Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormal degradation of beta-catenin caused by alteration of the glycogen synthase kinase-3beta (GSK-3beta) consensus motif is an important step for carcinogenesis. We hypothesize that beta- and gamma-catenin may play an important role in the pathogenesis of bladder cancer. We tested this hypothesis through analysis of beta- and gamma-catenin in both murine and human bladder cancers. A murine bladder cancer model was prepared by use of N-butyl-N-(-4-hydroxybutyl)nitrosamine (BBN) in 6-week-old male B6D2F1 mice. After 4, 8, 12, 16, 20, 24, and 28 weeks of BBN treatment, bladder specimens were harvested and analyzed for both protein and gene expression for beta- and gamma-catenin. Mutational analysis of the NH(2)-terminal regulatory domains of beta- and gamma-catenin was performed in each specimen by PCR-single-strand conformational polymorphism (SSCP) analysis. Mutations were further confirmed by direct DNA sequencing with a dye terminator method. Human bladder cancer specimens with normal tissues, dysplasia, carcinoma in situ, and carcinoma of grades, 1, 2, and 3 were also analyzed for beta- and gamma-catenin expression. beta- and gamma-catenin were analyzed for mutations by SSCP and direct DNA sequencing. Intracellular accumulation of beta- and gamma-catenin was observed in 6 of 20 invasive carcinoma specimens. There was no intracellular accumulation of beta- and gamma-catenin in mucosal dysplasia, papillary or nodular dysplasia, and carcinoma in situ specimens. On an SSCP analysis for beta-catenin, abnormal bandshifts were detected in two invasive carcinomas with intracellular beta-catenin accumulation. Further sequencing revealed two mutations [AGT(S) to ATT(I) and TCT(S) to CCT(P)] within the consensus motif for GSK-3beta phosphorylation. On the other hand, SSCP analysis for gamma-catenin followed by sequencing revealed three mutations in two invasive carcinomas with intracellular accumulation of gamma-catenin. These three alterations affected the 3' downstream region outside the GSK-3beta phosphorylation site [ACC(T) to GCC(A), CTC(L) to ATC(I), and CTC(L) to ATG(M)]. In human bladder cancer, beta- and gamma-catenin expression was significantly weaker than in normal bladder. On SSCP analysis one abnormal bandshift was observed in high-grade human bladder cancer with intracellular beta-catenin accumulation. DNA sequencing revealed mutation TCT(S) to TGT(C). In summary, alterations in beta- and gamma-catenin are late events favoring tumor progression in mouse BBN-induced bladder cancer. Changes affecting the GSK-3beta phosphorylation site appear to be associated with activation of beta-catenin, but not with activation of gamma-catenin. In human blabber cancer, beta- and gamma-catenin expression is similar to the expression in the mouse model. The present study demonstrates that beta- and gamma-catenin may play an important role in bladder cancer progression.
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PMID:Alterations of beta- and gamma-catenin in N-butyl-N-(-4-hydroxybutyl)nitrosamine-induced murine bladder cancer. 1158 41

Melanoma cells produce growth factors for autocrine growth control and for stimulating fibroblasts and endothelial cells in the tumor stroma. Activated stromal fibroblasts can in turn secrete growth factors that support tumor growth. We studied this feedback from fibroblasts to melanoma cells by overexpressing insulin-like growth factor 1 (IGF-1) with an adenoviral vector. Melanoma cells do not produce IGF-1. IGF-1 enhanced survival, migration, and growth of cells from biologically early lesions, but not from biologically late primary or metastatic lesions. Early melanoma cells were activated by IGF-1 to phosphorylate Erk1 and -2 of the mitogen-activated protein kinase pathway. IGF-1 also activated Akt, inhibited its down-stream effector GSK3-beta, and stabilized beta-catenin. Late primary and metastatic melanoma cells did not respond to growth stimulation by IGF-1 because of a constitutive activation of the mitogen-activated protein kinase pathway and a higher level of stabilized beta-catenin. These studies demonstrate that fibroblast-derived growth factors from the tumor environment can provide the malignant cells with a positive feedback through multiple mechanisms but that this stimulation is required only for cells from early and not late stages of tumor progression.
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PMID:Insulin-like growth factor-1 induces survival and growth of biologically early melanoma cells through both the mitogen-activated protein kinase and beta-catenin pathways. 1158 72

