Shuichiro Uchiyama

Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1) Is Required for Branching Morphogenesis in the Chorioallantoic Placenta

ABSTRACT Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a membrane-associated Kunitz-type serine proteinase inhibitor that was initially identified as a potent inhibitor of hepatocyte growth factor activator. HAI-1 is also a cognate inhibitor of matriptase, a membrane-associated serine proteinase. HAI-1 is expressed predominantly in epithelial cells in the human body. Its mRNA is also abundant in human placenta, with HAI-1 specifically expressed by villous cytotrophoblasts. In order to address the precise roles of HAI-1 in vivo, we generated HAI-1 mutant mice by homozygous recombination. Heterozygous HAI-1+/− mice underwent normal organ development. However, homozygous HAI-1−/− mice experienced embryonic lethality which became evident at embryonic day 10.5 postcoitum (E10.5). As early as E9.5, HAI-1−/− embryos showed growth retardation that did not reflect impaired cell proliferation but resulted instead from failed placental development and function. Histological analysis revealed severely impaired formation of the labyrinth layer, in contrast all other placental layers, such as the spongiotrophoblast layer and giant cell layer, which were formed. Our results indicate that mouse HAI-1 is essential for branching morphogenesis in the chorioallantoic placenta and lack of HAI-1 function may result in placental failure.

Role of cancer cell-stroma interaction in invasive growth of cancer cells

Invasive growth is one of the hallmarks of cancer malignancy. To date, a significant body of evidence is accumulating in favor of the notion that invasive growth results from the cross-talk between cancer cells and the host stromal cells, comprising fibroblasts (myofibroblasts), endothelial cells, and leukocytes, all of which are themselves invasive. In this review we describe cross-talk between invasive cancer cells and host stromal fibroblasts and an impact of pericellular microenvironment on the invasive phenotype of cancer cells, focusing on two molecules, extracellular matrix metalloproteinase inducer (EMMPRIN, also known as tumor cell-derived collagenase stimulatoty factor, basigin, CD147) and hepatocyte growth factor (HGF, also known as scatter factor). Both molecules are deeply involved in the regulation of invasion-associated cellular activities, such as pencellular proteolysis, migration and ectopic sunrival of cancer cells.

Multiple hepatic peribiliary cysts with cirrhosis

Multiple hepatic peribiliary cysts were found in three autopsy cases of patients who had had underlying liver diseases and obstructive jaundice. Macroscopically, the cysts were visible and present exclusively in the hepatic hilum and larger portal tracts. Histologically, the cysts were of varying size and were lined by a single layer of cuboidal or flattened epithelial cells without atypia. Intimate association between the cysts and peribiliary glands was found in the walls of large bile ducts. All three cases were associated with liver cirrhosis in patients with portal hypertension, and two of the patients had also had hepatocellular carcinoma. These findings support the previous assumption that multiple hepatic peribiliary cysts may be closely related to a portal hypertensive condition. Although peribiliary cysts have been considered to be clinically asymptomatic in general, in one of our patients, the cystic dilatation appeared to have been responsible for the progression of obstructive jaundice.

Intrapancreatic accessory spleen mimicking endocrine tumor of the pancreas: case report and review of the literature.

Accessory spleen is an anomaly that is observed in about 10% of individuals by the autopsy study, and most accessory spleens are located close to the splenic hilum. Although accessory spleen is a frequently encountered entity, intrapancreatic accessory spleen (IPAS) is rarely recognized radiologically and is sometimes mistaken for another type of pancreatic neoplasm. Only 10 IPAS cases surgically resected as solid pancreatic mass have been reported in the English literature. We herein report a case of IPAS mimicking an endocrine tumor of the pancreas and review of the literature.

Paradoxically enhanced immunoreactivity of hepatocyte growth factor activator inhibitor type 1 (HAI‐1) in cancer cells at the invasion front

We have previously demonstrated significantly decreased immu‐noreactivity of hepatocyte growth factor activator inhibitor type 1 (HAI‐1), an integral membrane protein that exhibits potent inhibitory activity against hepatocyte growth factor activator (HGFA) and matriptase, in colorectal adenocarcinomas. In this report, we describe further detailed analysis of HAI‐1 expression in colorectal adenocarcinoma by using three kinds of anti‐HAI‐1 antibodies, each of which recognizes a distinct epitope of the HAI‐1 molecule, and also by in‐situ hybridization for HAI‐1 mRNA. The results indicated that the decreased immunoreactivity of HAI‐1 in colorectal carcinoma cells is largely a result of enhanced ecto‐domain shedding of HAI‐1 in these cells. In contrast, immunore‐activity of mature membrane‐form HAI‐1 was paradoxically enhanced in cancer cells at the invasion front, showing intense cell‐stroma interactions and/or sprouting invasion. This finding indicates that these invading cells showed decreased ectodomain shedding of HAI‐1 and consequently might require the existence of the membrane‐form HAI‐1. Of particular interest was the observation of a possible inverse correlation between paradoxical up‐regulation of membrane‐form HAI‐1 expression and membrane‐associated E‐cadherin in these cells. These membrane‐form HAI‐1‐positive sprouting cancer cells were also negative for MIB‐1 immunohistochemically, indicating a low‐proliferating population. All these results suggest that HAI‐1 may mediate diverse functions in regard to the progression of colorectal carcinomas, and the immunoreactivity of membrane‐form HAI‐1 may serve as a marker of invading cancer cells.

