioside analogues and sphingolipid analogues that inhibit protein kinase C and receptor-associated tyrosine kinase have been applied for inhibition of metastasis. A crucial mechanism for inhibition of metastasis by these reagents may involve blocking of transmembrane signaling for expression of P- and E-selectin. This provides the basis for development of "ortho-signaling therapy."
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PMID:Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)lipid metabolism. 896 75

Increasing evidence suggests that E-selectin contributes to tumor growth and metastasis. E-selectin may increase tumoral angiogenesis and the adhesion of tumoral cells to endothelial cells at distant sites. The aim of this study was to assess the relationship between concentrations of circulating soluble E-selectin (sE-selectin) and clinical, pathological, and biological features in patients with breast cancer (BC). Concentrations of sE-selectin were analyzed by an ELISA method in sera from 113 patients with metastatic BC, 30 patients with primary inflammatory BC, 105 patients with primary noninflammatory BC, and 42 healthy controls. These concentrations were analyzed in terms of the clinical and pathological features of the tumors as well as in terms of the concentrations of serum inflammatory parameters (erythrocyte sedimentation rate, C reactive protein, interleukin 1 beta, and tumor necrosis factor alpha), the response to chemotherapy or hormone therapy, and the survival duration. Tumoral angiogenesis was also assessed in 68 patients with primary noninflammatory BC who had had primary surgery. The mean concentration of sE-selectin in the metastatic BC group was significantly higher than the mean concentration found in the healthy control group (33.5 versus 21.8 ng/ml; P < 0.01). In metastatic BC, the mean concentration of sE-selectin was significantly higher in patients with liver metastasis than in patients without liver metastasis (55.3 versus 26.0 ng/ml; P < 10(-5). The univariate analysis showed that high concentrations of sE-selectin were associated with reduced overall survival (P < 0.05), but this probably reflected the association between high concentrations of sE-selectin and liver metastasis. In patients with primary noninflammatory BC, a negative correlation was found between sE-selectin concentrations and the tumoral microvessel count (r = -0.47; P = 10(-4). In patients with primary inflammatory or noninflammatory BC, no correlation was found between concentrations of sE-selectin and tumor size, lymph node involvement, response to chemotherapy or hormone therapy, and survival. No correlation was found between the concentrations of sE-selectin and serum inflammatory parameters in any of the patient groups. This study suggests that in patients with metastatic BC, levels of sE-selectin are higher in the presence of liver metastasis. In patients with primary BC, high concentrations seem to be associated with reduced tumoral angiogenesis. Although several studies have previously demonstrated that the expression of cell surface E-selectin enhances the metastatic process, the shedding of sE-selectin in circulation may be considered a mechanism of inhibition of tumor progression.
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PMID:The relationship between concentrations of circulating soluble E-selectin and clinical, pathological, and biological features in patients with breast cancer. 951 25

Several studies have suggested that endothelial cells participate in tumor development. Soluble E-selectin (sE-selectin) is specifically released by activated endothelial cells, and its serum concentration can be considered a marker of endothelial activation. In this study, we assessed the prognostic value of sE-selectin concentrations in node-negative breast cancer patients. Serum sE-selectin concentrations were measured by an ELISA method prior to surgery in 456 node-negative breast cancer patients. We analyzed also tumor size (TS), histoprognostic grading, and steroid hormone receptor status. The mean sE-selectin concentration was 24.9 +/- 15.0 ng/ml. The sE-selectin concentrations were mildly correlated with the TS but not with the other factors. For prognostic analyses, the median follow-up duration was 7.5 years. The cutoff sE-selectin concentration used was 40 ng/ml. In overall survival studies, univariate analyses demonstrated a prognostic value of sE-selectin, TS, and histoprognostic grading, and multivariate analyses demonstrated a prognostic value of sE-selectin and TS. For disease-free survival, univariate and multivariate analyses demonstrated a prognostic value of sE-selectin and TS. sE-selectin concentration is an easily measurable and strong prognostic factor in node-negative breast cancer patients. These results provide further evidence for the role of adhesion molecules expression by endothelial cells in tumor progression.
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PMID:Prognostic value of circulating soluble E-selectin concentrations in node-negative breast cancer patients. 1038 28

Sialyl Le(a) antigen (CA19-9), a member of a family of high molecular weight glycoproteins, was originally described as a gastrointestinal- and pancreatic-specific tumor marker. Recent studies have demonstrated that sialyl Le(a) is a ligand for E-selectin and may play an important role in tumor metastasis. However, expression patterns of sialyl Le(a) have not yet been established in human esophageal carcinomas. In this study, we examined sialyl Le(a) expression and its histopathological localization in human esophageal squamous cell carcinoma. Sialyl Le(a) immunoreactivity was detected in 28 (51.9%) of the 54 esophageal squamous cell carcinomas, regardless of the depth of tumor invasion, vascular invasion or lymph nodal status. In 13 cases (29.5%), significant sialyl Le(a) expression was detected not only in the intramucosal carcinoma components, but also in the invasive carcinoma components. These observation suggested that sialyl Le(a) expression is associated with early-stage cancer progression.
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PMID:Frequent expression of sialyl Le(a) in human esophageal squamous cell carcinoma. 1099 80

