Altered Expression of E-cadherin by Hepatocyte Growth Factor and Effect on the Prognosis of Nasopharyngeal Carcinoma

Background and Purpose  

Hepatocyte growth factor (HGF)-related E-cadherin expression and prognosis of patients with nasopharyngeal carcinoma (NPC) are not fully understood. This study investigated HGF-induced altered expression of E-cadherin and the relationship between prognosis and modulation of E-cadherin by HGF in NPC.     

Elevated Hepatocyte Growth Factor Levels at the Beginning of High-Flux Hemodialysis Are Due to Heparin Administration

Background. It has been reported that hemodialysis (HD) stimulates hepatocyte growth factor (HGF) release, but it is not clear if this stimulation is due to HD itself or to heparin used during HD. To clarify this issue, we undertook the present study. Methods. We studied 18 HD patients using high-flux dialyzers, during a single 4-hr hemodialysis session (session A). The dialyzers were pre-rinse with normal saline without heparin, and HD was started with zero ultrafiltration and without anticoagulation. Anticoagulation was administered as IV injection (80 IU/kg of LMWH enoxaparin sodium) 10 min after the beginning of HD. HD was continued for 10 more minutes and then as prescribed. HGF serum levels were measured before the beginning of the HD session (sample t0) as well as 10 and 20 minutes after the beginning of the session (samples t10 and t20). In six more patients (controls), the same study was repeated but without the administration of LMWH during the first 20 min of HD initiation (session B). Results. In comparison with t0, t10 HGF serum levels changed significantly in neither session A nor in session B. However, at t20, HGF levels increased significantly in session A compared with t0 (increment 666.3 ± 211.0%, p < 0.0001) and t10 (increment 894.2 ± 506.0%, p < 0.0001), but not in session B. No differences were found between sessions A and B at samples t0 and t10 (p?=?NS). HGF serum levels at t20 in session A were found to be higher compared with corresponding levels in session B (p < 0.0001). Conclusion. Elevated HGF serum levels at the beginning of high-flux HD session are due to LMWH administration.     

参附注射液对单侧输尿管梗阻大鼠肾脏肝细胞生长因子表达的影响

目的：探讨单侧输尿管梗阻后大鼠肾间质纤维化发生过程中肝细胞生长因子（HGF）的表达及中药参附注射液对其的影响。方法：采用单侧输尿管结扎（UUO）制造梗阻性肾病模型，将56只大鼠随机分为对照组（假手术组）、手术组（UUO组）和治疗组（UUO＋参附），术后7d、14d观察肾组织病理改变，应用免疫组织化学方法检测肾组织中HGF的表达。结果：与对照组相比，手术组肾间质出现了明显的纤维化，HGF的表达在术后第7天明显增加，第14天较第7天减弱，与手术组相比，治疗组肾间质纤维化明显减轻，而且HGF的表达在术后第7天明显上调，第14天较第7天上调更明显，有统计学差异（P〈0．05）。结论：参附注射液可以上调肾组织HGF的表达，减轻肾小管一间质纤维化，发挥肾保护作用。     

Sentinel Node Concept in Clinically N0 Laryngeal and Hypopharyngeal Cancer

Background  Sentinel nodes (SNs) are the lymph nodes that directly receive lymphatic flow from a primary cancer lesion. The SN concept implies that lymphatic metastasis initially occurs at SNs. SN navigation surgery can be introduced for cancers in which the SN concept is established. In SN navigation surgery, lymph node dissection beyond SNs can be omitted if SNs are metastasis free. Although the SN concept has been investigated frequently for oral and oropharyngeal cancer, it has so far been investigated less for laryngeal and hypopharyngeal cancer. In this study, we investigated whether the SN concept is applicable for laryngeal and hypopharyngeal cancer. Methods  Twenty patients with T2–T4 and clinically N0 laryngeal and hypopharyngeal cancer were recruited. ^99mTc-phytate was injected into several sites surrounding the tumor on the day before surgery. Lymphoscintigrams were acquired from at least two different viewpoints. SNs were surveyed intraoperatively, and neck dissections including at least levels II, III, and IV were performed. Results  SNs had occult metastases in five cases. In the remaining 15 cases, neither SNs nor other lymph nodes contained metastases, consistent with the SN concept. There was one false-negative case showing delayed nodal metastasis 2 years after initial surgery. The overall accuracy of the SN concept was 95%. Conclusion  Our study shows that SN biopsy is a reliable strategy to determine correct lymph node status in N0 laryngeal and hypopharyngeal cancer. SN detection was valuable in evaluating the need for neck dissection, whether ipsilaterally or bilaterally. Presented at the 2004 Annual Meeting of the American Academy of Otolaryngology, New York.     