Sex Difference in Survival of Patients Treated by Surgical Resection for Esophageal Cancer

AbstractBackgroundSquamous cell carcinoma accounts for most of the esophageal cancers in Japan and is often related to excessive smoking and drinking. Although esophageal cancer occurs far more frequently in men than in women, it is not certain whether there are sex-specific differences in morbidity and mortality after surgical resection of the esophagus. We conducted a study to determine the influence of sex on the short- and long-term results of surgical resection in patients with esophageal cancer.MethodsThere were 295 patients with a newly diagnosed primary malignant neoplasm of the esophagus treated at our University hospital between January 1978 and December 2005. There were 185 patients (166 men, 19 women; age range 39–86 years) who underwent surgical resection for primary esophageal malignant neoplasms. Survival rates were calculated according to the Kaplan-Meier method and tested with the log-rank test. Cox proportional hazards model was used to assess independent predictors of survival. ResultsThe cumulative amount of alcohol consumed and number of cigarettes smoked were significantly higher in men than in women. Postoperative complications occurred in 101 men (60.8%) and 9 women (47.4%), but significant sex differences in postoperative morbidity and mortality were not observed. Overall survival was significantly better for women than for men.Conclusion Postoperative morbidity and mortality do not appear to differ between men and women with esophageal cancer treated by surgical resection. Long-term survival after surgical resection of the esophagus appears to be significantly better for women than for men.

An unusual variant of a left paraduodenal hernia diagnosed and treated by laparoscopic surgery: Report of a case

An 80-year-old woman who had undergone both a cholecystectomy and an appendectomy presented with intermittent abdominal pain. Computed tomography (CT) revealed an encapsulated circumscribed cluster of jejunal loops in the left upper quadrant. The hernia orifice was adjacent to the left side of the superior mesenteric artery and vein. An upper gastrointestinal series also revealed a cluster of jejunal loops, suggesting the possibility of an internal hernia. Laparoscopic surgery was performed. The hernia orifice was found to be caused by abnormal adhesion between the transverse mesocolon and the jejunum mesentery. An adhesiotomy reduced the jejunum entrapped in the hernia. The hernia space was a large mesocolic fossa composed of transverse mesocolon and mesentery, continuing to the splenic flexure. The hernia was classified as a variant of paraduodenal hernia.

Factors influencing outcome after surgery for stage IV colorectal cancer

PurposeAccording to the classification system of the Japanese Society for Cancer of the Colon and Rectum, Stage IV colorectal cancer is characterized by distant metastasis, which is defined by four factors: liver metastasis (H factor), metastasis to organs other than the liver (M factor), peritoneal dissemination (P factor), and distant lymph node metastasis (N factor). We conducted this study to investigate the postsurgical prognosis of patients with Stage IV colorectal cancer (CRC), in reference to each of these four factors.MethodsWe analyzed the medical records of 73 patients who underwent surgery for Stage IV CRC at our hospital between 1991 and 2001.ResultsUnivariate analysis revealed that P0 or P1 CRC (P < 0.001), absence of the M factor (P = 0.024), well or moderately differentiated adenocarcinoma (P < 0.001), resection of the primary tumor (P < 0.001), and curability B surgery (P < 0.0001) were associated with a better prognosis than other types of Stage IV CRC. Multivariate analysis revealed that tumor differentiation and surgical curability affected cancer-specific survival significantly.ConclusionSurgery with curative intent should be considered for patients with Stage IV CRC defined by the P1 factor or H factor.

A Case of Peribiliary Cyst Presenting with Obstructive Jaundice

A 77-year-old woman with a complaint of itching was shown to have an elevated serum bilirubin level. She had no history of liver disease. Computed tomography and magnetic resonance cholangiopancreatography revealed a 17-mm-diameter cystic lesion obstructing the main hepatic duct at the hepatic hilum. Drip infusion cholangiographic computed tomography and endoscopic retrograde cholangiography showed that the cyst did not communicate with the biliary tree; thus, a peribiliary cyst was diagnosed. Cystectomy was performed, and the jaundice resolved. Peribiliary cysts are generally asymptomatic and rarely cause obstructive jaundice. They are usually multiple and caused by an underlying liver disorder with a poor prognosis. Our case suggests that peribiliary cysts can arise in healthy liver and cause symptoms. Cystectomy is the treatment of choice if the cyst is solitary.

Synchronous adenocarcinoma and gastrointestinal stromal tumors of the stomach treated laparoscopically

Gastric adenocarcinomas account for approximately 95% of primary gastric tumors, and gastrointestinal stromal tumor (GIST) is the most common gastrointestinal mesenchymal tumor, accounting for 1%–3% of primary gastric tumors. However, the synchronous occurrence of GIST and gastric epithelial tumor is rare. We herein report a case of synchronous occurrence of gastric adenocarcinoma and two GISTs of the stomach. All lesions were resected laparoscopically. We discuss this case and review the literature.