Benign gastric carcinoid tumor with hypergastrinemia followed up for 12 years

Gastric carcinoid tumors associated with chronic atrophic gastritis type A have been reported to show good prognosis, because invasion and metastasis are rare. We report a case of gastric carcinoid tumor associated with hypergastrinemia that showed no malignant changes for 12 years. A 15-year-old man with abdominal discomfort underwent endoscopic examination. A polypoid lesion was detected on the atrophic mucosa of the fundus, and was diagnosed as a carcinoid tumor. Serological examination revealed a high level of anti-parietal-cell antibody, suggesting that the patient had chronic atrophic gastritis type A. The tumor was treated by endoscopic mucosal resection. Follow-up examinations were performed for 12 years, but showed no recurrence. This case confirms that gastric carcinoid tumors associated with chronic atrophic gastritis type A may have a good prognosis. Received: June 30, 2000 / Accepted: September 22, 2000     

右旋柠烯诱导人胃癌细胞凋亡

目的　探讨右旋柠烯 (D limonene)诱导人胃癌细胞株凋亡作用的机制。方法　采用噻唑蓝 (MTT)比色法、电镜、流式细胞术以及免疫细胞化学法 ,对p5 3和bcl 2在肿瘤细胞内的表达以及细胞凋亡的定性与定量指标进行检测。结果　经D limonene处理的BGC 82 3细胞出现核固缩 ,染色质边集 ,凋亡小体形成。凋亡细胞发生率与药物浓度呈正相关 ,即药物浓度为 0 .2 5 μg/ml(4 8h) ,凋亡细胞的发生率从 (2 .71± 0 .78) %上升至 (31.6 2± 7.81) %。经D limonene处理的BGC 82 3细胞内p5 3蛋白表达较对照组明显增加 ,bcl 2蛋白表达较对照组降低。结论　D limonene对人胃癌细胞的杀伤主要是通过诱导细胞凋亡 ,升提p5 3及降低bcl 2的蛋白表达为其诱发肿瘤细胞凋亡的机制之一。     

幽门螺杆菌感染和高胃泌素血症与结直肠癌的相关性研究

目的:探讨幽门螺杆菌(Helicobacter pylori)感染、高胃泌素血症和环氧合酶-2(cyclooxygenase-2,COX-2)与结直肠癌的相关性.方法:采用放射免疫分析法检测51例结直肠癌患者和43例非结直肠癌患者(对照组)血清中胃泌素的表达水平,ELISA法检测血清中抗幽门螺杆菌IgG的表达水平.给予结直肠癌患者口服塞来昔布6个月,分别于服药2、4和6个月时检测血清中胃泌素和抗幽门螺杆菌IgG的表达水平.结果:结直肠癌患者的幽门螺杆菌阳性率和血清胃泌素表达水平均明显高于对照组(P<0.05).结直肠癌患者血清中胃泌素的表达水平与抗幽门螺杆菌IgG的表达量显著相关(r=0.662,P<0.001).远端结肠与直肠癌患者幽门螺杆菌的阳性率显著高于近端结肠癌患者(P<0.05);同时,高胃泌素血症患者所占比率也明显高于近端结肠癌患者(P<0.05).此外,随着Duke分期的升高,幽门螺杆菌阳性率与高胃泌素血症患者所占比率均同步升高.口服塞来昔布后,结直肠癌患者血清中幽门螺杆菌阳性率和血清胃泌素的表达水平均呈下降趋势,并且随着服药时间的延长进一步下降. 结论:幽门螺杆菌感染诱导高胃泌素血症可能与结直肠癌的形成相关.选择性COX-2抑制剂塞来昔布可降低幽门螺杆菌阳性率和血清胃泌素的表达水平.     

