Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of epidermal growth factor (EGF) and urokinase plasminogen activator receptor (uPAR) have been observed in human gastric cancers. However, the interaction between EGF and uPAR in gastric cancer has not been well elucidated. In this study, we investigated the effect of EGF on uPAR expression and the underlying signal pathways in human gastric cancer AGS cells. EGF induced uPAR mRNA expression in a time- and concentration-dependent manner. EGF also induced uPAR promoter activity. In addition, EGF induced the activation of extracellular signal regulated kinase-1/2 (ERK-1/2) and P38 mitogen-activated protein kinase (MAPK) but not the activation of c-Jun amino terminal kinase. A specific inhibitor of MEK-1 (an upstream effector of ERK-1/2) and a dominant negative MEK-1 were able to suppress the EGF-induced uPAR promoter activity. Site-directed mutagenesis and electrophoretic mobility shift assays demonstrated that the binding sites of transcription factors, activator protein-1 (AP-1) and nuclear factor (NF)-kappaB, are involved in the EGF-induced uPAR transcription. Suppression of the EGF-induced uPAR promoter activity by the AP-1 decoy oligonuclotide, as well as expression vectors encoding mutated-type NF-kappaB-inducting kinase and I-kappaB, confirmed that the activation of AP-1 and NF-kappaB are essential for the EGF-induced uPAR upregulation. The AGS cells pretreated with EGF showed a remarkably enhanced invasiveness and this effect was partially abrogated by uPAR neutralizing antibodies and by the inhibitors of ERK-1/2, AP-1, and NF-kappaB. The above results suggest that EGF induces uPAR expression via ERK-1/2, AP-1, and NF-kappaB signaling pathways and, in turn, stimulates cell invasiveness in human gastric cancer AGS cells.
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PMID:EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-kappaB signaling in human gastric carcinoma cells. 1902 Jul 43

A number of advances recently have been made in the chemotherapeutic treatment of gastroesophageal cancer. Perioperative combination chemotherapy based on cisplatin and 5-fluorouracil (5-FU) improves the prognosis of patients with stage II and stage III disease. Preoperative initiation of chemotherapy seems to be essential for achieving this result, according to studies performed in the West. On the other hand, Japanese investigators demonstrated that postoperative administration of oral fluoropyrimidine prodrugs can substantially improve the prognosis of patients with curatively resected gastric cancer. The addition of docetaxel to cisplatin and 5-FU has significantly improved response rate, time to progression, and overall survival in patients treated for advanced gastric cancer, as well as prolonging time to definitive worsening of global health status and Karnofsky performance status. Due to increased hematologic toxicity with this regimen, particularly neutropenic infections, careful patient selection and optimal supportive care, including prophylactic granulocyte colonystimulating factor, are required. Alternative schedules are being investigated that could improve the tolerability of docetaxel plus platinum/fluoropyrimidine combination regimens. Further improvements in outcome may be achieved when even more active chemotherapy combinations including docetaxel are systematically implemented into the preoperative treatment of locally advanced gastroesophageal cancers. Initial results with biologic targeted agents in this setting are promising. Pathways currently under investigation include the epidermal growth factor receptors Her-1 and Her-2, vascular endothelial growth factor, and the epithelial cell adhesion molecule EpCAM. It is hoped that targeting these pathways will further increase the efficacy of biochemotherapy of gastroesophageal cancer. Evaluating early response to biochemotherapy using metabolic imaging is a novel approach that may allow for tailoring systemic therapy to individual tumor biology. A deeper understanding of the relevant pathognomonic molecular patterns and signatures in individual tumors may facilitate faster drug development and permit more accurate selection of active therapies in the future.
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PMID:Current status and future of chemotherapy and biochemotherapy in gastroesophageal cancers. 1996 33