Significant Correlation between Serum Level of Hepatocyte Growth Factor and Progression of Gastric Carcinoma

Hepatocyte growth factor (HGF) can promote proliferation of many types of tumor cells including gastric cancer cells. To study the role of HGF in the progression of gastric carcinoma, HGF levels were measured by an enzyme immunoassay (EIA) system in sera of gastric cancer patients and followed up the levels after the operation. The mean serum HGF level in 212 healthy control subjects, 140 patients with primary gastric cancer, and 13 patients with recurrent gastric cancer were 0.199 ± 0.073, 0.325 ± 0.209, and 0.578 ± 0.258 ng/ml, respectively. The increase of the levels was significantly correlated with the progression of tumor stage. The levels decreased to normal levels 1 month after curative resection of the tumors. However, the levels did not decrease significantly in nonresected cases. During the follow-up of the patients for several months, the level was significantly increased in recurrent gastric cancer patients, whereas there was no increase in nonrecurrent patients. In conclusion, the serum HGF levels significantly correlated with the aggressiveness of the tumors, suggesting an important role of HGF in the progression of gastric carcinoma.     

HGF/SF对姜黄素诱导大肠癌细胞凋亡的作用

目的 观察肝细胞生长因子／离散因子（HGF／SF）在姜黄素诱导的大肠癌细胞凋亡中的作用。方法 采用MTT法分析姜黄素对大肠癌细胞的抑制作用；流式细胞术评价HGF抗凋亡作用。结果不同浓度姜黄素作用Caco2细胞后发现，只在64μg／ml浓度发挥作用，即抑制细胞增殖；而同时加入不同浓度的HGF后可以拮抗姜黄素引起的Caco-2细胞生长的抑制作用，但HGF发挥作用无浓度依赖关系。流式细胞术检测结果发现，姜黄素只在64μg／ml浓度下诱导Caco-2细胞凋亡，在加入不同浓度HGF后，凋亡明显减少，但并无剂量依赖关系。MAPK途径在HGF拮抗姜黄素诱导的Caco-2细胞凋亡中的作用发现，阻断p42／p44MAPK和p38MAPK后，并不影响HGF对Caco-2细胞凋亡的保护作用。结论 HGF拈抗姜黄素诱导的Caco-2细胞凋亡，MAPK信号传导途径可能不参与此过程。     

Differential Expression of Hepatocyte Growth Factor in Papillary and Nodular Tumors of the Bladder

Background: The aim of this study was to investigate the expression of hepatocyte growth factor (HGF) and its receptor (c-met) during bladder tumorigenesis.
Methods: HGF and c-met expression were analyzed immunohistochemically in matched samples of normal, dysplastic, and carcinoma specimens from 49 human bladders resected at the time of radical cystectomy for nonmetastatic transitional cell carcinoma (TCC). The tumors were composed of papillary (n = 22), nodular (n = 16) or mixed papillary and nodular (mixed; n = 11) components. Results: The normal urothelium showed no significant immunoreactivity to HGF. Expression of HGF was observed in 45.5%, 77.3% and 90.9% of specimens demonstrating mild, moderate, and severe dysplastic lesions adjacent to papillary TCCs, respectively, whereas all of the papillary TCC samples were positive for HGF. No immunoreactivity for HGF was found in dysplastic lesions from nodular tumors, and only 2 specimens had positive immunostainingfor HGF in the tumor areas (1 showed weak immunostainingand 1 showed HGF immunostainingonly in the deeper invasive compartment). Additionally, 3 nodular lesions taken from mixed tumors showed weak immunostaining for HGF while the concurrent papillary lesions were HGF-positive. There was a significant difference of HGF immunoreactivity between papillary and nodular tumors (P < 0.01). c-met immunostaining was consistently detected in all specimens. HGF and c-met immunoreactivity did not significantly correlate with tumor stage and grade, nor with overall patient survival irrespective of the tumor growth pattern.
Conclusion: These results suggest that HGF expression may play a significant role in the development of papillary TCC.     