塞来昔布诱导人胃癌细胞凋亡抑制新生血管形成

目的 探讨环氧合酶2(COX-2)抑制剂塞来昔布对人胃癌细胞增殖和新生血管形成的抑制作用.方法 将59例胃癌患者随机分为试验组(37例)和对照组(22例),试验组术前给予常规剂量塞来昔布,共7d,然后行手术治疗;对照组行单纯手术治疗.免疫组化法检测胃癌组织中COX-2和血管内皮生长因子(VEGF)的表达及微血管密度(MVD),DNA末端原位标记染色法检测胃癌细胞凋亡.以20例健康人作为正常对照.结果 试验组胃癌细胞凋亡率为7.1%±1.0%,显著高于对照组(6.2%±0.9%,P<0.05).试验组和对照组中,COX-2阳性表达分别为16例(43.2%)和17例(77.3%),VEGF阳性表达分别为17例(45.9%)和16例(72.7%),差异均有统计学意义(P<0.05).试验组MVD为30.48±5.02,显著低于对照组(38.98±4.58,P<0.05).结论 塞来昔布可诱导人胃癌细胞凋亡,抑制胃癌新生血管形成.     

Nuclear translocation of pro-amphiregulin induces chemoresistance in gastric cancer

Amphiregulin (AR) is derived from a membrane-anchored form (proAR) by ectodomain shedding, and is a ligand that activates epidermal growth factor receptor (EGFR). We have recently shown that proAR translocates from the plasma membrane to the nucleus after truncation of 11 amino acids at the C-terminus, which is independent of the conventional EGFR signaling pathway. Although proAR immunoreactivity has reportedly been detected in the nucleus of cancer cells, its biological meaning has never been investigated. This study was performed to investigate the roles of proAR nuclear translocation in human gastric cancer. We constructed proAR truncated 11 amino acids at the C-terminus (proARΔC11) that spontaneously translocates to the nucleus, and established proARΔC11-expression regulatable gastric cancer cells (MKN45, MKN28) using the tet-off system. Using these cells, we found that proAR nuclear translocation significantly induced chemoresistance in vitro and in vivo. Analyzing the relationship between immunoreactive localization of proAR and the clinical outcome for 46 advanced gastric cancer cases treated with chemotherapy, median survival time was 311 days in 16 patients with AR-positive staining in the nucleus and 387 days in 30 patients with AR-negative staining (P < 0.05). The present study demonstrates that proAR nuclear translocation increases resistance to anti-cancer drugs, which might be associated with poor prognosis in human gastric cancer.     

Extravasation of liposomal doxorubicin induces irritant reaction without vesicant injury

Anthracycline extravasation is an uncommon but very serious complication. Very few data are available in the literature concerning the consequences and the management of extravasation of liposomal doxorubicin. This report describes the cases of two patients with liposomal doxorubicin extravasation who developed irritant reaction without vesicant or necrotic lesions. It is concordant with other cases described in the literature and suggests that extravasation of liposomal doxorubicin can be relatively well tolerated. The process applied to extravasations of irritant and non-vesicant agents could be used to manage extravasations of liposomal doxorubicin.     

N-nitroso compounds, nitrite and pH in human fasting gastric juice

Total N-nitroso compounds, ethyl acetate-extractable N-nitrosocompounds and nitrite were measured in 146 samples of fastinggastric juice to investigate their relationship with pH. A positivecorrelation was found between pH and extractable N-nitroso compounds(r = 0.206, P < 0.02), whereas total N-nitroso compoundswere pH-independent It was inferred that pre-cancerous conditionsassociated with high gastric pH may be produced by an increasein the extractable N-nitroso compounds, which constitue onlya small fraction of the total gastric N-nitroso compounds.     