Breast cancer resistance protein (BCRP)/ABCG2 is a drug efflux pump responsible for multidrug resistance in cancer cells. We report that dephosphorylation of extracellular signal-regulated kinase (ERK) by treatment with mitogen-activated protein kinase/ERK kinase (MEK) inhibitors causes two opposing effects, transcriptional upregulation and prompted protein degradation of endogenous BCRP in breast cancer MCF-7 cells. Endogenous BCRP was eventually found to be upregulated. Conversely, treatment with epidermal growth factor was associated with its downregulation in the cells. MEK inhibitors also caused prompted degradation of exogenous BCRP in MCF-7 and gastric cancer NCI-N87 cells that express exogenous BCRP without affecting its transcriptional levels, and potentiated anticancer agents in the cells. A lysosomal inhibitor abolished this prompted degradation of exogenous BCRP, but a proteasome inhibitor did not. Inhibition of p90 ribosomal protein S6 kinase (RSK), one of the downstream effectors of ERK, resulted in transcriptional upregulation of endogenous BCRP but did not affect the protein degradation of exogenous BCRP. The data suggest that BCRP expression is differentially regulated downstream of the MEK-ERK pathway, transcriptionally upregulated through the inhibition of the MEK-ERK-RSK pathway, and posttranscriptionally downregulated through the inhibition of the MEK-ERK-non-RSK pathway. Although the immediate downstream effector of ERK remains to be elucidated, the data provide new insights into regulatory mechanisms of BCRP activity and may assist the development of BCRP-specific expression modulators.
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PMID:Breast cancer resistance protein/ABCG2 is differentially regulated downstream of extracellular signal-regulated kinase. 1951 21

Cetuximab is a monoclonal antibody targeting epidermal growth factor receptor (EGFR). The present study investigated the association between germline genetic polymorphisms and the treatment outcome of cetuximab plus modified leucovovin, fluorouracil, and oxaliplatin (FOLFOX)6 chemotherapy in advanced gastric cancer (AGC). DNA from peripheral blood mononuclear cells of 38 patients enrolled in a phase II study of cetuximab plus modified FOLFOX6 were analyzed for 16 polymorphisms in eight genes (EGFR, epidermal growth factor, transforming growth factor-alpha (TGFA), thymidylate synthase, excision repair cross-complementation group 1, Xeroderma pigmentosum group D, and fragment c gamma receptors (FCGR)2A and 3A). The EGFR intron 1 CA repeat polymorphism was associated with survival. Twenty-one patients had low repeats (sum of both alleles <or=37), and 17 patients had high repeats (sum >or=38). Patients with low CA repeats had longer progression-free survival (adjusted hazard ratio [HR] 0.42 [95% confidence interval [CI] 0.19-0.96], P = 0.040) and overall survival (adjusted HR 0.40 [95% CI 0.16-0.99], P = 0.048) compared with patients with high CA repeats. In addition, the tumor EGFR expression was higher in patients with a lower number of CA repeats. The association between the CA repeat status and survival was not found in a separate cohort of AGC patients (n = 68) treated only with modified FOLFOX6. These results suggest that the EGFR intron 1 CA repeat polymorphism could be a useful, predictive biomarker of cetuximab efficacy in AGC and merits further investigation in randomized studies.
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PMID:Epidermal growth factor receptor intron 1 CA dinucleotide repeat polymorphism and survival of advanced gastric cancer patients treated with cetuximab plus modified FOLFOX6. 2004 92

