Ming-Hsun Wu

Elevated Expression of Cyr61 Enhances Peritoneal Dissemination of Gastric Cancer Cells through Integrin α2β1

Cysteine-rich 61 (Cyr61/CCN1) is involved in human gastric cancer development and progression. Nonetheless, the role of Cyr61 as regards peritoneal dissemination of such cancers has not yet been completely characterized. We used liposome-mediated transfection to establish Cyr61, or antisense Cyr61, expression vectors into gastric cancer AGS or MKN45 cell lines. Transfectants were tested by means of a cancer-cell adhesion assay in vitro and ex vivo. Furthermore, a functional integrin fluorescence-activated cell sorting assay, reverse transcription-PCR, and an AP-1 reporter assay were performed to investigate the potential signaling pathway of Cyr61. It was shown that stable transfection of Cyr61 into the AGS cell line strongly enhanced its adhesion ability. The overexpression of Cyr61 within AGS cells significantly increased the functional expression of integrin α2β1. Function-neutralizing antibody to integrin α2β1 effectively suppressed the Cyr61-mediated enhanced adhesion of AGS cells to peritoneal tissue. Promoter assays of integrin α2 gene further revealed that the AP-1 pathway was evidently activated within Cyr61-expressing AGS cells. Animal studies have revealed that mice injected with Cyr61-overexpressed AGS cells featured a greater number of peritoneal seeding nodules and a lower survival rate than the Neo control cell lines, and when such cells were treated with functional blocking antibody to integrin α2β1, they were able to elicit a decline in the peritoneal dissemination. The data suggest that Cyr61 may contribute to the peritoneal dissemination of gastric cancer by promoting tumor-cell adhesion ability through the up-regulation of the functional integrin α2β1 via an AP-1-dependent pathway.

Cysteine-Rich 61 (CCN1) Enhances Chemotactic Migration, Transendothelial Cell Migration, and Intravasation by Concomitantly Up-Regulating Chemokine Receptor 1 and 2

Cysteine-rich 61 (Cyr61; CCN1) plays an important role in tumor development and progression in many kinds of human malignancies. Here, we further show the enforced expression of the Cyr61 gene or treatment with recombinant Cyr61 protein enhanced expression of chemokine receptors CXCR1 and CXCR2 in gastric cancer AGS cells. Attenuation of Cyr61 levels in MKN-45 cells by transfecting with antisense Cyr61 significantly reduced the level of CXCR1 and CXCR2. It is suggested that Cyr61 tightly regulates the downstream genes CXCR1 and CXCR2 in gastric cancer cells. Supportively, reverse transcription–PCR and immunohistochemical analysis of human gastric adenocarcinoma showed that there was a high correlation between the expression level of Cyr61 and CXCR1/CXCR2. The up-regulated functionality of CXCR1 andCXCR2 in Cyr61-overexpressing AGS cells could facilitate their chemotactic migration toward interleukin-8, a physiologic ligand of CXCR1 and CXCR2. In addition, the Cyr61-mediated up-regulation of CXCR1/CXCR2 also contributed to transendothelial migration, as well as intravasation in a chick embryo model. Pharmacologic and genetic approaches revealed that phosphoinositide 3-kinase (PI3K)/Akt, but not extracellular signal-regulated kinase 1/2 or p38, signaling pathway is requisite for the up-regulation of CXCR1/CXCR2 mRNA and protein induced by Cyr61. Function-neutralizing antibody to integrin αvβ3, but not α2β1, effectively abolished Cyr61-elicited Src activation and the subsequent PI3K/Akt pathway. Antagonists toward integrin αvβ3, Src kinase, and PI3K/Akt not only suppressed CXCR1/CXCR2 elevation but also blocked chemotactic migration induced by Cyr61. In conclusion, we suggest that Cyr61 promotes interleukin-8–dependent chemotaxis, transendothelial migration, and intravasation by induction of CXCR1/CXCR2 through integrin αvβ3/Src/PI3K/Akt–dependent pathway. (Mol Cancer Res 2007;5(11):1111–23)

Home Parenteral Nutrition Support in Adults: Experience of a Medical Center in Asia

