Paracrine activation of MET promotes peritoneal carcinomatosis in scirrhous gastric cancer

がん進展制御研究所Scirrhous gastric cancer is associated with abundant stroma and frequently develops into peritoneal carcinomatosis with malignant ascites. Although malignant ascites is among the most deadly diseases worldwide, its molecular pathogenesis is poorly understood. We investigated the role of hepatocyte growth factor (HGF) in the production of peritoneal carcinomatosis with malignant ascites. We examined three scirrhous and three non-scirrhous human gastric cancer cell lines for the production of peritoneal carcinomatosis in vivo and responses to HGF in vitro. Furthermore, clinical scirrhous gastric cancer specimens were examined for HGF production. Among the six cell lines examined, only two scirrhous cell lines (NUGC4 and GCIY) produced peritoneal carcinomatosis with massive ascites after intraperitoneal injection in nude mice. Their proliferation was stimulated by exogenous HGF in vitro. On the other hand, a non-scirrhous cell line, MKN45, with MET amplification generated peritoneal tumors but not ascites. MET tyrosine kinase inhibitors, crizotinib and TAS-115, inhibited HGF-stimulated proliferation of NUGC4 and GCIY as well as constitutive proliferation of MKN45. Furthermore, crizotinib and TAS-115 prolonged the survival of mice bearing established tumors by NUGC4 or MKN45. In clinical specimens, HGF was markedly produced by stromal fibroblasts. Malignant ascitic fluids from patients with peritoneal carcinomatosis contained high levels of HGF. Our results strongly suggest that paracrine HGF-induced activation of MET-mediated signaling pathways plays an important role in the pathogenesis of peritoneal carcinomatosis in scirrhous gastric cancer. Thus, MET signaling pathway may be a potential therapeutic target for peritoneal carcinomatosis of gastric cancer, even without MET amplification. © 2013 Japanese Cancer Association

Effects of moderate thermal anomalies on Acropora corals around Sesoko Island, Okinawa.

Over the past several decades, coral reef ecosystems have experienced recurring bleaching events. These events were predominantly caused by thermal anomalies, which vary widely in terms of severity and spatio-temporal distribution. Acropora corals, highly prominent contributors to the structural complexity of Pacific coral reefs, are sensitive to thermal stress. Response of Acropora corals to extremely high temperature has been well documented. However, studies on the effects of moderately high temperature on Acropora corals are limited. In the summer of 2016, a moderate coral bleaching event due to moderately high temperature was observed around Sesoko Island, Okinawa, Japan. The objective of this study was to examine thermal tolerance patterns of Acropora corals, across reefs with low to moderate thermal exposure (degree heating weeks ~2-5°C week). Field surveys on permanent plots were conducted from October 2015 to April 2017 to compare the population dynamics of adult Acropora corals 6 months before and after the bleaching events around Sesoko Island. Variability in thermal stress response was driven primarily by the degree of thermal stress. Wave action and turbidity may have mediated the thermal stress. Tabular and digitate coral morphologies were the most tolerant and susceptible to thermal stress, respectively. Growth inhibition after bleaching was more pronounced in the larger digitate and corymbose coral morphologies. This study indicates that Acropora populations around Sesoko Island can tolerate short-term, moderate thermal challenges

Possible involvement of Tachylectin-2-like lectin from Acropora tenuis in the process of Symbiodinium acquisition

Most reef-building corals in tropical and subtropical areas symbiose with microalgae from the genus Symbiodinium (dinoflagellate) and depend on the photosynthate produced by the microalgae. The majority of corals acquire Symbiodinium from the surrounding environment through horizontal transfer, but the molecular mechanisms involved in the acquisition of Symbiodinium remain unknown. It has been hypothesized that carbohydrate-binding proteins, or lectins, of the host coral recognize cell surface carbohydrates of Symbiodinium in the process of acquiring symbionts. Thus, we examined the molecular mechanisms involving lectins and carbohydrates using model organism Acropora tenuis, a common reef-building coral, and Symbiodinium culture strains. Juvenile polyps acquire more cells of Symbiodinium strain NBRC102920 at 72–96 h of metamorphosis induction than in any other period. Glycosidase treatment of Symbiodinium inhibited the acquisition of Symbiodinium by juvenile coral polyps. The presence of carbohydrates D-galactose, N-acetyl-D-galactosamine, and N-acetyl-D-glucosamine at 10 mM also tended to decrease Symbiodinium acquisition. We isolated two N-acetyl-D-galactosamine binding lectins with apparent molecular masses of 14.6 and 29.0 kDa from A. tenuis, and de novo sequencing and cDNA cloning showed that the 29.0 kDa protein is Tachylectin-2-like lectin (AtTL-2). The anti-Tachylectin-2 antibody is suggested to bind specifically to AtTL-2. The antibody also inhibited binding of AtTL-2 to N-acetyl-D-galactosamine-resin and the acquisition of Symbiodinium by juvenile A. tenuis polyps. Based on these results, AtTL-2 is likely involved in the process of Symbiodinium acquisition