Regulation of lnvasive Potential of Human Prostate Cancer Cell Lines by Hepatocyte Growth Factor

Background: The growth and progression of prostate cancer depends on the stromal-epithelial interaction which is under paracrine control. Hepatocyte growth factor (HGF), produced by mesenchymal cells, is a multifunctional growth factor stimulating the movement and growth of epithelial cells including cancer cells. We therefore assessed the relationship between the invasive potential of prostate cancer and HGF in vitro.
Methods: Three human prostate cancer cell lines were used including PC-3 and DU145 (androgenindependent), and LNCaP (androgen-dependent). We studied the expression of the HCF receptor c-met proto-oncogene (c-met) by Western blotanalysis, and alsodetermined theeffectsof HGF on cell scattering, and the mechanisms of invasion and proliferation, by microscopic observation, the matrigel invasion chamber assay, and the MTT assay.
Results: c-met was detected in PC-3 and DU145 cells, but not in the LNCaP cells. There was increased cell motility in the scatter assay and an increased cell invasive potential in the matrigel invasion chamber assay by stimulation with HGF only with DU145 cells.
Conclusion: HGF plays an important role in the invasion and metastasis of the DU145 cell line through a paracrine mechanism mediated by the c-metreceptor. In the PC-3 cell line, the lack of downstream signal transduction after the c-met receptor is suggested.     

Altered E-Cadherin Expression and p120 Catenin Localization in Esophageal Squamous Cell Carcinoma

Background E-cadherin is a well-known tumor suppressor and its dysregulated expression correlates with tumor differentiation, metastasis and survival in esophageal squamous cell carcinoma (ESCC). p120 catenin is an Armadillo protein normally bound to E-cadherin in the cadherin–catenin complex at the adherens junction. Dysregulated expression and mislocalization of p120ctn affect the protective function of the complex. The objective of the present study was to evaluate the clinical significance of E-cadherin and p120ctn expression in ESCC. Methods Immunohistochemistry was performed to investigate the expression of E-cadherin and p120ctn proteins in 71 patients with ESCC. The relationships between protein expression and clinicopathological characteristics were analyzed. Results Reduced E-cadherin and p120ctn expressions were observed in 42.3% and 8.5% of ESCC cases, respectively. Reduction of membranous p120ctn was observed in 33.8% of cases. Membranous E-cadherin was preserved when p120ctn co-localized on the membrane of tumor cells (72.3%, P = 0.001). High level E-cadherin expression and membranous p120ctn preservation positively correlated with tumor differentiation (P = 0.001 and P = 0.008, respectively). p120ctn expression was also significantly related to lymph node metastasis (P = 0.003). Heterogeneous expression of both E-cadherin and p120ctn was observed in dysplasia. Conclusions Altered E-cadherin expression and p120ctn localization were related to tumor differentiation, indicating their important roles in the pathogenesis of ESCC.     

Prognostic Value of Epithelial Growth Factor Receptor,Vascular Endothelial Growth Factor,E-Cadherin,and p120 Catenin in Resected Non-Small Cell Lung Carcinoma

IntroductionSeveral markers have been investigated to predict the prognosis of lung cancer. In the present study, the prognostic values of epithelial growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), E-cadherin, and p120 catenin expression were investigated by immunohistochemistry in patients with a surgically resected non-small cell lung carcinoma (NSCLC).Patients and methodEGFR, VEGF, E-cadherin, and p120 catenin expression were prospectively determined in resected specimens from patients with NSCLC who had undergone surgery between 2003 and 2007. Patients’ and disease-related general characteristics and survival rate were recorded.ResultsOne hundred seventeen patients with a mean age of 61.3 years were included in the study. After a mean follow-up of 27.5 months, the median survival was determined to be 44.0 months and the 5-year survival was 46.2%. The 5-year survival in negative and positive staining groups were as follows; 32% and 66.7% for EGFR (P=.02), 37.8%, and 50.7% for VEGF (P=.5), 41% and 66% for E-cadherin (P=.19), and 46% and 50% for p120 catenin (P=.27). The differentiation, N status, stage, and EGFR staining were variables significantly affecting survival (P=.001, .006, .03, and .02, respectively). In multivariate Cox analysis, the EGFR staining level and N status were variables those significantly affecting survival (P=.021 and P=.010).ConclusionsWhile negative staining of EGFR was related with poor survival, staining of VEGF, E-cadherin, and p120 catenin were not related with survival in patients with resected NSCLC.     

