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

Activation of the Raf/MEK/ERK (MAPK) signal transduction cascade by RAS mutations has been found in a variety of human cancers. Mutations of BRAF provide an alternative route for activation of this signalling pathway. To determine the role of mutations in BRAF and KRAS2 in the neoplastic progression of Barrett's adenocarcinoma, we analysed both genes for common mutations. After microdissection, DNA of 19 Barrett's adenocarcinomas, 56 Barrett's intraepithelial neoplasias (n=29 low-grade intraepithelial neoplasia (LGIN) and n=27 high-grade intraepithelial neoplasia (HGIN)), 30 Barrett's mucosa without neoplasia and normal squamous, as well as gastric epithelium, were analysed for BRAF and KRAS2 mutation. Activating BRAF mutations were identified in 2/19 Barrett's adenocarcinomas (11%) and in 1/27 HGIN (4%). KRAS2 mutations were found in four out of 19 (21%) Barrett's adenocarcinomas examined and in three cases of HGIN (11%). In LGIN as well as in normal gastric or oesophageal mucosa, neither BRAF nor KRAS2 mutations were detected. All lesions with KRAS2 mutations had an intact BRAF gene. The status of mismatch-repair proteins was neither related to BRAF nor KRAS2 mutations. These data indicate that RAS or BRAF mutations are detected in about 32% of all Barrett's adenocarcinomas. We conclude that the disruption of the Raf/MEK/ERK (MAPK) kinase pathway is a frequent but also early event in the development of Barrett's adenocarcinoma.
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PMID:Mutations of BRAF and KRAS2 in the development of Barrett's adenocarcinoma. 1472 83

Follicular epithelial cell-derived thyroid tumors are common neoplasms comprised mainly of benign thyroid adenomas, follicular thyroid cancers, and papillary thyroid cancers (PTCs). Hypermethylation of the tumor suppressor gene RASSF1A and activating mutation of BRAF gene have been reported recently in thyroid cancers. To additionally investigate the roles of these two epigenetic/genetic alterations in thyroid tumor progression, we examined their occurrences and relationship in both benign and malignant thyroid neoplasms. With real-time quantitative methylation-specific PCR, we found that 4 of 9 (44%) benign adenomas, 9 of 12 (75%) follicular thyroid cancers tumors, and 6 of 30 (20%) of PTC tumors harbored promoter methylation in > or = 25% of RASSF1A alleles. Additional quantitative analysis revealed RASSF1A methylation only in BRAF mutation-negative PTCs. A similar inverse correlation of RASSF1A methylation with BRAF mutation was seen in thyroid tumor cell lines. Our results, therefore, suggest that epigenetic inactivation of RASSF1A through aberrant methylation is an early step in thyroid tumorigenesis. Like the previously reported mutually exclusive relationship between BRAF mutation and other Ras pathway components such as RET/PTC rearrangement, a mutually exclusive relationship also exists between BRAF mutation and RASSF1A methylation in thyroid tumorigenesis.
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PMID:Early occurrence of RASSF1A hypermethylation and its mutual exclusion with BRAF mutation in thyroid tumorigenesis. 1499 25

