Tania Roskams

A possible role for microRNA-141 down-regulation in sunitinib resistant metastatic clear cell renal cell carcinoma through induction of epithelial-to-mesenchymal transition and hypoxia resistance.

PURPOSEnWe identified microRNA driven mechanisms in clear cell renal cell carcinoma associated with the tumor response to the multitargeted receptor tyrosine kinase inhibitor sunitinib.nnnMATERIALS AND METHODSnWe performed screening genome-wide microRNA real-time quantitative polymerase chain reaction on 20 freshly frozen clear cell renal cell carcinoma tissue samples of patients who received sunitinib as first line targeted therapy. Nine patients with progressive disease within 6 months after initiating therapy were considered poor responders and 11 with at least 1-year progression-free survival were considered good responders. We studied microRNA-141 function in vitro by stable up-regulation of microRNA-141, quantification of target gene expression and cell viability in normoxic and hypoxic conditions. Relative expression in clinical and cell line samples was determined by real-time quantitative polymerase chain reaction. Localization of microRNA-141 and its targets was assessed by microRNA in situ hybridization and immunohistochemistry. Hypoxia induced cytotoxicity was assessed by a luminescence adenosine triphosphate detection assay.nnnRESULTSnCompared to good responders, microRNA-141 was significantly down-regulated in tumors of poor responders to sunitinib. This seemed spatially linked to epithelial-to-mesenchymal transition in vivo. Reintroduction of microRNA-141 in vitro reversed epithelial-to-mesenchymal transition and decreased cell viability in hypoxic conditions.nnnCONCLUSIONSnIn our study microRNA-141 down-regulation driven epithelial-to-mesenchymal transition in clear cell renal cell carcinoma was linked to an unfavorable response to sunitinib therapy. Reintroduction of microRNA-141 in vitro led to epithelial-to-mesenchymal transition reversal and increased sensibility to a hypoxic environment. Future experiments should be done in vivo to see whether microRNA-141 driven reversal of epithelial-to-mesenchymal transition could affect the efficacy of sunitinib treatment.

Aggregated colon cancer cells have a higher metastatic efficiency in the liver compared with nonaggregated cells: an experimental study.

BACKGROUNDnIt remains unclear whether aggregated colon cancer cells have a higher tendency for metastasis formation than nonaggregated cells. Also, the absolute number of cancer cells required for hepatic metastasis remains undefined. The aim of the present study was to compare in the liver the metastatic efficiency of viable nonaggregated colon cancer cells versus cell aggregates for equivalent numbers of cancer cells.nnnMATERIALS AND METHODSnDHD/K12/TRb colon cancer cells were administered through the portal vein in syngeneic male BD IX rats. Surgical exploration was performed 8 weeks after injection. Four groups of rats were injected with 0.25 or 0.5 x 10(6) DHD/K12/TRb viable cancer cells, either as single nonaggregated cells or as cell aggregates.nnnRESULTSnHepatic metastases were observed in 81% of the rats after intraportal injection of cell aggregates equivalent to 0.5 x 10(6) cancer cells. A significant lower metastatic efficiency was found after the injection of 0.5 x 10(6) non-aggregated, and 0.25 x 10(6) aggregated or nonaggregated cancer cells i.e., 16%, 32%, and 27%, respectively.nnnCONCLUSIONnAggregated colon cancer cells have a higher metastatic efficiency in the liver compared with non-aggregated cells, although a critical number of cancer cells are necessary.

Human liver growth and development

Human liver development commences during the third to fourth week of gestation. Endodermal cells give rise to hepatic cords representing liver progenitor cells. These progenitor cells are pluripotent because they differentiate along both the hepatocyte lineage (hepatoblasts) and the biliary epithelial cell lineage (ductal plate cells). In addition, ductal plate cells give rise to peri-biliary glands and in some cases to ectopic exocrine pancreatic tissue. Thus, the progenitor cells in the human fetal liver appear to have a broad differentiation potential similar to the putative hepatic stem cells or oval cells in the rat liver, which may develop into hepatocytes, biliary epithelial cells, pancreatic cells, and intestinal cells. Over the last decade, the existence and location of hepatic stem cells has been hotly debated and therefore hepatic development and the pluripotential capacities of liver progenitor cells have generated much interest. This chapter concisely presents the current stage of understanding of human liver development.