Expression of Hepatocyte Growth Factor Activator Inhibitor Type 1 in Human Hepatocellular Carcinoma and Postoperative Outcomes

Background  

Hepatocyte growth factor activator inhibitor type 1 (HAI-1), one of the Kunitz-type serine protease inhibitors, has an important role in cancer progression through regulation of the activity of hepatocyte growth factor. HAI-1 is expressed in hepatocellular carcinoma (HCC) to various degrees. Investigation of the relationship between HAI-1 expression and clinicopathological features of HCC may contribute to improved treatment outcomes for HCC through understanding the mechanism of tumor progression or improvement in the prediction of tumor malignancy.     

E-钙黏蛋白在肝细胞癌中的表达及临床意义

目的　探讨E -钙黏蛋白 (E -Cad)在肝细胞癌中的表达及其与临床特性之间的关系。方法　采用免疫组化sABC法和E -Cad抗体对 40例肝细胞癌及其相应癌旁组织中的E -Cad的表达进行研究。结果　肝癌组织中E -Cad表达阳性率为 3 0 % ,癌旁组织阳性率表达为93 .3 % ,两者差异有显著性 (P <0 .0 1)。E -Cad的表达与癌TNM分期密切相关 (P <0 .0 1) ,与肿瘤分级有无门静脉癌栓、有无包膜相关 (P <0 .0 5 ) ,与年龄、肿瘤大小无关 (P >0 .0 5 )。结论　E -Cad表达对评价肝细胞癌临床分期有重要意义。检测E -Cad可以判断肝细胞癌生物学行为。     

Prognostic Impact of Surgical Complications and Preoperative Serum Hepatocyte Growth Factor in Hepatocellular Carcinoma Patients After Initial Hepatectomy

Introduction  The relationship between postoperative complications and survival after hepatectomy is not completely understood. The purpose of this study was to determine if surgical complications would have a prognostic impact and to identify any difference of the prognostic factors between a complication group and complication-free group for hepatocellular carcinoma (HCC) patients after initial hepatectomy. Patients and Methods  One hundred consecutive HCC patients were analyzed in this study. Operative variables and liver functional markers were compared between the complication group and complication-free group. The diagnostic accuracy for predicting complications was evaluated by the receiver operating characteristic (ROC) curve. The Kaplan–Meier method with log-rank test was employed for survival analysis. Univariate and multivariate analyses were performed to identify the prognostic factors in each group. Results and discussion  A total of 45 complications in 32 patients were observed according to the modified Clavien classification. The albumin, γ-glutamyl transferase, choline esterase, indocyanine green retention rate at 15 min (ICGR₁₅), hyaluronic acid, prealbumin, hepatocyte growth factor (HGF), HH15, and LHL15 levels before hepatectomy, operative time, and blood loss were significantly different between the two groups. Multivariate analysis revealed that γ-glutamyl transferase, ICGR₁₅, and HGF were independent risk factors for postoperative complications. The values of the areas under the ROC curve for predicting complications proved the significance of the predictions. Although the recurrence-free survival rates were not significantly different, the overall survival rates were significantly different between the two groups. Univariate and multivariate analyses for the overall survival rate showed that the stage of the HCC and HGF for the complication group and tumor size for the complication-free group were independent prognostic factors for overall survival. Conclusion  Postoperative surgical complications could have a prognostic impact on overall survival in HCC patients after initial hepatectomy. Serum HGF could be a factor connected to complications and survival in this group.     

Therapeutic Angiogenesis Induced by Injecting Hepatocyte Growth Factor in Ischemic Canine Hearts

Purpose Therapeutic angiogenesis, induced by the direct injection of angiogenic growth factors or by transmyocardial laser revascularization (TMLR), has shown great potential as a new therapeutic strategy for end-stage coronary artery disease. However, no significant differences in angiogenic effects of TMLR and vascular endothelial growth factor (VEGF) have been reported. We compared the effects of the intramyocardial injection of hepatocyte growth factor (HGF), a novel angiogenic factor, with those of TMLR, by evaluating the improvement in regional blood flow and regional function in a canine heart model of chronic ischemia.Methods To create a model of chronic ischemia, we ligated the left anterior descending artery (LAD) in 15 beagles. We divided the dogs into three groups according to the treatment given 1 month after ligation. Four dogs were given an intracardial injection of human recombinant HGF (H group), six dogs were given TMLR (T group), and five dogs were used as a control (C group). We compared the degree of improvement in regional blood flow and regional function 1 month after the treatment.Results The regional myocardial blood flow and function were significantly better in the H group than in the T or C groups (P < 0.05). Histologically, there were significantly more von Willebrand factor-positive cells in the LAD region in the H group than in the T or C groups.Conclusion The intramural injection of recombinant human HGF resulted in therapeutic angiogenesis with an intrinsic contractile state, and it may have greater advantages than TMLR for the treatment of chronic ischemic heart disease.     