The pathogenesis of ovarian carcinoma, the most lethal gynecological malignancy, is unknown because of the lack of a tumor progression model. Based on a review of recent clinicopathological and molecular studies, we propose a model for their development. In this model, surface epithelial tumors are divided into two broad categories designated type I and type II tumors that correspond to two main pathways of tumorigenesis. Type I tumors tend to be low-grade neoplasms that arise in a stepwise manner from borderline tumors whereas type II tumors are high-grade neoplasms for which morphologically recognizable precursor lesions have not been identified, so-called de novo development. As serous tumors are the most common surface epithelial tumors, low-grade serous carcinoma is the prototypic type I tumor and high-grade serous carcinoma is the prototypic type II tumor. In addition to low-grade serous carcinomas, type I tumors are composed of mucinous carcinomas, endometrioid carcinomas, malignant Brenner tumors, and clear cell carcinomas. Type I tumors are associated with distinct molecular changes that are rarely found in type II tumors, such as BRAF and KRAS mutations for serous tumors, KRAS mutations for mucinous tumors, and beta-catenin and PTEN mutations and microsatellite instability for endometrioid tumors. Type II tumors include high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcoma), and undifferentiated carcinoma. There are very limited data on the molecular alterations associated with type II tumors except frequent p53 mutations in high-grade serous carcinomas and malignant mixed mesodermal tumors (carcinosarcomas). This model of carcinogenesis reconciles the relationship of borderline tumors to invasive carcinoma and provides a morphological and molecular framework for studies aimed at elucidating the pathogenesis of ovarian cancer.
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PMID:Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. 1511 Dec 96

Molecular genetic changes that are associated with the initiating stage of tumor development are important in tumorigenesis. Ovarian serous borderline tumors (SBTs), putative precursors of low-grade serous carcinomas, are among the few human neoplasms with a high frequency of activating mutations in BRAF and KRAS genes. However, it remains unclear as to how these mutations contribute to tumor progression. To address this issue, we compared the mutational status of BRAF and KRAS in both SBTs and the adjacent epithelium from cystadenomas, the presumed precursor of SBTs. We found that three of eight SBTs contained mutant BRAF, and four SBTs contained mutant KRAS. All specimens with mutant BRAF harbored wild-type KRAS and vice versa. Thus, seven (88%) of eight SBTs contained either BRAF or KRAS mutations. The same mutations detected in SBTs were also identified in the cystadenoma epithelium adjacent to the SBTs in six (86%) of seven informative cases. As compared to SBTs, the cystadenoma epithelium, like ovarian surface epithelium, lacks cytological atypia. Our findings provide cogent evidence that mutations of BRAF and KRAS occur in the epithelium of cystadenomas adjacent to SBTs and strongly suggest that they are very early events in tumorigenesis, preceding the development of SBT.
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PMID:Mutations of BRAF and KRAS precede the development of ovarian serous borderline tumors. 1546 81

The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. The novel bi-aryl urea BAY 43-9006 is a potent inhibitor of Raf-1, a member of the RAF/MEK/ERK signaling pathway. Additional characterization showed that BAY 43-9006 suppresses both wild-type and V599E mutant BRAF activity in vitro. In addition, BAY 43-9006 demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3, and c-KIT. In cellular mechanistic assays, BAY 43-9006 demonstrated inhibition of the mitogen-activated protein kinase pathway in colon, pancreatic, and breast tumor cell lines expressing mutant KRAS or wild-type or mutant BRAF, whereas non-small-cell lung cancer cell lines expressing mutant KRAS were insensitive to inhibition of the mitogen-activated protein kinase pathway by BAY 43-9006. Potent inhibition of VEGFR-2, platelet-derived growth factor receptor beta, and VEGFR-3 cellular receptor autophosphorylation was also observed for BAY 43-9006. Once daily oral dosing of BAY 43-9006 demonstrated broad-spectrum antitumor activity in colon, breast, and non-small-cell lung cancer xenograft models. Immunohistochemistry demonstrated a close association between inhibition of tumor growth and inhibition of the extracellular signal-regulated kinases (ERKs) 1/2 phosphorylation in two of three xenograft models examined, consistent with inhibition of the RAF/MEK/ERK pathway in some but not all models. Additional analyses of microvessel density and microvessel area in the same tumor sections using antimurine CD31 antibodies demonstrated significant inhibition of neovascularization in all three of the xenograft models. These data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis.
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PMID:BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. 1546 6

