Metabolic microenvironment of tumor cells: a key factor in malignant progression.

The hostile metabolic microenvironment of solid tumors, which is quite heterogeneous both spatially and temporally (« 4-D-heterogeneity »), can trigger malignant progression. Above all, acute and fluctuating hypoxia elicits multiple cellular response pathways that alter gene expression and phenotype (at moderate hypoxia with oxygen concentrations below 1%). Upon severe hypoxia (oxygen concentrations below 0.1%), genomic instability can lead to cell variants with adaptations favorable to survival. These cell variants have growth advantages in the hostile tumor microenvironment and finally expand through clonal selection thus promoting tumor aggressiveness. In addition to hypoxia, high lactate concentrations (above approximately 8 mM) may promote malignant progression. The interpretation of the role of tumor pH in tumor progression is complicated by the frequently occurring coexistence of tumor hypoxia and acidosis.