Question:

Extracellular acidosis is a common feature of the tumor microenvironment. However, the role of low pH on cell motility, invasiveness and metastasis formation as well as the underlying molecular mechanism remain not fully understood. Therefore the effect of extracellular acidosis (pH 6.6) on the migration and metastatic ability of AT-1 prostate carcinoma cells, and a possible involvement of the MAP kinases ERK1/2 and p38, was studied.

Methods:

Rat prostate carcinoma cells (AT-1) and cells derived from normal tissue (NRKE, NRKF) were serum-starved for 24 h and subsequently incubated at pH 7.4 or pH 6.6. Migratory speed was determined using single cell microscopy. Metastatic ability of fluorescent labeled AT-1 cells was analyzed after intravenous injection of pre-incubated cells (2x10⁶ cells/animal) into the tail vein of male Copenhagen rats. After 4 days the lungs were isolated and lung metastases were quantified by using fluorescence imaging.

Results:

Extracellular acidosis increased migratory speed of AT-1 cells, but not of NRKE or NRKF non-tumor cells. These changes remained for at least 3 h after retransfer from acidic to normal pH. Basal migration depended on ERK1/2 and p38 signaling; however acidosis-induced increase in migratory speed was independent of the MAP kinases. In addition, acidic priming increased metastases formation of AT-1 cells in vivo.

Conclusion:

Tumor cell motility and metastatic behavior is increased by extracellular acidosis, giving evidence that the tumor microenvironment contributes to tumor aggressiveness and might be a promising target for tumor therapy.