Cytokines and growth factors in malignant ascites are thought to modulate a variety of cellular activities of cancer cells and normal host cells. The motility of cancer cells is an especially important activity for invasion and metastasis. Here, we examined the components in ascites, which are responsible for cell motility, from patients and cancer cell-injected mice. Ascites remarkably stimulated the migration of pancreatic cancer cells. This response was inhibited or abolished by pertussis toxin, monoglyceride lipase, an enzyme hydrolyzing lysophosphatidic acid (LPA), and Ki16425 and VPC12249, antagonists for LPA receptors (LPA 1 and LPA 3 ), but not by an LPA 3 -selective antagonist. These agents also inhibited the response to LPA but not to the epidermal growth factor. In malignant ascites, LPA is present at a high level, which can explain the migration activity, and the fractionation study of ascites by lipid extraction and subsequent thin-layer chromatography indicated LPA as an active component. A significant level of LPA 1 receptor mRNA is expressed in pancreatic cancer cells with high migration activity to ascites but not in cells with low migration activity. Small interfering RNA against LPA 1 receptors specifically inhibited the receptor mRNA expression and abolished the migration response to ascites. These results suggest that LPA is a critical component of ascites for the motility of pancreatic cancer cells and LPA 1 receptors may mediate this activity. LPA receptor antagonists including Ki16425 are potential therapeutic drugs against the migration and invasion of cancer cells.
Visceral pleural invasion is a significant poor-prognostic factor, regardless of N status. Our analyses indicated that visceral pleural invasion is an independent indicator of non-small cell lung cancer invasiveness and aggressiveness.
Cadherin adhesion molecules are believed to be important for synaptic plasticity. -Catenin, which links cadherins and the actin cytoskeleton, is a modulator of cadherin adhesion and regulates synaptic structure and function. Here we show that -catenin interacts with a novel GTPase-activating protein, named RICS, that acts on Cdc42 and Rac1. The RICS--catenin complex was found to be associated with N-cadherin, N-methyl-D-aspartate receptors, and postsynaptic density-95, and localized to the postsynaptic density. Furthermore, the GTPase-activating protein activity of RICS was inhibited by phosphorylation by Ca 2؉ /calmodulin-dependent protein kinase II. These results suggest that RICS is involved in the synaptic adhesion-and N-methyl-D-aspartate-mediated organization of cytoskeletal networks and signal transduction. Thus, RICS may regulate dendritic spine morphology and strength by modulating Rho GTPases.Activity-induced changes in synaptic transmission efficacy, such as long term potentiation (LTP) 1 and long term depression, have been postulated to be involved in information storage during learning. Many studies have revealed that synaptic remodeling and plastic changes in dendritic spine morphology play a role in synaptic plasticity (1-6). Furthermore, changes in synaptic strength have been shown to involve the structural and functional modifications of the molecules present in the postsynaptic density (PSD) (7-10), an electrondense structure containing various structural and signaling molecules such as ion channels, scaffolding proteins, protein kinases, small G-proteins, cell adhesion proteins, and cytoskeletal proteins (11, 12).The cadherins are a family of single-pass transmembrane proteins that mediate Ca 2ϩ -dependent, homophilic intercellular adhesion (13). Some members of the cadherin family of adhesion proteins are localized to synaptic junctions and have been implicated in synaptic plasticity (14, 15). For example, inhibitory antibodies to the first extracellular domain of Ncadherin, one of the classical cadherins enriched in neural cells, have been shown to attenuate the induction of LTP (16,17). Also, antagonistic peptides containing the consensus sequence for cadherin dimer formation prevent the induction of LTP (16). Furthermore, inhibition of cadherin activity by a dominantnegative N-cadherin, as well as by mutation of ␣N-catenin, has been shown to alter dendritic spine morphology (18), suggesting that cadherins function as regulators of synaptic plasticity by modulating spine morphology.-Catenin interacts with the cytoplasmic domain of classical cadherins and links cadherins and the actin cytoskeleton (19,20). -Catenin and N-cadherin are present in axons and dendrites prior to synapse formation and then cluster at developing synapses and form a symmetrical adhesion structure in synaptic junctions (21). Moreover, it has been reported recently (10) that neural activity induces redistribution of -catenin from dendritic shafts into spines, where it interacts with cadherin to influence synaptic...
Expression of the proto-oncogene c-myc has been implicated in liver regeneration and hepatocarcinogenesis. The biologic significance of c-myc gene amplification in human hepatocellular carcinoma, however, is unconfirmed. We correlated c-myc gene amplification with clinicopathologic features, proliferative activity, and p53 expression in 42 resected tumors. c-myc amplification in tumor tissue was determined using a differential polymerase chain reaction, a useful procedure for the evaluation of gene amplification in archival formalin-fixed paraffin-embedded tissues, in comparison with a dopamine D2 receptor gene. Proliferative activity was estimated by numbers of argyrophilic nucleolar organizer regions and immunohistochemical nuclear labeling rates using a monoclonal antibody against Ki-67. The c-myc gene was amplified in 14 of 42 tumors (33.3%). Amplification of c-myc was more frequent in younger patients and in larger tumors, and less differentiated tumors. No correlation was noted with α-fetoprotein level or viral hepatitis state. The amplification showed positive correlation with both proliferative activity and p53 overexpression. Disease-free survival in patients showing c-myc amplification was significantly shorter than in those without amplification. These results suggest that c-myc amplification is an indicator of malignant potential and poor prognosis in hepatocellular carcinoma. c-myc amplification and p53 alteration may be coparticipating events in the progression of these tumors.
Background-A novel immunomodulator, KRP-203, the molecular structure of which has some similarity to FTY720, has been developed for use in organ transplantation. The present study was designed to investigate the potency and safety of KRP-203 on allograft survival against both acute and chronic rejection in rat skin and heart transplantation. Methods and Results-KRP-203 significantly prolonged skin or heart allograft survival of a minor histocompatibility complex (mHC)-disparate (LEW to F344) rat combination. Histopathological and immunohistochemical analysis at 100 days after mHC-disparate rat heart transplantation revealed that KRP-203 treatment significantly inhibited infiltration of inflammatory cells, including macrophages and T cells; expression of endothelin-1 and transforming growth factor- 1 ; and IgG deposition and eventually attenuated neointimal formation and myocardial fibrosis. KRP-203 also prolonged heart allograft survival in a major histocompatibility complex (MHC)-incompatible (DA to LEW) rat combination, but the efficacy was not as significant. However, KRP-203 combined with a subtherapeutic dose of cyclosporin A synergistically prolonged the heart allograft survival. Flow cytometric analysis demonstrated that KRP-203 reduced the number of peripheral blood mononuclear cells (lymphocytes and monocytes) but not granulocytes and enhanced lymphocyte homing into peripheral lymph nodes. The influence of KRP-203 on heart rate changes in Hartley guinea pigs was examined. KRP-203 had less of a tendency to cause bradycardia than FTY720. Conclusions-These findings demonstrated that KRP-203 prolonged skin and heart allograft survival and significantly attenuated chronic rejection and bradycardia as an adverse effect. Therefore, KRP-203 offers considerable potential as a novel therapeutic immunosuppressant in patients with organ transplantation. (Circulation. 2005;111:222-229.)
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