Promoter hypermethylation of tumor-related genes in gastric intestinal metaplasia of patients with and without gastric cancer

Promoter hypermethylation is an alternative mechanism of gene silencing in human cancers including gastric cancer. While intestinal metaplasia (IM) is generally regarded as a precancerous lesion of the stomach, our study examines the presence of gene promoter hypermethylation in IM of patients with and without gastric cancer. We examined 31 samples of gastric cancer, 36 gastric IM (21 associated with gastric cancer and 15 from noncancer patients) and 10 normal gastric biopsies. Tissues containing foci of IM were carefully microdissected from paraffin-embedded section. Bisulfite-modified DNA was examined for gene promoter hypermethylation in DAP-kinase, E-cadherin, GSTP1, p14, p15, p16, RASSF1A and hMLH1 by methylation-specific-PCR. None of the control gastric tissues had hypermethylation detected, but gene promoter hypermethylation was frequently detected in gastric cancer and IM. The mean number of methylated genes in cancer and IM was 3.0 and 1.4, respectively (p < 0.0001). Methylation in IM from cancer patients was all associated with concurrent methylation in the corresponding tumor samples. The numbers of methylated genes were similar in IM obtained from cancer and noncancer patients. By examining the methylation patterns of these genes, 3 differential methylation patterns were recognized: hypermethylation was more frequent in cancer than in IM (DAP-kinase, p14, p15 and p16); comparable frequencies of methylation in cancer and IM (E-cadherin and hMLH1); and no methylation (GSTP1). Aberrant methylation in tumor-related genes is frequently detected in gastric IM of both cancer and noncancer patients, suggesting their early involvement in the multistep progression of gastric carcinogenesis.     

Capsaicin reactivates hMOF in gastric cancer cells and induces cell growth inhibition

Capsaicin (CAP) is the major pungent component of chili pepper and is being evaluated for use against numerous types of tumors. Although CAP is indicated to target multiple signaling pathways, exact mechanisms of how it disturb cancer cell metablism remain obscure. Recent studies revealed Sirtuin 1 (SIRT1) serves as a potential target of CAP in cancer cells, indicating a direct regulation of cancer cell histone acetylation by capsaicin. The present study evaluated the effect of CAP on gastric cancer (GC) cell lines to understand the mechanism of cell growth inhibition. The results showed that CAP could significantly suppress cell growth, while altering histone acetylation in GC cell lines. Further studies found that hMOF, a major histone acetyltranferase for H4K16, is central to CAP-induced epigenetic changes. Reduced hMOF activity was detected in GC tissues, which could be restored by CAP both in vivo and in vitro. These findings revealed an important role of hMOF-mediated histone acetylation in CAP-directed anti-cancer processes, and suggested CAP as a potential drug for use in gastric cancer prevention and therapy.     

Hyperthermia induces differentiation without apoptosis in permissive temperatures in human erythroleukaemia cells

Purpose: The aim of the present study was to investigate whether induction of differentiation by hyperthermia is accompanied by apoptosis and necrosis to further evaluate the benefits of using hyperthermia as a differentiation inducing physical modality.

Materials and method: Differentiation was evaluated in K562 erythroleukaemia cells by measuring haemoglobin synthesis and flow cytometric measurement of glycophorin A expression. Apoptosis was measured by Annexin-V-FITC and Propidium Iodide (PI) double staining assay. Apoptosis and necrosis was also evaluated morphologically using staining with acridine orange/ethidium bromide (AO/EtBr) by fluorescence microscopy. Heat shock protein 70 (HSP70) level was measured by ELISA kit.

Results: Hyperthermia (43°C) induced differentiation as judged by increased haemoglobin synthesis and glycophorin A expression. No sign of apoptosis or necrosis could be detected at this temperature. Cell viability did not change due to heat treatment, and cellular proliferation was reduced in a dose (heating time) dependent manner. At 45°C, hyperthermia induced apoptosis and necrosis with minimal or no sign of differentiation. HSP70 level was significantly increased at 43°C along with differentiation of leukaemic cells, while at 45°C no significant effect on HSP70 production could be observed.

