UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the screening of apoptosis-related genes, an elevated 4.5-kb transcript representing the full-length cDNA of human secreted frizzled-related protein (hsFRP) was cloned. To investigate its possible role in the regulation of cell proliferation, gene expression of hsFRP was examined in human immortalized breast epithelial cell line HBL-100 during growth arrest and apoptosis. Serum deprivation caused G arrest and induction of hsFRP. When serum was re-introduced into the cell culture, the expression of hsFRP declined. Adriamycin treatment induced accumulation of hsFRP mRNA and decrease of beta-catenin. This indicates that the regulation of hsFRP may be involved in the cell-cycle/apoptosis mechanism and possibly in the wnt signaling pathway. hsFRP transcripts were undetectable in cells derived from malignant breast carcinomas, but detectable in 3 immortalized non-malignant breast epithelial cell lines, indicating the involvement of hsFRP in the breast malignant transformation. When tumor and adjacent normal tissues from the same patients were examined, lower expression was found in 5/5 of breast tumors, 2/4 of ovary tumors and 3/5 of kidney tumors. These data suggest the possible involvement of hsFRP in regulation of cell proliferation and breast tumorigenesis.
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PMID:Up-regulation of human secreted frizzled homolog in apoptosis and its down-regulation in breast tumors. 972 99

The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that is inactivated in most colorectal cancers. Mutations of APC cause aberrant accumulation of beta-catenin, which then binds T cell factor-4 (Tcf-4), causing increased transcriptional activation of unknown genes. Here, the c-MYC oncogene is identified as a target gene in this signaling pathway. Expression of c-MYC was shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c-MYC promoter. These results provide a molecular framework for understanding the previously enigmatic overexpression of c-MYC in colorectal cancers.
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PMID:Identification of c-MYC as a target of the APC pathway. 975 Jan 12

The development of colorectal cancer, one of the most frequent cancers, is influenced by prostaglandins and fatty acids. Decreased prostaglandin production, seen in mice with mutations in the cyclooxygenase 2 gene or in animals and humans treated with cyclooxygenase inhibitors, prevents or attenuates colon cancer development. There is also a strong correlation between the intake of fatty acids from animal origin and colon cancer. Therefore, the peroxisome proliferator-activated receptor gamma (PPARgamma), a downstream transcriptional mediator for prostaglandins and fatty acids which is highly expressed in the colon may be involved in this process. Activation of PPARgamma by two different synthetic agonists increased the frequency and size of colon tumors in C57BL/6J-APCMin/+ mice, an animal model susceptible to intestinal neoplasia. Tumor frequency was only increased in the colon, and did not change in the small intestine, coinciding with the colon-restricted expression of PPARgamma. Treatment with PPARgamma agonists increased beta-catenin levels both in the colon of C57BL/61-APCMin/+ mice and in HT-29 colon carcinoma cells. Genetic abnormalities in the Wnt/wingless/APC pathway, which enhance the transcriptional activity of the beta-catenin-T-cell factor/lymphoid enhancer factor 1 transcription complex, often underly the development of colon tumors. Our data indicate that PPARgamma activation modifies the development of colon tumors in C57BL/61-APCMin/+ mice.
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PMID:Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. 973 99