BACKGROUND Parenteral nutrition (PN) support is mandatory in patients with gut failure. Short bowel syndrome is a term used for symptoms and pathophysiological disorders brought about by the removal or malfunction of a large portion of the small bowel. Inflammatory bowel disease, vascular disease, and malignancy are the most common causes of short bowel syndrome in adults. There are many complications associated with chronic use of PN. Cholestasis, nutrient deficiency, small bowel bacterial overgrowth, and catheter-related infections were noted in these patients. Due to the various etiologies, we tried to find the optimal method to manage these patients. METHODS We reviewed all patients over 16 years old, from 1989 to 2002, who required home PN support for at least 30 days. Charts were reviewed to obtain information regarding demographics, nutrition management, outcome, and complications related to PN. Survival was estimated by using the Kaplan-Meier method. The association of survival with primary disease, length of small bowel, age, and gender was assessed by proportional hazard regression analysis. RESULTS There were 31 patients who needed home PN support during this period, 14 male and 17 female. The average age was 55 (median age, 53; range, 28-88); the average period of PN administration was 19 months (median, 7; range, 1-115 months). The most common indications for home PN were alimentary tract obstruction and short bowel syndrome. Most deaths were related to their original diseases and catheter-related sepsis. Malignant diseases were a major indication for home PN (HPN). However, 20% of these patients with incurable diseases lived longer than 1 year. The disease patterns were different from those in western societies. Most patients had malignancies and vascular insults in our series. There was much less inflammatory bowel disease in our patients than in western countries; catheter-related infections were frequent and caused 25% of mortality. CONCLUSIONS HPN is very important to patients with intestinal failure or who are waiting for recovery from temporal intestine insufficiency. Even in malignant diseases, a significant number of patients survived for >1 year with treatment of HPN. Most complications related to their underlying diseases and associated infections. Improving patient education and treatment might improve the prognosis of these patients and expand the application of this technique to help more patients with small intestine failure.

Prognostic significance of extranodal extension of regional lymph node metastasis in papillary thyroid cancer

The presence and location of regional lymph node metastasis affect the prognosis of patients with thyroid cancer. Lymph node classification of the current TNM system may be inadequate because it insufficiently characterizes the nature and severity of lymph node metastasis that may influence prognosis.

Eicosapentaenoic acid and docosahexaenoic acid inhibit macrophage-induced gastric cancer cell migration by attenuating the expression of matrix metalloproteinase 10.

Uptake of docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) improves the treatment of cancer and reduces tumor-associated macrophage count. However, the mechanism of this relationship is still unclear. In this study, macrophages enhanced gastric cancer cell migration ability and induced the differentially expressed matrix metalloproteinase genes (MMP1, MMP3 and MMP10) of N87 as identified by polymerase chain reaction array. Furthermore, DHA and EPA inhibited macrophage-enhanced cancer cell migration and attenuated MMP10 at both the RNA and protein level. The suppression of MMP10 expression was further verified by zymography and antibody blocking experiments. Additionally, DHA and EPA attenuated expression of macrophage-activated extracellular-signal-regulated kinase (ERK) and signal transducers and activators of transcription 3 (STAT3) in cancer cells. Attenuation was verified by demonstrating blockade with specific inhibitors and thereby increased MMP10 expression. Accordingly, we hypothesized that macrophage enhances cancer cell migration through ERK and STAT3 phosphorylation and subsequent increased MMP10 expression and that DHA and EPA could attenuate these signals. These findings not only explain the beneficial effects of DHA/EPA, but also point to ERK/STAT3/MMP10 as the potential targets for gastric cancer treatment.

Glutamine Supplementation Attenuates Expressions of Adhesion Molecules and Chemokine Receptors on T Cells in a Murine Model of Acute Colitis

Background. Migration of T cells into the colon plays a major role in the pathogenesis in inflammatory bowel disease. This study investigated the effects of glutamine (Gln) supplementation on chemokine receptors and adhesion molecules expressed by T cells in mice with dextran sulfate sodium- (DSS-) induced colitis. Methods. C57BL/6 mice were fed either a standard diet or a Gln diet replacing 25% of the total nitrogen. After being fed the diets for 5 days, half of the mice from both groups were given 1.5% DSS in drinking water to induce colitis. Mice were killed after 5 days of DSS exposure. Results. DSS colitis resulted in higher expression levels of P-selectin glycoprotein ligand- (PSGL-) 1, leukocyte function-associated antigen- (LFA-) 1, and C-C chemokine receptor type 9 (CCR9) by T helper (Th) and cytotoxic T (Tc) cells, and mRNA levels of endothelial adhesion molecules in colons were upregulated. Gln supplementation decreased expressions of PSGL-1, LFA-1, and CCR9 by Th cells. Colonic gene expressions of endothelial adhesion molecules were also lower in Gln-colitis mice. Histological finding showed that colon infiltrating Th cells were less in the DSS group with Gln administration. Conclusions. Gln supplementation may ameliorate the inflammation of colitis possibly via suppression of T cell migration.