A constitutive complex of beta-catenin and LEF-1 has been detected in melanoma cell lines expressing either mutant beta-catenin or mutant APC (Rubinfeld et al., Science, 275, 1790-1792, 1997). However, it has been recently reported that beta-catenin mutations are rare in primary malignant melanoma, but its nuclear and/or cytoplasmic localization, a potential indicator of Wnt/beta-catenin pathway activation, is frequently observed in melanoma (Rimm et al., Am. J. Pathol., 154, 325-329, 1999). In human malignant melanoma, the appearance of the tumorigenic phase represents a capacity for metastasis and is the significant phenotypic step in disease progression. Cell motility in invasive melanoma is thought to play a crucial role in metastatic behavior. In this work, we sought to determine which transcription factor of the LEF/TCF family was preferentially involved in human melanoma from different stages of tumor progression. We show that LEF-1 mRNA expression is predominant in highly migrating cells from metastatic melanomas. These actively migrating melanoma cells showed nuclear and cytoplasmic accumulation of beta-catenin and active transcription from a reporter plasmid of the LEF/TCF binding site. These results may provide a new insight into the role of the Wnt/beta-catenin signaling pathway in the tumor progression of malignant melanoma.
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PMID:Constitutive activation of Wnt/beta-catenin signaling pathway in migration-active melanoma cells: role of LEF-1 in melanoma with increased metastatic potential. 1159 45

The migration-inducing gamma2 chain of laminin-5, one of the best known invasion markers, is strongly overexpressed in disseminating and infiltrating tumor cells at the invasive front of colorectal carcinomas. The same tumor cells show nuclear accumulation of the oncoprotein beta-catenin, which together with T-cell factor-DNA-binding proteins, functions as transcriptional activator of genes involved in tumor progression. Here we show that beta-catenin activates the human laminin-5 gamma2 gene through two T-cell factor-binding elements in a synergistic manner together with hepatocyte growth factor and conclude that laminin-5 gamma2 is another important target gene of nuclear beta-catenin during tumor progression.
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PMID:Expression of the invasion factor laminin gamma2 in colorectal carcinomas is regulated by beta-catenin. 1171 33

The Wnt signaling pathway modulates the transcription of genes linked to proliferation, differentiation and tumor progression. beta-Catenin-Tcf (BCT)-dependent Wnt signaling is influenced by the short-chain fatty acid sodium butyrate, which induces growth arrest and/or maturation of colonic carcinoma cells. We have compared the effects of sodium butyrate on BCT-dependent signaling in 2 colon carcinoma cell lines that differ in their physiologic response to butyrate, with SW620 cells responding to butyrate by undergoing terminal differentiation and apoptosis, and HCT-116 cells undergoing reversible growth arrest, but no significant apoptotic cell death. Furthermore, these colon carcinoma cell lines differ in their mechanism of Wnt pathway activation, with adenomatous polyposis coli (APC) mutant SW620 cells having high levels of BCT complexes and APC wild-type HCT-116 cells having mutant beta-catenin, low levels of BCT complexes and correspondingly higher levels of free Tcf. We have demonstrated that in SW620 cells, butyrate downregulates BCT-dependent expression of the Tcf-TK, matrilysin and cyclin D1 promoters, whereas in HCT-116 cells, butyrate upregulates expression of these promoters. Cotransfection with expression vectors that interfere with the Wnt pathway suggests that butyrate enhances BCT complex-DNA binding. Butyrate reduces the expression of Tcf4 in HCT-116 cells, consistent with the induction by butyrate of Tcf-repressible promoters in these cells. These findings indicate that sodium butyrate modulates the Wnt pathway in SW620 and HCT-116 cells in a different manner and that these differences have consequences for promoter activity that may influence the physiologic response to butyrate.
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PMID:Cell type- and promoter-dependent modulation of the Wnt signaling pathway by sodium butyrate. 1177 42