Conclusions: The encouraging results obtained here indicate that by heat treatment at 43°C, hyperthermia can be used alone or in combination with other modalities as a differentiation inducing agent without any detectable apoptotic activity. Positive correlation between HSP70 production and induction of differentiation and lack of apoptosis by hyperthermia confirm the possible role of HSP70 in the heat-induced differentiation and apoptosis in leukaemic cells.     

顺铂诱导胃腺癌细胞凋亡及非凋亡性死亡

目的：阐明顺铂诱导胃腺癌细胞死亡的方式并进一步探讨其分子机制。方法：MTT法检测细胞生存率；Annexin V-FITC流式细胞术检测细胞凋亡；PI流式细胞术检测细胞膜的完整性；吖啶橙染色后荧光显微镜下观察细胞酸性自噬泡（AVO）的形成；半定量RTPCR法检测p53、Noxa、Beclin 1的mRNA水平。结果：顺铂诱导胃腺癌细胞死亡具有剂量和时间依赖性，48h时IC50为3μg／mL；顺铂诱导后SGC7901细胞主要以凋亡方式死亡，而BGC-823细胞主要以非凋亡方式死亡；顺铂作用早期BGC823细胞膜的完整性就被破坏；顺铂诱导前后两种细胞AVO没有明显变化，并且两种细胞中自噬基因Beclin 1的表达水平都无显著增高；在对顺铂诱导的凋亡相对敏感的SGC-7901细胞系中，顺铂诱导后p53、Noxa的表达水平显著上调，而在不敏感的BGC823细胞系中p53、Noxa的表达水平变化不显著。结论：顺铂不但诱导胃腺癌细胞凋亡，而且诱导凋亡耐受的胃腺癌细胞非凋亡性死亡，后者可能是坏死；p53及其靶基因Noxa的活化可能是顺铂诱导SGC-7901细胞凋亡的棚．制之一．     

大蒜油诱导人胃癌细胞分化和凋亡的机制研究

目的从细胞和基因水平阐明大蒜油对人胃癌ＢＧＣ８２３细胞的作用机理。方法用激光扫描共聚焦显微镜及Ｎｏｒｔｈｅｒｎ杂交等技术进行分析。结果大蒜油对癌细胞形态、增殖和致瘤性有明显影响。结论大蒜油通过促进ｐ５３、ｐ２１等的表达,诱导肿瘤细胞分化,同时诱导肿瘤细胞凋亡。     

pseudo-G-Rh2 induces mitochondrial-mediated apoptosis in SGC-7901 human gastric cancer cells

This study was designed to investigate the effect of pseudo-G-Rh2, a novel metabolite of ginsenoside Rh2, on the apoptosis of SGC-7901 human gastric cancer cells. Pseudo-G-Rh2 demonstrated antitumor activity and significantly inhibited the proliferation of SGC-7901 cells in a concentration-dependent manner. After treatment with pseudo-G-Rh2, SGC-7901 cells showed typical apoptotic morphological features, such as chromatin condensation and DNA fragmentation. Pseudo-G-Rh2 could induce mitochondrial membrane potential loss, which led to the release of cytochrome c (Cyt?c), Smac/Diablo and apoptosis-inducing factor (AIF) to the cell cytoplasm. Furthermore, pseudo-G-Rh2 exposure not only decreased the expression of the Bcl-2 protein but also increased the expression of the Bax protein and the activities of caspase-9 and caspase-3 in SGC-7901 cells. These results demonstrated that pseudo-G-Rh2 inhibited the proliferation of SGC-7901 cells by initiating apoptosis. Pseudo-G-Rh2-induced apoptosis was associated with a drop in the mitochondrial transmembrane potential, down-regulation of Bcl-2, up-regulation of Bax and activation of caspase-9 and caspase-3.     

Duodenal reflux through the pylorus induces gastric adenocarcinoma in the rat.