Gasless laparoscopy-assisted versus open resection for gastrointestinal stromal tumors of the upper stomach: preliminary results.

INTRODUCTION Gastrointestinal stromal tumors (GISTs) are rare neoplasms with malignant potential. Surgery is the definitive management for resectable nonmetastatic lesions. Although minimally invasive resection has been established for GISTs, it is still considered unfeasible when tumors are near the esophagogastric junction. This study aimed to compare the relative efficacy of gasless laparoscopy-assisted (GLA) and open approaches for resection of GISTs. PATIENTS AND METHODS Between January 2006 and December 2008, 28 consecutive patients undergoing surgery for upper GIST were reviewed retrospectively. Among these patients, 15 underwent GLA procedures and 13 underwent open surgeries. RESULTS Patient demographics, comorbidities, and tumor characteristics (mean tumor size and prognosis) were similar for both groups. All patients underwent wedge resection. The mean operating time (129.6 versus 110.8 minutes), mean estimated blood loss (35.5 versus 40.3 mL), mean day of first flatus (2.7 versus 3.2 days), mean tumor size (2.5 versus 2.6 cm), and tumor prognosis or complication rate (13.3% versus 7.7%) between the GLA and open surgery groups were not significantly different. The length of maximal wound (P < 0.001), visual analog scale on postoperative days 1 (P = 0.001), 2 (P = 0.001), and 3 (P = 0.001), the mean time for resuming oral intake (P = 0.028), and the length of hospital stay (P = 0.005) in the GLA group were significantly lesser than the corresponding values in the open surgery group. None of the patients had dysphagia or died. CONCLUSIONS GLA method is a safe and feasible procedure for resecting GISTs of the upper stomach. In addition, it offers better cosmetic results, less pain, and faster recovery.

Multiple small-bowel intussusceptions caused by metastatic malignant melanoma

Intussusceptions of the small bowel, along with multiple intraluminal metastatic tumors, were noted during surgery. A segmental resection of the small bowel was performed, and the histologic diagnosis of metastatic melanoma was made. Long-term survival remains poor; therefore, complete surgical resection of macroscopic tumors remains the best treatment of choice.

Gasless Laparoscopy-Assisted Subtotal Gastrectomy for Early Gastric Cancer: A Novel Minimally Invasive Surgery

BackgroundDue to the highly invasive nature of traditional surgery and the limitation of gas-filling laparoscopic surgery in gastric cancers, we developed a new method of gasless laparoscope-assisted subtotal gastrectomy (GLASG). This study investigated the technique and clinical results of this procedure and compared it with traditional radical subtotal gastrectomy (TRSG) for early gastric cancers.MethodologyFrom December 2004 to January 2006, 41 patients diagnosed with early gastric cancer were included in the study. All cases underwent subtotal gastrectomy with standard radical lymph node dissection. Twenty patients underwent GLASG, whereas the other 21 patients underwent TRSG. In the GLASG group, we performed our newly developed method using three working ports created at the bilateral subcostal and umbilicus, which provided a 3-dimensional sensation by direct vision through a minilaparotomy and laparoscopic view simultaneously. B-II gastrojejunostomy reconstruction was performed by intracorporeal anastomosis using an endostapler. The TRSG group underwent the standard open method used for gastric cancer. Preoperative characteristics and postoperative recovery between the two groups were compared.ResultsThe operative time was comparable between the two groups, but the bleeding was significantly less severe in the GLASG group. Postoperative pain was significantly less in the GLASG group, as well as body temperature from postoperative day 2 to 7. The number of days to first flatus, first oral intake, and discharge were all significantly less in the GLASG group. No major complications were noted in either group.ConclusionsGLASG may be a feasible and safe procedure for early gastric cancer. Gasless laparoscopic gastrectomy has the advantages of less pain, better cosmetic outcome, and earlier recovery. The newly developed gasless environment may hybridize the advantages of open method and pure laparoscopic method.

The Psoas Muscle as an Unusual Site for Metastasis of Hepatocellular Carcinoma : Report of a Case

Extrahepatic metastasis of hepatocellular carcinoma (HCC) is an indicator of a poor prognosis. The most common extrahepatic sites of metastatic HCC are the lungs, intra-abdominal organs, and bone. Metastasis of carcinoma from any site to skeletal muscle is rare, and to the best of our knowledge, the hematogenous spread of HCC to skeletal muscle has never been described before. We report a case of isolated metastasis in the left side of the psoas muscle, which was found 1 year after trisegmentectomy. The lesion was successfully resected with the muscle, and no other metastatic lesions have been found in 5 months of follow-up.