Mutation in exon 15 of the BRAF gene is a characteristic feature of human thyroid papillary carcinoma (PTC). To determine the role of such mutation(s) in the neoplastic progression of thyroid papillary microcarcinoma (PMC), we analyzed 46 cases from 31 Russian and 15 Japanese patients with PMC. Mutated BRAF (the BRAFT1796A transversion in all cases) was detected in 13/46 (28.2%) of the tumors: 9/31 (29.0%) and 4/15 (26.6%) in Russian and Japanese individuals, respectively, displaying no signs of difference in the mutational rates in the PMCs from patients with diverse genetic background seen in PTCs. Occurrence of the BRAF mutation did not significantly correlate with the patients' gender, age at presentation, metastatic indices or with papillary, mixed papillary and follicular, and solid/trabecular PMC histotype. On the contrary, the tumors of follicular morphology significantly associated with the mutation-free genotype (P=0.018), and in the mixed-type tumors characterized by co-occurrence of well-differentiated and less differentiated components, the BRAF mutational frequency was significantly elevated (P=0.020). The results indicate the BRAFT1796A mutation is prevalent in PMCs, and thus these tumors may have a spectrum of genetic events partly overlapping with that of PTCs.
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PMID:The BRAFT1796A transversion is a prevalent mutational event in human thyroid microcarcinoma. 1554 11

CT120, a novel membrane-associated gene implicated in lung carcinogenesis, was previously identified from chromosome 17p13.3 locus, a hot mutation spot involved in human malignancies. In the present study, we further determined that CT120 ectopic expression could promote cell proliferation activity of NIH3T3 cells using MTS assay, and monitored the downstream effects of CT120 in NIH3T3 cells with Atlas mouse cDNA expression arrays. Among 588 known genes, 133 genes were found to be upregulated or downregulated by CT120. Two major signaling pathways involved in cell proliferation, cell survival and anti-apoptosis were overexpressed and activated in response to CT120: One is the Raf/MEK/Erk signal cascades and the other is the PI3K/Akt signal cascades, suggesting that CT120 might contribute, at least in part, to the constitutively activation of Erk and Akt in human lung cancer cells. In addition, some tumor metastasis associated genes cathepsin B, cathepsin D, cathepsin L, MMP-2/TIMP-2 were also upregulated by CT120, upon which CT120 might be involved in tumor invasiveness and metastasis. In addition, CT120 might play an important role in tumor progression through modulating the expression of some candidate "Lung Tumor Progression" genes including B-Raf, Rab-2, BAX, BAG-1, YB-1, and Cdc42.
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PMID:Altered gene expression profiles of NIH3T3 cells regulated by human lung cancer associated gene CT120. 1562 16

Elastin peptides (EPs) produced during cancer progression bind to the elastin binding protein (EBP) found at the surface of dermal fibroblasts, leading to the expression of collagenase-1 gene. The production of this enzyme involved in stromal reaction is caused by the sustained activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway via cAMP/protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K). However, the mechanism of these signaling events remains unknown. We show that kappa-elastin (kappaE), a commonly used EP, induces maximum phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK)1/2 and ERK1/2 after 30 min. The simultaneous inhibition of PKA and PI3K, by N-(2-(p-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide (H89) and 2-(4-morpholynil)-8-phenyl-4H-1-bemzopyran-4-one (LY294002), respectively, blocked MEK1/2 and ERK1/2 phosphorylation, as did lactose, an EBP antagonist. kappaE induced Raf-1 phosphorylation and activation in a PI3K-dependent manner. In our system, the PI3K p110gamma is expressed and activated by betagamma-derived subunits from a pertussis toxin-sensitive G protein after fibroblast stimulation. Pertussis toxin also blocks the Raf-1/MEK1/2/ERK1/2 phosphorylation cascade. In addition, we found that B-Raf is expressed in dermal fibroblasts and activated in a PKA-dependent manner after kappaE treatment, thereby integrating PKA signals to MEK1/2. It is noteworthy that Ras involvement was excluded because ERK1/2 activation by kappaE was not blocked in RasN17-transfected fibroblasts. Together, our results identify a novel Ras-independent ERK1/2 activation system in which p110gamma/Raf-1/MEK1/2 and PKA/B-Raf/MEK1/2 cooperate to activate ERK1/2. Thus, p110gamma and B-Raf seem to be important modulators of dermal fibroblasts physiology and should now qualify as therapeutic targets in strategies aiming at limiting elastin degradation contribution to cancer progression.
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PMID:Elastin peptides activate extracellular signal-regulated kinase 1/2 via a Ras-independent mechanism requiring both p110gamma/Raf-1 and protein kinase A/B-Raf signaling in human skin fibroblasts. 1565 54