Our studies on glycosphingolipids (GSLs) were initiated through isolation and structural characterization of lacto-series type 1 and 2 GSLs, and globo-series GSLs. Lacto-series structures included histo-blood group ABH and I/i antigens. Our subsequent studies were focused on GSL changes associated with: (i) ontogenic development and differentiation; (ii) oncogenic transformation and tumor progression. Various novel types of GSLs such as extended globo-series, sialyl-Le(x) (SLe(x)), sialyl-dimeric-Le(x) (SLe(x)-Le(x)), dimeric-Le(x) (Le(x)-Le(x)), Le(y)-on-Le(x), dimeric-Le(a) (Le(a)-Le(a)), Le(b)-on-Le(a), etc. were identified as tumor-associated antigens. These studies provide an essential basis for up- or down-regulation of key glycosyltransferase genes controlling development, differentiation, and oncogenesis. GSL structures established in our laboratory are summarized in Table 1, and structural changes of GSLs associated with ontogenesis and oncogenesis are summarized in Sections 2 and 3. Based on these results, we endeavored to find out the cell biological significance of GSL changes, focused on (i) cell adhesion, e.g., the compaction process of preimplantation embryo in which Le(x)-to-Le(x), Gb4-to-GalGb4 or -nLc4 play major roles; and (ii) modulation of signal transduction through interaction of growth factor receptor tyrosine kinase with ganglioside, e.g., EGF receptor tyrosine kinase with GM3. Recent trends of studies on i and ii lead to the concept that GSL clusters (microdomains) are organized with various signal transducer molecules to form 'glycosignaling domains' (GSD). GSL-dependent adhesion occurs through clustered GSLs, and is coupled with activation of signal transducers (cSrc, Src family kinase, Rho A, etc.). Clustered GSLs involved in cell adhesion are recognized by GSLs on counterpart cells (carbohydrate-to-carbohydrate interaction), or by lectins (e.g., siglecs, selectins). Our major effort in utilization of GSLs in medical science has been for: (i) cancer diagnosis and treatment (vaccine development) based on tumor-associated GSLs and glycoepitopes; (ii) genetically defined phenotype for susceptibility to E. coli infection; (iii) clear identification of physiological E-selectin epitope (myeloglycan) expressed on neutrophils and myelocytes; (iv) characterization of sialyl poly-LacNAc epitopes recognized as male-specific antigens. Utilization of these GSLs or glycoepitopes in development of anti-adhesion approach to prevent tumor metastasis, infection, inflammation, or fertilization (i.e., contraceptive) is discussed. For each approach, development of mimetics of key GSLs or glycoepitopes is an important subject of future study.
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PMID:Traveling for the glycosphingolipid path. 1142 54

A large variety of glycosylation patterns in combination with different ceramide structures in glycosphingolipids provide a basis for cell type-specific glycosphingolipid pattern in membrane, which essentially reflects the composition of glycosphingolipid-enriched microdomains. Functions of glycosphingolipids as antigens, mediators of cell adhesion, and modulators of signal transduction are all based on such organization. Of particular importance is the assembly of glycosphingolipids with signal transducers and other membrane proteins to form a functional unit termed a, through which glycosylation-dependent cell adhesion coupled with signal transduction takes place. The microenvironment formed by interfacing glycosynapses of interacting cells plays a central role in defining phenotypic changes after cell adhesion, as occur in ontogenic development and cancer progression. These basic functional features of glycosphingolipids in membrane can also be considered roles of glycosphingolipids and gangliosides characteristic of neutrophils, myelocytes, and other blood cells. A series of sialyl fucosyl poly-N-acetylgalactosamine gangliosides without the sialyl-Le epitope, collectively termed, have been shown to mediate E-selectin-dependent rolling and tethering under dynamic flow with physiologic shear stress conditions. Functional roles of myeloglycan in neutrophils during inflammatory processes are discussed.
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PMID:Structure, organization, and function of glycosphingolipids in membrane. 1248 7

Cell adhesion is a basic count in inter- and intracellular communication and plays an important role in tumor progression. In this study, the expression of E-selectin, ICAM-1 and VCAM-1 were evaluated by means of immunohistochemistry in a group of 153 lung cancer specimens. E-selectin immunoreactivity was localized mostly on endothelial cell venules and capillaries with an average staining intensity of 75% of cells in the NSCLC, while in SCLC the intensity of the staining was 69%. The staining pattern for ICAM-1 reached an average intensity of 57%, in both NSCLC and SCLC. Finally, VCAM-1 immunoreactivity was detected only in NSCLC with an average intensity of 12% on endothelial cell venules and capillaries. This study provides a contribution towards the understanding of the basic mechanisms of cell adhesion in lung cancer progression.
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PMID:Expression of surface protein receptors in lung cancer. 1255 29