The family of epidermal growth factor (EGF, EGFR, c-erbB-2) plays a pivotal role in gastric cancer progression, invasion and metastasizing. Helicobacter pylori infection is known to contribute significantly to the formation and progression of gastric cancer. However, the mechanisms responsible for this process have not been yet elucidated. We analysed the relationship between H. pylori infection and expression of proteins belonging to the family of epidermal growth factor (EGF, EGFR, c-erbB-2). Fifty-five patients with gastric cancer were analysed for Helicobacter pylori infection. The expressions of EGF, EGFR, c-erbB-2 proteins were determined using an immunohistochemical method. No statistically significant correlation was found between the degree of H. pylori infection and the expressions of EGF, EGFR and c-erbB-2 in gastric cancer. However, c-erbB-2 expression in the main mass of tumour correlated with tumour expression of EGF and EGFR and with c-erbB-2 expression in local lymph nodes. The expression of c-erbB-2 in lymph nodes was statistically significantly related to the expressions of EGF and EGFR both in the main mass of tumour and in lymph nodes. The expression of EGF was found to correlate with EGFR in the main mass of tumour and the expression of EGF in lymph nodes was related to lymph node EGFR level. Our study did not confirm the relationship between H. pylori infection and the expression of epidermal growth factor in gastric cancer.
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PMID:Helicobacter pylori infection and expressions of EGF, EGFR and c-erbB-2 proteins in gastric carcinoma. 2016 30

Upon binding of interferon (IFN) and epidermal growth factor (EGF) to their cell surface receptors, tyrosine phosphorylation of latent cytoplasmic Stat91 (Ras-independent signal transducer and activator of transcription, Stat1 alpha) protein is promptly induced and translocate from the cytoplasm to the nucleus to transduce the signal. The expression of mRNA for Stat91 was examined in 8 gastric carcinoma cell lines and 21 gastric carcinoma tissues as well as corresponding normal mucosa. Of the 8 gastric carcinoma cell lines, all expressed a 4.7 kb Stat91 mRNA and a 91 kD protein at various levels. In gastric carcinoma cell lines, the levels of Stat91 mRNA expression were compatible with those of Stat91 protein expression. In surgical cases, all the gastric carcinoma tissues and their adjacent non-neoplastic mucosa expressed Stat91 mRNA and protein. Interestingly, 14 (66%) out of 21 tumors expressed Stat91 mRNA at higher levels than their corresponding normal mucosas. Moreover, 6 (75%) of 8 tumor tissues expressed higher levels of Stat91 protein as compared with those of the corresponding normal gastric mucosa. No significant correlation was detected between the expression of Stat91 and clinicopathological feature of gastric carcinoma. These results suggest that the majority of gastric cancer in vivo harbour overexpression of Stat91 as a signal transducer in response to various cytokines or growth factors which may be implicated in the growth of gastric cancer.
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PMID:The expression of stat91, ras-independent signal transducer and activator, in human gastric carcinomas. 2155 22

To evaluate a potential role of an autocrine mechanism in gastric cancer, we carried out an immunohistochemical study of epidermal growth factor (EGF), transforming growth factor alpha (TGFalpha), and epidermal growth factor receptor (EGFR) in 167 primary gastric cancer tissues. Slot blot hybridization was also performed to detect the amplification of EGFR gene. Immunohistochemically, 70 (42%), 87 (52%), 68 (41%) of 167 primary gastric cancers were stained positively for EGF, TGFalpha, and EGFR, respectively. Tumors with synchronous expression of EGFR and its ligands were most frequent in the following clinicopathological groups: tumors greater than 6 cm in size, those of the infiltrating type, and those of the poorly differentiated type. Among poorly differentiated carcinomas, the synchronous expression of EGFR and its ligands was more frequent in the infiltrating gross type than in the localized type. EGFR gene amplification was found in 5 (4.9%) of 103 primary tumors. EGFR gene amplification was also observed more frequently in infiltrating gross type of poorly,differentiated adenocarcinomas, as compared to localized gross type. These results indicate that the autocrine mechanism through EGFR may play an important role in the progression of infiltrating gross type of poorly differentiated adenocarcinoma of the stomach.
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PMID:Evidence of autocrine mechanism in poorly differentiated adenocarcinoma of the stomach. 2157 5