Aggressive fibromatosis is a monoclonal proliferation of spindle (fibroblast-like) cells. A subset of lesions contain somatic truncating adenomatous polyposis coli (APC) gene mutations, and all of the lesions contain an elevated beta-catenin protein level. A major function of APC is to regulate beta-catenin protein level. Beta-catenin has a dual function in the cell: it is a member of the adherens junction, and it binds transcription factors in the tcf-lef family, transactivating transcription. Cell cultures from aggressive fibromatoses containing an APC mutation were studied. Transient transfection of the full-length APC gene caused decreased proliferation and beta-catenin protein level in these cultures. To determine whether beta-catenin protein level was responsible for the change in proliferation rate, stable transfections of deltaN89beta-catenin (a stabilized form that is not degraded by APC, but retains all other functions) were achieved in half of the cultures derived from each tumor, whereas the other half were transfected with an empty vector. Transfection of the full-length APC gene in cultures that were stably transfected with deltaN89beta-catenin did not result in a change in proliferation. The type I promotor of p56lck contains an HMG consensus region, to which members of the tcf-lef family can bind. p56lck was expressed in cultures not transfected with the full-length APC gene and in cultures transfected with the full-length APC gene and deltaN89beta-catenin, but not in cultures transfected with only the full-length APC gene. These data show that APC truncating mutations give aggressive fibromatosis cells a proliferative advantage through beta-catenin and suggest that beta-catenin acts to transactivate transcription.
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PMID:Adenomatous polyposis coli gene mutation alters proliferation through its beta-catenin-regulatory function in aggressive fibromatosis (desmoid tumor). 973 21

During the last 7 years significant progress has been made in the identification of melanoma-associated antigens recognized by cytotoxic T lymphocytes (CTL). These antigens belong to three main groups: cancer/testis-specific antigens (MAGE, BAGE, GAGE, PRAME and NY-ESO-1), melanocyte differentiation antigens (tyrosinase, Melan-A/MART-1, gp100, TRP-1 and TRP-2), and mutated or aberrantly expressed antigens (MUM-1, CDK4, beta-catenin, gp100-in4, p15 and N-acetylglucosaminyltransferase V). In this review we have summarized the available data concerning the characterization of melanoma-associated antigens, focusing on their immunogenic and protective properties. The development of a strong immune response to differentiation antigens is limited by the existence of tolerance to these "self"-antigens, permitting the involvement of only T cells with low affinity T-cell receptors. Among the melanoma differentiation antigens, only gp100 has been shown to be a tumor regression antigen. The cancer/testis-specific antigens such as MAGE and PRAME should potentially be highly immunogenic antigens. They contain several potential HLA class I binding epitopes and are present only in the testes, which are not accessible to the cells of the immune system owing to the lack of direct contact with the immune cells and the lack of HLA class I expression on the surface of germ cells. But only two patients have been found who responded to these antigens in vivo, indicating their genuinely low immunogenicity. A comparison of the predicted secondary structures of these two groups of antigens (cancer/testis-specific and differentiation antigens) revealed enrichment of long alpha-helical stretches in the cancer/testis-specific antigens. We hypothesize that such highly organized stable structures could, first, reduce denaturation of the protein and, thus, ubiquitinylation as a degradation signal, and, second, diminish the efficiency of the protein unfolding - a necessary step in the proteolytic cleavage by proteasomes. High structural stability could therefore be responsible for the low immunogenicity of these proteins. In this case, modifications decreasing the stability of these proteins might be a means of improving the immune response to these potentially therapeutically useful antigens.
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PMID:Melanoma-associated antigens recognized by cytotoxic T lymphocytes. 974 May 4

The E-cadherin-mediated cell adhesion system is now considered to be an "invasion suppressor system" in cancer cells. Dysfunction of the E-cadherin system due to mutations of the genes of E-cadherin and catenins has not been reported in colorectal cancer. Histologically, well-differentiated colorectal cancer cells are found to be scattered at the invasive front in primary lesions and form glands again in metastatic sites. We have reported the association and presence of signal transduction between c-erbB-2/epidermal growth factor receptor (EGF-R) and beta-catenin in human cancer cells. This temporal dysfunction of the E-cadherin system observed in colon cancers may be caused by tyrosine phosphorylation of beta-catenin through activated receptor-type tyrosine kinases. Overexpression of EGF-R and tyrosine phosphorylation of beta-catenin are often observed in "focal dedifferentiated cells" at the invasive front of colorectal cancers. In addition, beta-catenin expression is regulated by the APC tumor suppressor gene product. Thus the E-cadherin-catenin system may play important roles not only in invasion and metastasis but also in the carcinogenesis of colorectal cancer.
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PMID:[Dysfunction of E-cadherin-catenin system in invasion and metastasis of colorectal cancer]. 974 18