Microvascular endothelial cells play a critical role in tumor progression and metastasis by forming capillary networks that encourage tumor growth and by promoting the attachment of circulating tumor cells to the vascular wall of distant tissues. Efforts to study the molecular mechanisms that mediate these complex processes in different anatomical compartments have been impeded by difficulties in the isolation and propagation of endothelial cells from different organs. To overcome these limitations, we used two-color flow cytometry to identify and select microvascular endothelial cells from primary cultures obtained from different organs of mice whose tissues harbor a temperature-sensitive SV40 large T antigen (H-2K(b)-tsA58 mice; ImmortoMice). The selection strategy targeted cell populations expressing the inducible endothelial cell adhesion molecules, E-selectin and VCAM-1, and proved successful in generating microvascular endothelial cell lines from a number of different organs. When cultured under permissive temperatures (33 degrees C), individual cell lines displayed doubling times consistent with endothelial cells possessing an angiogenic phenotype. The transfer of endothelial cells to nonpermissive temperatures (37 degrees C) resulted in cell differentiation and the induction of a quiescent state. Established cell lines exhibited several inherent endothelial properties, including the expression of constitutive and inducible levels of endothelial cell adhesion molecules E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, internalization of acetylated low-density lipoprotein, and formation of loop structures on Matrigel surfaces. The immortalized endothelial cell lines established from H-2K(b)-tsA58 mice provide, for the first time, a cell culture system to examine factors regulating angiogenesis and tumor cell arrest in different organ systems.
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PMID:Tissue-specific microvascular endothelial cell lines from H-2K(b)-tsA58 mice for studies of angiogenesis and metastasis. 1278 5

Tumors expressing a high level of certain types of tumor-associated carbohydrate antigens (TACAs) exhibit greater metastasis and progression than those expressing low level of TACAs, as reflected in decreased patient survival rate. Well-documented examples of such TACAs are: (i) H/Le(y)/Le(a) in primary non-small cell lung carcinoma; (ii) sialyl-Le(x) (SLe(x)) and sialyl-Le(a) (SLe(a)) in various types of cancer; (iii) Tn and sialyl-Tn in colorectal, lung, breast, and many other cancers; (iv) GM2, GD2, and GD3 gangliosides in neuroectodermal tumors (melanoma and neuroblastoma); (v) globo-H in breast, ovarian, and prostate cancer; (vi) disialylgalactosylgloboside in renal cell carcinoma. Some glycosylations and TACAs suppress invasiveness and metastatic potential. Well-documented examples are: (i) blood group A antigen in primary lung carcinoma; (ii) bisecting beta1 --> 4GlcNAc of N-linked structure in melanoma and other cancers; (iii) galactosylgloboside (GalGb4) in seminoma. The biochemical mechanisms by which the above glycosylation changes promote or suppress tumor metastasis and invasion are mostly unknown. A few exceptional cases in which we have some knowledge are: (i) SLe(x) and SLe(a) function as E-selectin epitopes promoting tumor cell interaction with endothelial cells; (ii) some tumor cells interact through binding of TACA to specific proteins other than selectin, or to specific carbohydrate expressed on endothelial cells or other target cells (carbohydrate-carbohydrate interaction); (iii) functional modification of adhesive receptor (integrin, cadherin, CD44) by glycosylation. So far, a few successful cases of anti-cancer vaccine in clinical trials have been reported, employing TACAs whose expression enhances malignancy. Examples are STn for suppression of breast cancer, GM2 and GD3 for melanoma, and globo-H for prostate cancer. Vaccine development canbe extended using other TACAs, with the following criteria for success: (i) the antigen is expressed highly on tumor cells; (ii) high antibody production depending on two factors: (a) clustering of antigen used in vaccine; (b) choice of appropriate carrier protein or lipid; (iii) high T cell response depending on choice of appropriate carrier protein or lipid; (iv) expression of the same antigen in normal epithelial tissues (e.g., renal, intestinal, colorectal) may not pose a major obstacle, i.e., these tissues are not damaged during immune response. Idiotypic anti-carbohydrate antibodies that mimic the surface profile of carbohydrate antigens, when administered to patients, elicit anti-carbohydrate antibody response, thus providing an effect similar to that of TACAs for suppression of tumor progression. An extension of this idea is the use of peptide mimetics of TACAs, based on phage display random peptide library. Although examples are so far highly limited, use of such "mimotopes" as immunogens may overcome the weak immunogenicity of TACAs in general.
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PMID:Tumor-associated carbohydrate antigens defining tumor malignancy: basis for development of anti-cancer vaccines. 1453 9

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