Preventive Effect of Fibroblast Growth Factor and Hepatocyte Growth Factor on Ceramide‐Induced Dysfunction Human Small Intestinal Cells

Aim:  To investigate whether TNF‐ is necessary for hepatocyte proliferation, we study liver regeneration after partial hepatectomy in mice lacking TNF receptor‐1.
Methods:  TNF receptor type‐1 knockout mice and wild‐type mice were subjected to two‐thirds partial hepatectomy (PHx). Liver regeneration was evaluated by assessing liver weights and Ki67 immunohistochemistry. Riken cDNA microarray analysis was performed on liver samples from mice undergoing PHx to compare clearly differentiated mouse PHx models (TNFR‐1 knockout mice‐K group, and wild type mice‐W group).
Results:  The cumulative survival after PHx in K group was lower than in W group. The mortality rate in K group during the first 3 days after PHx was higher (33%) than in W group. The time to regain the liver weight in K group was 14 days and 7 days in W group. The plasma IL‐6 levels in K type at 3 hr was significantly higher than in W group. The Ki67 expression in K group at 4 days was lower than in W group. LPS, Toll like receptor 4 precursor and MAPK 8 interacting protein in K group was higher than in W group. For cell cycle‐regulated genes, cyclin D1, NFB light chain and TNF receptor super family membrane 1a in K group was lower than in W group.
Conclusions:  Lack of TNF‐ signaling through TNF receptor type 1 suppresses liver regeneration after partial hepatectomy in spite of enhancement of LPS–JNK pathway, no TNF‐a and IL‐6 pathway.     

Tubulointerstitial Lesions in IgA Nephropathy and Localization of Hepatocyte Growth Factor

To investigate the relationship between localization of hepatocyte growth factor (HGF) and tubulointerstitial lesions (TILs) in the cortical area of renal biopsy specimens, a clinicopathological study was performed in 55 patients with IgA nephropathy. HGF was detected by an enzyme-antibody method and TILs were assessed semiquantitatively by light microscopy. HGF was observed mainly on epithelial cells in the tubules, but not in the glomeruli. Fourteen patients had biopsies that were positive for HGF. There was a correlation between HGF positivity and histological damage, the TIL grade, and several clinical parameters determined at biopsy. Thus, HGF is related to TILs in IgA nephropathy and may be a factor in the exacerbation of this disease.     

Expression of the Vascular Endothelial Growth Factor and Angiopoietins in Mucoepidermoid Carcinoma of Salivary Gland

Disrupted coordination of angiogenesis regulating signals, among them the vascular endothelial growth factor (VEGF) and angiopoietins (Angs), has been associated with abnormal angiogenesis and tumor progression. While VEGF induces endothelial cell proliferation, thereby initiating vessel formation, Angs are subsequently required for mural cell attachment, thus influencing remodeling and maturation of this vasculature. In addition to tumor cell, endothelial and mural cells, as well as myofibroblasts may also contribute to the secretion of these factors. In this study, we have analyzed by immunohistochemistry the expression of VEGF, Ang-1, Ang-2 and the Angs receptor Tie2 in both the stroma and tumor cells of mucoepidermoid carcinoma (MEC) of salivary gland. We have demonstrated that when myofibroblasts were detected adjacent to the cancer cells, they were frequently associated with intense positive staining for Ang-1 and Ang-2, and no reactivity to VEGF and Tie2. These myofibroblast-rich Ang-1 and Ang-2-stained areas were more commonly found in high-grade MEC cases than in low-grade ones. As for the malignant cells, they frequently expressed all proteins studied, but Ang-2 and VEGF were detected at higher levels compared to Ang-1 and Tie2. Our results indicate that the MEC environment favors cooperative activity between Angs and VEGF in modulating vascular growth and tumor aggressiveness.