It has recently been shown that tumor-associated antigens (TAAs) can evoke tumor-specific T-cell-defined immune responses in cancer patients, thereby offering the possibility of treating patients with such antigens. To develop T-cell-based immunotherapeutic approaches for renal cell carcinoma (RCC), we studied the mRNA expression profile of the TAAs RAGE-1, tyrosinase, MAGE-1, MAGE-2, NY-ESO-1, Melan-A/MART-1, glycoprotein (gp) 75, gp100, beta-catenin, PRAME, and MUM-1 in 14 human RCC cell lines and in tissue specimens of 37 primary RCCs, 2 related metastases, and 33 specimens of normal renal epithelium. Reverse transcription-PCR was performed with TAA-reactive primers, and the specificity of the PCR products was confirmed by Southern blot and/or direct sequencing. PRAME (10 of 14 cell lines), RAGE-1 (7 of 14 cell lines), and gp75 (4 of 14 cell lines) antigens were expressed in a high percentage of RCC cell lines, although the level of TAA expression varied among the different RCC cell lines. However, low levels of TAA expression in RCC cells are sufficient for recognition by TAA-specific CTLs. Transcription of tyrosinase, Melan-A/MART-1, MAGE-1, MAGE-2, NY-ESO-1, gp100, beta-catenin, and MUM-1 was not detected in any RCC cell line. Approximately 50% of surgically removed neoplasias expressed at least one TAA. RAGE-1 mRNA expression was found in 8 of 39 (21%) RCC samples, PRAME mRNA expression was found in 15 of 39 (40%) RCC samples, and gp75 mRNA expression was found in 4 of 39 (11%) RCC samples, but the expression levels of these TAAs were heterogeneous in the different RCC lesions. One RCC specimen expressed MAGE-2, whereas transcription was not detected in any RCC specimen for MAGE-1, NY-ESO-1, tyrosinase, Melan-A/MART-1, gp100, beta-catenin, and MUM-1. The normal kidney epithelium samples were negative for any TAA tested. Thus, RAGE-1, PRAME, and gp75 expression is found with a different frequency in surgically removed lesions and in RCC cell lines, suggesting that a subgroup of RCC patients could be selected for immunotherapeutic strategies that may benefit from immunization against the RAGE-1, gp75, and/or PRAME antigens. However, additional targets for T-cell-based immunotherapy of RCC have yet to be identified.
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PMID:Heterogeneous expression of the tumor-associated antigens RAGE-1, PRAME, and glycoprotein 75 in human renal cell carcinoma: candidates for T-cell-based immunotherapies? 975 17

In the metastatic process, various cell-cell adhesion molecules seem to play an important role. E-cadherin, a transmembrane protein with an extracellular and an intracellular domain, is one of the key players involved in cell-cell adhesion. The function of E-cadherin in preventing metastasis in tumour development is believed to be dependent on intracellular catenins. In a previous study, the expression of E-cadherin was examined in a series of human breast carcinomas. In that study, down-regulation of E-cadherin failed to correlate with lymph node and/or distant metastasis. In the present study, the expression of alpha-, beta-, and gamma-catenins has been examined in a subset of the same tumours in order to evaluate their possible role in breast cancer metastasis. Tumour tissues from 90 primary breast carcinomas were immunostained for alpha-, beta-, and gamma-catenins. Reduced or absent immunoreactivity in the tumour tissue was seen in 63 (70.0 per cent) for alpha-catenin, in 50 (55.6 per cent) for beta-catenin, and in 50 (55.6 per cent) for gamma-catenin. Reduced expression of each of the catenins alone failed to correlate to metastasis. However, when all of the four proteins (E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin) were analysed as one group, a significant association was seen between reduction in immunoreactivity of at least one of these four proteins and the presence of metastases. These results indicate that if one of these proteins is down-regulated, the function of the others in suppressing metastasis is altered. A significant association was seen between lobular invasive tumours and beta-catenin expression.
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PMID:E-cadherin and alpha-, beta-, and gamma-catenin protein expression in relation to metastasis in human breast carcinoma. 977 79