Although combination chemotherapy has been shown to be more effective than single agents in advanced esophagogastric cancer, the better response rates have not fulfilled their promise as overall survival times from best combination still range between 8 to 11 months. So far, the development of targeted therapies stays somewhat behind their integration into treatment concepts compared to other gastrointestinal diseases. Thus, the review summarizes the recent advances in the development of targeted therapies in advanced esophagogastric cancer. The majority of agents tested were angiogenesis inhibitors or agents targeting the epidermal growth factor receptors EGFR1 and HER2. For trastuzumab and bevacizumab, phase III trial results have been presented recently. While addition of trastuzumab to cisplatin/5-fluoropyrimidine-based chemotherapy results in a clinically relevant and statistically significant survival benefit in HER 2+ patients, the benefit of the addition of bevacizumab to chemotherapy was not significant. Thus, all patients with metastatic disease should be tested for HER-2 status in the tumor. Trastuzumab in combination with cisplatin/5-fluoropyrimidine-based chemotherapy is the new standard of care for patients with HER2-positive advanced gastric cancer.
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PMID:Esophagogastric cancer: integration of targeted therapies into systemic chemotherapy. 2165 62

With the availability of a therapeutic target and an effective agent in trastuzumab, a systematic examination of the literature to investigate the role of human epidermal growth factor 2 (HER2) as a prognostic factor for survival and its association with clinicopathologic markers may improve treatment. An electronic search of the MEDLINE and PubMed databases (January 1990 to January 2011) was undertaken to identify translational studies that correlated HER2 with clinicopathologic markers and/or survival outcome. This review included 49 studies totaling 11,337 patients. Forty-four percent of patients had Stage I/II, and 56% had Stage III/IV disease. Immunohistochemistry was most commonly used to assess HER2 expression, identifying a median rate of 18% (range, 4-53%) of gastric cancer demonstrating HER2 overexpression. In patients with and without HER2 overexpression, the median 3-year disease-free survival rate was 58% (range, 50-88%) and 86% (range, 62-97%), respectively. Of the 35 studies reporting the impact of HER2 overexpression on survival, 20 studies (57%) reported no difference in overall survival, two studies (6%) reported significantly longer overall survival in patients with HER2 overexpression and 13 studies (37%) reported significantly poorer overall survival in patients with HER2 overexpression. The median overall survival and 5-year survival rate was 21 (range, 10-57) months and 42%, and 33 (range, 13-80) months and 52% in patients with and without HER2 overexpression, respectively. HER2 overexpression appears to be associated with poorer survival and with intestinal-type gastric cancer in this group of patients for whom majority undergone curative gastrectomy.
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PMID:Clinicopathologic factors associated with HER2-positive gastric cancer and its impact on survival outcomes--a systematic review. 2178 Jan 8

The human epidermal growth factor (EGF) receptor (HER) family consists of four receptors that bind to ligands sharing an EGF-like motif. The HER family of receptor tyrosine kinases and their ligands (EGF family) are known to play a significant role in gastrointestinal cancer. In particular, the EGF receptor, HER1, is one of the main candidates for the molecular-targeted therapy of colon cancer, and HER2 is a candidate for the treatment of gastric cancer which overexpresses HER2. In contrast, the role of the HER and EGF families in malignant lymphoma has not been fully elucidated. In this study, we investigated the expression and function of the HER and EGF families in lymphoma cell lines and tumor samples. Reverse transcription polymerase chain reaction revealed that the ligands for HER1 were mainly expressed in gastric cancer and colon cancer cell lines, but not in lymphoma cell lines. On the other hand, the EGF family member, neuregulin (NRG) 4, was highly expressed in lymphoma cell lines. Immunohistochemical analyses of malignant lymphoma clinical samples revealed that NRG4 and HER4 were mainly expressed in mucosa-associated lymphoid tissue (MALT) and follicular lymphoma. Immunoprecipitation of Raji and Daudi cell lines revealed that recombinant NRG4 induced the tyrosine phosphorylation of HER4. Additionally, recombinant NRG4 activated the proliferation of lymphoma cell lines. These findings suggest that the NRG4-HER4 axis plays a major role in the proliferation of malignant lymphoma cells in the gastrointestinal tract.
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PMID:The role of neuregulin4 and HER4 in gastrointestinal malignant lymphoma. 2180 36


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