The Acidic Tumor Microenvironment Affects Epithelial-Mesenchymal Transition Markers as Well as Adhesion of NCI-H358 Lung Cancer Cells.

Epithelial-mesenchymal transition (EMT), which is involved in metastasis formation, requires reprogramming of gene expression mediated by key EMT transcription factors. However, signals from the cellular microenvironment, including hypoxia, can also modulate the process of EMT. Hypoxia is often associated with a reduction in the extracellular pH of the tumor microenvironment (acidosis). Whether acidosis alone has an impact on the expression of the EMT markers E-cadherin, N-cadherin, and vimentin was studied in NCI-H358 lung cancer cells. Reducing extracellular pH decreased E-cadherin mRNA, while vimentin and N-cadherin mRNA were doubled. However, at the protein level, E-cadherin and N-cadherin were both reduced, and only vimentin was upregulated. E-cadherin and N-cadherin expression at the cell surface, which is the relevant parameter for cell-cell and cell-matrix interaction, decreased too. The reduction of cell surface proteins was due to diminished protein expression and not changes in cellular localization, since localization of EMT markers in general was not affected by acidosis. Acidosis also affected NCI-H358 cells functionally. Adhesion was decreased when the cells were primed in an acidic medium before measuring cell adherence, which is in line with the reduced expression of cadherins at the cell surface. Additionally, migration was decreased after acidic priming. A possible mechanism for the regulation of EMT markers involves the action of microRNA-203a (miR-203a). In NCI-H358 lung cancer cells, miR-203a expression was repressed by acidosis. Since a decrease in the level of miR-203a has been shown to induce EMT, it might be involved in the modulation of EMT marker expression, adhesion, and migration by the acidic tumor microenvironment in NCI-H358 lung cancer cells.

Extracellular Acidosis Regulates the Expression of Inflammatory Mediators in Rat Epithelial Cells.

Acidification of the cellular microenvironment is found in different pathological states such as inflammation, ischemia and in solid tumors. It can affect cell function and phenotype, and by this aggravate the pathological process. Epithelial cells are a relevant functional part in several normal organs as well as in tumors and will thus be challenged by the acidic extracellular pH (acidosis). Therefore, the impact of acidosis on the expression of different inflammatory mediators (MCP-1, IL-6, osteopontin, iNOS, TNF-α, and COX-2), as well as the role of different signaling pathways regulating the expression, was studied in epithelial normal rat kidney cells (NRK-52E). Acidosis led to an increase in TNF-α expression but a down-regulation of MCP-1, iNOS and COX-2. Expression of IL-6 was only slightly modulated, while osteopontin was not regulated at all. Since acidosis activates ERK1/2 and p38 signaling in NRK-52E cells, the impact of MAP kinase signaling pathways on the expression of the inflammatory markers was analyzed. At normal pH, blocking ERK1/2 or p38 decreased the level of MCP-1, iNOS and partly TNF-α. However, the effect of acidosis on the expression of inflammatory mediators was not affected by inhibition of the MAP kinase pathways. In conclusion, our results show that an acidic microenvironment affects the transcriptional program of epithelial cells. Low pH mostly reduced the expression of pathological relevant genes and might thus repress inflammatory processes induced by epithelial cells.

[Behavior of important serum lipid fractions in chronic hemodialysis patients and following kidney transplantation]. / Zum Verhalten wichtiger Serumlipidfraktionen bei chronisch hämodialysierten Patienten und nach Nierentransplantation.

In patients in the chronic programme of haemodialysis and 51 patients with transplanted kidney selected lipid-chemical parameters were investigated and compared. 1. Disturbances of the lipid metabolism more frequently occurred in patients with transplanted kidney than in chronically haemodialyzed patients. 2. Triglycerides, total cholesterol and LDL cholesterol were more frequently increased in patients with transplanted kidney than in chronically haemodialysed patients. 3. The HDL cholesterol of patients with transplanted kidney was only somewhat higher in comparison to patients in the chronic haemodialysis programme. 4. Sex-specific differences of the HDL cholesterol level were neither in chronically haemodialysed patients nor in patients with transplanted kidney. 5. Klimov-index and LDL/HDL cholesterol quotient referred to a permanently high risk of cardiovascular complications even after transplantation of a kidney.