We investigated whether duodenal reflux through the pylorus is involved in the development of gastric cancer. Male Wistar rats weighing 230-250 g were subjected to three types of operative procedures: (i) allowing reflux through the pylorus; (ii) allowing reflux through a gastrojejunal stoma; and (iii) gastrotomy. No carcinogens were given, and the animals were killed 50 weeks after surgery. No cancers were detected in any of the 18 animals with gastrotomy. In contrast, seven (41%) of 17 animals with reflux through the pylorus and four (31%) of 13 animals with reflux through the stoma had adenocarcinoma. Differences in the incidence between both reflux groups and the gastrotomy group were significant (P < 0.01 and P < 0.05 respectively). All of the adenocarcinomas developed in the pyloric mucosa near the pylorus in the animals with reflux through the pylorus, and in the oxyntic mucosa near the stoma in those with reflux through the stoma. Adenocarcinomas appeared as a polyploid mass with or without slight central erosion. Most of the adenocarcinomas were of the well-differentiated tubular type, and the others were of the mucinous type. No differences in either the histologic type or depth of invasion of the adenocarcinoma were recognized between the two duodenogastric reflux groups. Precancerous or paracancerous lesions, such as adenoma, adenocystic proliferation, and stomal pseudopyloric metaplasia, were more frequently found in the same region as the adenocarcinomas. These findings suggest that duodenogastric reflux in the rat has potent carcinogenic activities not only in the oxyntic mucosa through the stoma, but also in the pyloric mucosa through the pylorus.     

An acidic extracellular pH induces Src kinase-dependent loss of beta-catenin from the adherens junction

Little attention has been paid to the role of adherens junctions (AJs) in acidic extracellular pH (pHe)-induced cell invasion. Incubation of HepG2 cells in acidic medium (pH 6.6) induced cell dispersion from tight cell clusters, and this change was accompanied by downregulation of beta-catenin at cell junctions and a rapid activation of c-Src. Pretreatment with PP2 prevented the acidic pH-induced downregulation of beta-catenin at AJ and in the membrane fractions. The acidic pHe-induced c-Src activation increased tyrosine phosphorylation of beta-catenin and decreased the amount of beta-catenin-associated E-cadherin. The depletion of membrane-bound beta-catenin coincided with enhanced cell migration and invasion, and this acidic pHe-increased cell migration and invasion was prevented by PP2. In conclusion, this study characterizes a novel signaling pathway responsible for acidic microenvironment-promoted migration and invasive behaviors of cancer cells.     

The farnesyltransferase inhibitor Lonafarnib induces growth arrest or apoptosis of human lung cancer cells without downregulation of Akt

Farnesyltransferase inhibitors (FTIs) have been demonstrated to induce growth arrest or apoptosis independent of Ras mutation. Alternatively, Akt has been proposed as a potential target for the FTI's actions. This study investigated whether Lonafarnib was effective in inhibiting the growth of human nonsmall cell lung cancer (NSCLC) cells and elucidated the role of Akt in mediating such growth inhibitory effects. Lonafarnib, at clinical achievable concentration ranges, was effective in inhibiting the growth of 10 NSCLC cell lines, particularly after a prolonged treatment, regardless of Ras mutational status. Lonafarnib arrested cells growth at G(1) or G(2)/M phase in the majority tested cell lines. However it induced apoptosis when cells were cultured in a low serum (0.1%) medium. The majority of NSCLC cell lines expressed undetectable level of phosphorylated Akt (p-Akt). Lonafarnib at up to 10 muM did not decrease either total Akt level or p-Akt level in any of the tested cell lines, even after a 48 h treatment. Unexpectedly, Lonafarnib even increased p-Akt level in one cell line, although it was as sensitive as others to Lonafarnib treatment and underwent G(2)/M arrest. Bovine serum albumin completely rescued cells from Lonafarnib-induced apoptosis in low serum medium, indicating that proteins rather than cytokines or growth factors in serum masks Lonafarnib's pro-apoptotic effect. Therefore, we conclude that Lonafarnib is effective in inhibiting the growth of NSCLC cells either via growth arrest or induction of apoptosis without downregulation of Akt.