Discoveries of oncogenic signaling molecules lead to the comprehension of molecular mechanisms of tumor progression, as well as to the development of novel therapeutic tools for hepatocellular carcinoma. We have identified critical functions of intracellular signals transmitted from insulin-like growth factor and Wnt oncoprotein in carcinogenesis. The insulin-like growth factor system activates a number of signaling cascades resulting not only in hepatic mitogenesis, but also in cell survival. The secreted oncoprotein Wnt transforms beta-catenin potentials as a component of cell adhesion complexes with cadherins, into a transcription factor in the nucleus. Here, the important role of such signal transduction is reviewed, and we emphasize its control as a promising approach for the treatment of hepatocellular carcinoma.
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PMID:Oncogenic signal transduction and therapeutic strategy for hepatocellular carcinoma. 1182 1

The majority of the adenocarcinomas arising in Barrett esophagus manifest clinically at an advanced stage and have a poor prognosis. As a result of this poor prognosis, much attention has been directed toward the exploration of markers for neoplastic progression in Barrett esophagus. The objective of the present study was to determine the expression of beta-catenin by immunohistochemical analysis in 70 adenocarcinomas developed in Barrett esophagus and to examine its relationship to various prognostic factors currently in use. Abnormal beta-catenin expression, consisting of the loss of membranous staining and the appearance of the nuclear staining, was found in 43 cases (61%). Of patients with the 43 tumors showing abnormal beta-catenin expression, 25 (58%) survived more than 1 year. In contrast, only 7 (26%) of 27 patients with tumors showing normal beta-catenin expression survived longer than 1 year. Most of the superficial (Tis-T1) tumors (83% [10/12]) exhibited abnormal beta-catenin expression compared with only 53% (31/58) in the T2-T3 group. These results suggest a possible correlation among beta-catenin expression, tumor stage, and length of survival as prognostic factors in patients with adenocarcinoma in Barrett esophagus.
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PMID:Beta-catenin expression and its association with prognostic factors in adenocarcinoma developed in Barrett esophagus. 1188 85

Solid-pseudopapillary tumors (SPTs) are unusual pancreatic neoplasms of low malignant potential that most frequently affect young women. Genetic events contributing to the development of SPTs are unknown. Whereas the more common ductal adenocarcinomas of the pancreas essentially never harbor beta-catenin or APC gene mutations, we have recently identified alterations of the APC/beta-catenin pathway in other nonductal pancreatic neoplasms including pancreatoblastomas and acinar cell carcinomas. We analyzed a series of 20 SPTs for somatic alterations of the APC/beta-catenin pathway using immunohistochemistry for beta-catenin protein accumulation, direct DNA sequencing of beta-catenin exon 3, and direct DNA sequencing of the mutation cluster region in exon 15 of the APC gene in those SPTs that did not harbor beta-catenin mutations. Immunohistochemical labeling for cyclin D1 was performed to evaluate the overexpression of this cell-cycle protein as one of the putative downstream effectors of beta-catenin dysregulation. In addition, we analyzed the SPTs for genetic alterations commonly found in pancreatic ductal adenocarcinomas, including mutations in the K-ras oncogene and p53 and DPC4 tumor suppressor genes, using direct DNA sequencing of K-ras and immunostaining for p53 and Dpc4. Almost all SPTs harbored alterations in the APC/beta-catenin pathway. Nuclear accumulation of beta-catenin protein was present in 95% (19 of 20), and activating beta-catenin oncogene mutations were identified in 90% (18 of 20) of the SPTs. Seventy-four percent (14 of 19) showed overexpression of cyclin D1, ranging from 10 to 70% of tumor nuclei. In contrast, no K-ras mutations were present in any of the 20 SPTs, and Dpc4 expression was intact in all 16 SPTs for which immunohistochemical labeling was successful. Overexpression of p53 was limited to only 3 of 19 (15.8%) SPTs. These results emphasize the two distinct, divergent genetic pathways of neoplastic progression in pancreatic ductal and nonductal neoplasms.
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PMID:Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. 1194 21

