Sulforaphane is a chemopreventive agent present in various cruciferous vegetables, including broccoli. Here, we show that treatment with tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL) in combination with subtoxic doses of sulforaphane significantly induces rapid apoptosis in TRAIL-resistant hepatoma cells. Neither TNF-A-nor Fasmediated apoptosis was sensitized in hepatoma cells by cotreatment with sulforaphane, suggesting that sulforaphane can selectively sensitize cells to TRAIL-induced apoptosis but not to apoptosis mediated by other death receptors. We found that sulforaphane treatment significantly up-regulated mRNA and protein levels of DR5, a death receptor of TRAIL. This was accompanied by an increase in the generation of reactive oxygen species (ROS). Pretreatment with N-acetyl-Lcysteine and overexpression of catalase inhibited sulforaphane-induced up-regulation of DR5 and almost completely blocked the cotreatment-induced apoptosis. Furthermore, the sulforaphane-mediated sensitization to TRAIL was efficiently reduced by administration of a blocking antibody or small interfering RNAs for DR5. These results collectively indicate that sulforaphane-induced generation of ROS and the subsequent up-regulation of DR5 are critical for triggering and amplifying TRAIL-induced apoptotic signaling. We also found that sulforaphane can sensitize both Bcl-xL-and Bcl-2-overexpressing hepatoma cells to TRAIL-induced apoptosis, indicating that treatment with a combination of TRAIL and sulforaphane may be a safe strategy for treating resistant hepatomas. (Cancer Res 2006; 66(3): 1740-50)
Liver cirrhosis is characterized by hepatic dysfunction with extensive accumulation of fibrous tissue in the liver. In response to chronic hepatic injury, hepatic portal myofibroblasts and activated hepatic stellate cells (HSCs) play a role in liver fibrosis. Although administration or gene expression of hepatocyte growth factor (HGF) leads to improvement in hepatic fibrosis/cirrhosis, the related mechanisms are not fully understood. We investigated mechanisms involved in resolution from liver cirrhosis by HGF, focusing on growth regulation and apoptosis in portal myofibroblasts. Cultured rat HSCs could not proliferate, were withdrawn after passage, and were replaced by proliferating portal myofibroblasts during the passages. In quiescent HSCs, c-Met receptor expression was undetected whereas c-Met receptor expression was detected in activated HSCs and liver myofibroblasts expressing alpha-smooth muscle actin (alpha-SMA), suggesting that activated HSCs and portal myofibroblasts are targets of HGF. For cultured rat portal myofibroblasts, HGF counteracted phosphorylation of extracellular signal-regulated kinase (Erk) 1/2 and mitogenic stimulus induced by platelet-derived growth factor, induced c-jun N-terminal kinase (JNK) 1 phosphorylation, and promoted apoptotic cell death. In the dimethylnitrosamine rat model of liver cirrhosis, administration of HGF suppressed proliferation while promoting apoptosis of alpha-SMA-positive cells in the liver, events that were associated with reduced hepatic expressions of alpha-SMA and histological resolution from liver cirrhosis. Growth inhibition and enhanced apoptosis in portal myofibroblasts by HGF are newly identified mechanisms aiding resolution from liver fibrosis/cirrhosis by HGF.
Objectives. This study was designed to provide safe management guidelines for ampullary adenoma by analysis of clinicopathological features. Background. The treatment of ampullary cancer has been established; however, the indications for treatment of ampullary adenoma remain controversial. Methods. Between July 1997 and July 2008, a total of 33 patients were diagnosed with ampullary adenoma prior to procedures: 20 endoscopic papillectomies (ESP), 5 transduodenal resections (TDR), and 8 pancreatoduodenectomies (PD). Results. The false-negative rate of biopsy for cancer was 27.5% (8/29). Coexistence of cancer in patients with prehigh-grade dysplasia (HGD) was 50.0% (5/10), whereas it was 15.7% in pre-low-grade dysplasia (LGD). In addition, the rate of recurrence was 80% (8/10) in patients with pre-HGD. The size of tumor by final pathology was 1.27 ± 0.89 cm in LGD, 1.81 ± 0.99 cm in HGD, and 1.98 ± 1.08 cm in cancer group. There was a significant correlation between size of tumor and final pathology (P = 0.036). According to receiver operating characteristic (ROC) curve, criterion to predict HGD/cancer was tumor size larger than 1.5 cm; sensitivity and specificity were 55.6% and 80.0%, respectively, and likelihood ratio was 2.778. However, size of tumor was not associated with preprocedural pathology. Conclusions. Ampullary adenoma with preprocedural HGD was highly associated with coexistence of cancer and recurrence. Moreover, most of large tumors were treated by surgical procedures and proved to be cancer. Therefore, we suggest that ampullary adenoma with preprocedural HGD or more than 1.5 cm should not be managed with endoscopic papillectomy due to high associated rates of recurrence.Since 1935, pancreatoduodenectomy (PD) has been used as the treatment of choice for periampullary tumors.1,2 For the treatment of ampullary cancer, Beger et al. reported that oncological resection of ampullary cancer by means of PD is the surgical procedure of choice; the 3-and 5-year survival rates were 72% and 52%, respectively.3 Moreover, Yoon et al. reported that PD should preferably be performed even in early ampullary cancer. 4 The management criteria for ampullary cancer have already been established.As a noninvasive treatment, transduodenal resection (TDR) is usually indicated in patients with high operative risk.3 However, most surgeons have no great desire to try local resection of ampullary tumors, because of high recurrence rate and lack of established management criteria. Recently, endoscopic papillectomy (ESP) has been accepted as an alternative therapy to surgery in ampullary adenoma. According to some studies, the tumor size criterion for endoscopic papillectomy is up to 4-4.5 cm. [5][6][7] Nevertheless, ampullary adenoma is considered as a precancerous lesion, and the rate of development of carcinoma has been shown to be 30%. 8 Moreover, the coexistence of carcinoma within adenoma cannot be excluded by preprocedural biopsy. 9,10 As described above, the management strategies for ampulla adenoma are expanding...
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