Oncogenesis is a complicated process involving signal transduction pathways that mediate many different physiological events. Typically, oncogenes cause unregulated cell growth and this phenotype has been attributed to the growth-stimulating activity of oncogenes such as ras and src. In recent years, much research effort has focused on proteins that function downstream of Ras, leading to the identification of the Ras/Raf/MAPK pathway, because activation of this pathway leads to cellular proliferation. Activated receptor tyrosine kinases (RTKs) also utilize this pathway to mediate their growth-stimulating effects. However, RTKs activate many other signaling proteins that are not involved in the cellular proliferation process, per se and we are learning that these pathways also contribute to the oncogenic process. In fact, RTKs and many of the proteins involved in RTK-dependent signal transduction can also function as oncogenes. For example, the catalytic subunit of phosphoinositide 3-kinase (P13-K) was recently identified as an oncogenic protein. The scope of pathways that are activated by oncogenic RTKs is expanding. Thus, not only do RTKs activate Ras-dependent pathways that drive proliferation, RTKs activate P13-K-dependent pathways which also contribute to the oncogenic mechanism. P13-K can initiate changes in gene transcription, cytoskeletal changes through beta-catenin, changes in cell motility through the tumor suppressor, adenomatous polyposis coli (APC), and phosphorylation of BAD, a protein involved in apoptotic and antiapoptotic signaling. There is also cross-talk between RTKs and the oncostatin cytokine receptor which may positively and negatively influence oncogenesis. For this review, we will focus on oncogenic RTKs and the network of cellular proteins that are activated by RTKs because multiple, divergent pathways are responsible for oncogenesis.
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PMID:Tyrosine kinase receptor-activated signal transduction pathways which lead to oncogenesis. 977 82

During the last years significant progress has been achieved in the identification of melanoma-associated antigens (MAA) recognized by cytotoxic T lymphocytes (CTL). These antigens belong to three main groups: tumor-associated testis-specific antigens (MAGE, BAGE, GAGE and PRAME), melanocyte differentiation antigens (tyrosinase, Melan-A/MART-1, gp100, TRP-1 and TRP-2) and mutated or aberrantly expressed antigens (MUM-1, CDK4, beta-catenin, gp100-in4, p15 and N-acetylglucosaminyltransferase V). For the identification of these antigens, CTL cultures from mainly only 4 different melanoma patients have been used. These patients developed a strong anti-melanoma response resulting in long-lasting disease-free periods, pointing to the importance of the identification of highly immunogenic melanomas. In each of these patients, the immune response was observed against a unique set of 4 to 6 individual antigenic epitopes, on one hand suggesting the low immunogenicity of the individual antigens, and on the other pointing to the importance of the identification of additional highly immunogenic melanomas for the discovery of new MAA. The analysis of the available data on the immunogenic and protective properties of individual MAA confirms their low immunogenicity. In our study, we focused on the identification of especially highly immunogenic melanomas among a panel of 40 newly established melanoma cell lines. So far, only two such melanoma cell lines, FM3 and FM57 have been identified in this panel. The immunogenic properties of uncloned FM3 cells and several FM3 clones have been further investigated. It was found that the immunogenic properties of melanoma cells are mainly determined by the expression of progression-associated antigens as well as by ecto-ATPase, a molecule which is able to modulate cell adhesion. Cloning the cultures of PBL, stimulated with uncloned FM3 or with the highly immunogenic FM3 clone, FM3.29, has permitted us to identify the immune response against eight different MAA, five of these probably representing not previously described antigens. (Tab. 2, Fig. 2, Ref. 68.)
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PMID:The immunogenic properties of human melanomas and melanoma-associated antigens recognized by cytotoxic T lymphocytes. 981 Jul 66

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