Cadherins function to promote adhesion between adjacent cells and play critical roles in such cellular processes as development, tissue maintenance, and tumor suppression. We previously demonstrated that heterotrimeric G proteins of the G12 subfamily comprised of Galpha12 and Galpha13 interact with the cytoplasmic domain of cadherins and cause the release of the transcriptional activator beta-catenin (Meigs, T. E., Fields, T. A., McKee, D. D., and Casey, P. J. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 519-524). Because of the importance of beta-catenin in cadherin-mediated cell-cell adhesion, we examined whether G12 subfamily proteins could also regulate cadherin function. The introduction of mutationally activated G12 proteins into K562 cells expressing E-cadherin blocked cadherin-mediated cell adhesion in steady-state assays. Also, in breast cancer cells, the introduction of activated G12 proteins blocked E-cadherin function in a fast aggregation assay. Aggregation mediated by a mutant cadherin that lacks G12 binding ability was not affected by activated G12 proteins, indicating a requirement for direct G12-cadherin interaction. Furthermore, in wound-filling assays in which ectopic expression of E-cadherin inhibits cell migration, the expression of activated G12 proteins reversed the inhibition via a mechanism that was independent of G12-mediated Rho activation. These results validate the G12-cadherin interaction as a potentially important event in cell biology and suggest novel roles for G12 proteins in the regulation of cadherin-mediated developmental events and in the loss of cadherin function that is characteristic of metastatic tumor progression.
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PMID:Galpha12 and Galpha13 negatively regulate the adhesive functions of cadherin. 1197 33

BACKGROUND: Beta-catenin plays two distinct roles, in intercellular adhesion by E-cadherin, and in transcriptional activation via TCF/LEF. Theoretically, the former role is tumor-suppressive, while the latter is oncogenic. We investigated the involvement of beta-catenin in the histogenesis and clinical outcome of gastric cancers.METHODS: The expression pattern of beta-catenin was evaluated in stomach and lymph nodes from 82 patients with gastric cancer by immunohistochemistry and Western blot. Its association with E-cadherin expression and clinicopathological factors, including histological type and postoperative survival, was examined.RESULTS: Beta-catenin expression was classified into two patterns, normal (23.2%; 19 patients) and disordered (76.8%; 63 patients), the latter being subclassified as overexpressed (7.3%; 6 patients) and reduced (69.5%; 57 patients). A disordered beta-catenin expression pattern was significantly correlated with diffuse type adenocarcinoma and deep tumor infiltration ( P = 0.0154), but was not associated with lymph node metastasis ( P = 0.7877). E-cadherin was always expressed at the cell membrane, and disordered beta-catenin expression was significantly associated with reduced E-cadherin expression ( P < 0.0001). On univariate analysis, the beta-catenin pattern, as well as depth of invasion and lymph node metastasis, was associated with postoperative prognosis; however, only lymph node metastasis was an independent prognostic factor on multivariate analysis. Interestingly, different disordered patterns of beta-catenin expression, both overexpressed and reduced, were associated with E-cadherin reduction and poorer postoperative survival.CONCLUSION: Although disordered patterns of beta-catenin expression varied in gastric cancers, they were consistently associated with cancer progression.
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PMID:Clinical significance of disordered beta-catenin expression pattern in human gastric cancers. 1198 36


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