Gene mutations in APC, K-ras, and p53 are thought to be essential events for colorectal cancer development. Recent data seem to indicate that K-ras and p53 mutations rarely co-exist in the same tumor, indicating that these alterations do not represent a synergistic evolutionary pathway. Moreover, an inverse relation between K-ras gene activation and BRAF mutations has been demonstrated, suggesting alternative pathways for colorectal cancer transformation. To reconstruct the chronological modulation of these gene mutations during cell transformation and colorectal cancer progression, mutations of p53, K-ras, and BRAF genes were analyzed by Single Strand Conformation Polymorphism (SSCP) or sequencing analysis in 100 colorectal cancer samples, evenly distributed among different Dukes' stages. We found mutations in p53, K-ras, and BRAF genes in 35%, 30%, and 4% of tumors, respectively, and observed a minimal or no co-presence of these gene alterations. Moreover, the frequency of molecular p53 mutations increased as tumor stage increased, suggesting an important role for this gene in the progression of colorectal cancer. Conversely, K-ras or BRAF genes were not related to tumor stage or location. These data seem to indicate the absence of a co-presence of the genes, highlighting the possibility of multiple pathways for colorectal tumor progression. Moreover, mutations in p53, K-ras, and BRAF are not present in about one-third of colorectal cancers and therefore other gene mutations need to be investigated to better understand molecular mechanisms at the basis of cell transformation and the progression of colorectal cancer.
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PMID:Mutation analysis of p53, K-ras, and BRAF genes in colorectal cancer progression. 1570 78

We analyzed RASSF1A and NORE1A methylation and BRAF mutation in 89 thyroid tumors, 42 non-neoplastic thyroid tissues and three thyroid tumor cell lines using polymerase chain reaction (PCR), methylation-specific PCR, Western blotting and DNA sequencing in order to study thyroid tumor pathogenesis and progression. RASSF1A promoter methylation was present in all three thyroid cell lines and in 27/78 (35%) of benign and malignant thyroid tumors. We showed for the first time that there was generally good agreement between RASSF1A methylation status and RASSF1A protein expression. We also examined for the first time NORE1A promoter region methylation in thyroid cell lines and primary tumors and showed that two of three thyroid cell lines were methylated in the NORE1A promoter region, while all primary thyroid tumors analyzed (n=51) were unmethylated. BRAF mutation was present in 38% of papillary thyroid carcinomas (PTC), including 20% of PTC with a follicular variant pattern and 67% of the tall cell variant of PTC. Hyalinizing trabecular tumors (n=23), which had nuclear features similar to PTC, did not have BRAF mutations, indicating that the presence of BRAF mutations can help to separate these two tumor types. Phospho-MEK expression was increased in the NPA cell line, which had a BRAF mutation, supporting the importance of the BRAF pathway alterations in PTC pathogenesis. These results indicate that RASSF1A epigenetic changes are an early event in thyroid tumor pathogenesis and progression and that NORE1A methylation is uncommon in primary thyroid tumors. BRAF mutation occurs later in thyroid tumor progression and is restricted mainly to PTC and anaplastic thyroid carcinoma.
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PMID:RASSF1A and NORE1A methylation and BRAFV600E mutations in thyroid tumors. 1598 Aug 87


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