TGF-ß1-dependent L1CAM expression has an essential role in macrophage-induced apoptosis resistance and cell migration of human intestinal epithelial cells.

Patients with chronic inflammatory bowel disease (IBD) have an increased risk to develop colorectal cancer (CRC) particularly after long duration of the disease. Chronic inflammation of the intestinal mucosa is characterized by a marked enrichment of immune cells such as macrophages as well as by high expression of cytokines and growth factors including transforming growth factor-beta 1 (TGF-ß1). The adhesion molecule L1CAM mediates chemoresistance and migration of tumor cells and is elevated in CRC tissues being associated with metastatic spread and poor prognosis for the patients. In this study, we examine the role of TGF-ß1-induced L1CAM expression and macrophages in malignant transformation of intestinal epithelial cells. We demonstrate that TGF-ß1 stimulation leads to a Slug-dependent upregulation of L1CAM expression already in the colonic intestinal epithelial cell line NCM460 thereby enhancing cell motility and apoptosis resistance. Accordingly, NCM460 cells acquired a migratory and apoptosis-resistant phenotype if transfected with L1CAM. Immunohistochemistry of colonic biopsies revealed considerable L1CAM expression in intestinal epithelial cells in tissues from IBD patients but not in normal colonic tissues. Moreover, L1CAM expression increased with duration of disease being associated with the presence of CD33+ macrophages. Coculture with macrophages generated from monocyte colony-stimulating factor (MCSF)-treated monocytes led to the upregulation of Slug and L1CAM in NCM460 cells thereby elevating cell motility and apoptosis resistance. Pharmacological inhibition of TGF-ß1 signalling abolished expression of Slug and L1CAM in cocultured NCM460 cells resulting in decreased cell migration and apoptosis resistance. In conclusion, these data provide new insights into the mechanisms by which IBD promotes malignant transformation of intestinal epithelial cells and underscore the role of L1CAM and macrophages in this scenario.

Statistical evaluation of ecosystem properties influencing the uptake of As, Cd, Co, Cu, Hg, Mn, Ni, Pb and Zn in seaweed (Eucus vesiculosus) and common mussel (Mytilus edulis).

In order to evaluate the influence of geographically varying marine ecosystem properties on the uptake of trace elements in bioindicators, samples were taken of seaweed (Fucus vesiculosus) and common mussel (Mytilus edulis) along the North Sea and Baltic Sea coast. Seasonal variations of the bioindicator status were minimized by sampling within 1 month. Ecosystem properties considered were the geographical position, the salinity and the concentrations of the macroelements Ca, Fe, K, Mg, Na, P and S in the bioindicators. Trace elements studied were As, Cd, Co, Cu, Hg, Mn, Ni, Pb and Zn. Factor analysis of the concentration patterns in the bioindicators and of salinity as a function of location confirmed the influence of the geographically varying salinity on the biological uptake of macroelements and trace elements. This influence of salinity was higher in the case of seaweed than in the case of mussel. Comparison of the geographical courses of the macroelement and trace-element concentrations by cluster analysis revealed corresponding courses for As and Hg in both bioindicators. All other elements showed different courses in seaweed and mussel. Subsequent cluster analysis comparing locations with respect to the macroelement or trace-element concentration patterns in the bioindicators, indicated a clear separation of North and Baltic Sea locations. However, the trace-element concentration patterns provided a regionally less distinctive ecosystem arrangement than those of the macroelement ones. The results of the cluster analysis were verified by discriminant analysis forming groups of locations with respect to geographical position and salinity. Results of discriminant analysis demonstrated, both for seaweed and for mussel as bioindicators, that the location groups formed according to the macroelement concentration patterns corresponded well with the geographical regions in the order of salinity. On the other hand, location groups based on the trace-element concentration patterns again showed a modified less distinctive ecosystem arrangement than the location groups based on macroelement concentration patterns. This confirms modified conditions for the uptake of trace elements in seaweed or mussel in comparison to the uptake of macroelements.