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Oncogenic Pathways (oncogenic + pathway)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

Mouse models of gastric tumors: Wnt activation and PGE2 induction

PATHOLOGY INTERNATIONAL, Issue 9 2010
Hiroko Oshima
Accumulating evidence has suggested that cooperation of oncogenic activation and the host responses is important for cancer development. In gastric cancer, activation of Wnt signaling appears to be a major oncogenic pathway that causes tumorigenesis. In the chronic gastritis caused by Helicobacter pylori infection, cyclooxigenase-2 induces prostaglandin E2 (PGE2) biosythesis, which plays an important role in tumorigenesis. We constructed a series of mouse models and investigated the role of each pathway in the gastric tumorigenesis. Wnt activation in gastric epithelial cells suppresses differentiation, and induces development of preneoplastic lesions. On the other hand, induction of the PGE2 pathway in gastric mucosa induces development of spasmolytic polypeptide-expressing metaplasia (SPEM), which is a possible preneoplastic metaplasia. Importantly, simultaneous activation of Wnt and PGE2 pathways leads to dysplastic gastric tumor development. Moreover, induction of the PGE2 pathway also promotes gastric hamartoma development when bone morphogenetic protein (BMP) signaling is suppressed. These results indicate that alteration in the Wnt or BMP signaling impairs epithelial differentiation, and the PGE2 pathway accelerates tumor formation regardless of the types of oncogenic pathways. We review the phenotypes and gene expression profiles of the respective models, and discuss the cooperation of oncogenic pathways and host responses in gastric tumorigenesis. [source]

Multiple pathways in the FGF signaling network are frequently deregulated by gene amplification in oral dysplasias

INTERNATIONAL JOURNAL OF CANCER, Issue 9 2009
Ivy F.L. Tsui
Abstract Genetic alteration in oral premalignant lesions (OPLs), the precursors of oral squamous cell carcinomas (OSCCs), may represent key changes in disease initiation and development. We ask if DNA amplification occurs at this early stage of cancer development and which oncogenic pathways are disrupted in OPLs. Here, we evaluated 50 high-grade dysplasias and low-grade dysplasias that later progressed to cancer for gene dosage aberrations using tiling-path DNA microarrays. Early occurrences of DNA amplification and homozygous deletion were frequently detected, with 40% (20/50) of these early lesions exhibiting such features. Expression for 88 genes in 7 recurrent amplicons were evaluated in 5 independent head and neck cancer datasets, with 40 candidates found to be overexpressed relative to normal tissues. These genes were significantly enriched in the canonical ERK/MAPK, FGF, p53, PTEN and PI3K/AKT signaling pathways (p = 8.95 × 10,3 to 3.18 × 10,2). These identified pathways share interactions in one signaling network, and amplification-mediated deregulation of this network was found in 30.0% of these preinvasive lesions. No such alterations were found in 14 low-grade dysplasias that did not progress, whereas 43.5% (10/23) of OSCCs were found to have altered genes within the pathways with DNA amplification. Multitarget FISH showed that amplification of EGFR and CCND1 can coexist in single cells of an oral dysplasia, suggesting the dependence on multiple oncogenes for OPL progression. Taken together, these findings identify a critical biological network that is frequently disrupted in high-risk OPLs, with different specific genes disrupted in different individuals. © 2009 UICC [source]

Mouse models of gastric tumors: Wnt activation and PGE2 induction

Biology, clinical characteristics, and management of adrenocortical tumors in children

PEDIATRIC BLOOD & CANCER, Issue 3 2005
Carlos Rodriguez-Galindo MD
Abstract Childhood adrenocortical tumors (ACT) are very aggressive endocrine neoplasms whose incidence is quite low. Little is known about their pathogenesis, clinical presentation, and optimal treatment. In recent years, however, new information has been derived from the International Pediatric Adrenocortical Tumor Registry (IPACTR), and new clues to its pathogenesis have emerged. To provide an overview of the available data that may apply to pediatric ACT, we reviewed the epidemiology, pathogenesis, and treatment of ACT in adults and in children. Germline TP53 mutation is almost always the predisposing factor in childhood ACT. A unique germline mutation (TP53,R337H) has been described in Southern Brazil, where the incidence of ACT is 10,15 times the general incidence. Childhood ACT typically present during the first 5 years of life and has female predominance. Hormone hyperproduction is almost universal, and most patients present with virilization. Two-thirds of patients have resectable tumors. Surgery is the definitive treatment for ACT, and a curative complete resection should always be attempted. Cisplatin-based chemotherapy with mitotane is indicated for unresectable or metastatic disease, although its impact on overall outcome is slight. In childhood ACT, age, tumor size, and tumor resectability are the most important prognostic indicators. Outcome is stage-dependent; patients with small, resectable tumors have survival rates in excess of 80%, whereas the outcome for patients with unresectable disease is dismal. Patients with large, resectable tumors have an intermediate outcome. Childhood ACT are rare, but their unique epidemiology appear to implicate novel oncogenic pathways that are unique to the pediatric population. Multi-institutional and prospective studies are necessary to further our understanding of the pathogenesis and to improve outcomes. © 2005 Wiley-Liss, Inc. [source]

Prostaglandin E2, Wnt, and BMP in gastric tumor mouse models

CANCER SCIENCE, Issue 10 2009
Hiroko Oshima
The development of gastric cancer is closely associated with Helicobacter pylori (H. pylori) infection. The expression of cylooxigenase-2 (COX-2), a rate-limiting enzyme for prostaglandin biosynthesis, is induced in H. pylori -associated chronic gastritis, which thus results in the induction of proinflammatory prostaglandin, PGE2. The COX-2/PGE2 pathway plays a key role in gastric tumorigenesis. On the other hand, several oncogenic pathways have been shown to trigger gastric tumorigenesis. The activation of Wnt/,-catenin signaling is found in 30,50% of gastric cancers, thus suggesting that Wnt signaling plays a causal role in gastric cancer development. Mutations in the bone morphogenetic protein (BMP) signaling pathway are responsible for the subset of juvenile polyposis syndrome (JPS) that develops hamartomas in the gastrointestinal tract. BMP suppression appears to contribute to gastric cancer development because gastric cancer risk is increased in JPS. Wnt signaling is important for the maintenance of gastrointestinal stem cells, while BMP promotes epithelial cell differentiation. Accordingly, it is possible that both Wnt activation and BMP suppression can cause gastric tumorigenesis through enhancement of the undifferentiated status of epithelial cells. Recent mouse model studies have indicated that induction of the PGE2 pathway is required for the development of both gastric adenocarcinoma and hamartoma in the Wnt-activated and BMP-suppressed gastric mucosa, respectively. This article reviews the involvement of the PGE2, Wnt, and BMP pathways in the development of gastric cancer, and gastric phenotypes that are found in transgenic mouse models of PGE2 induction, Wnt activation, BMP suppression, or a combination of these pathways. (Cancer Sci 2009; 100: 1779,1785) [source]