Figure 1.

The proposed model of molecular mechanisms regulating the three choices of tumor cells under stress. Microenvironmental factors regulate the activity of HIF-1α. In addition to normoxia or hypoxia, changes of the proteolytic network can also determine the response of the tumor cell. While normoxia and proteolytic balance favor proliferation (right panel), which reflects the adaption of the tumor cell in situ, hypoxia or alterations in the proteolytic network promote the induction of pro-evasive mechanisms (left panel). Respiration is impaired upon HIF-1α stabilization not only by hypoxia but also in the case of proteolytic imbalance imposed by high TIMP-1 levels or similar environmental stress. It leads to upregulation of miR-210 which directly inhibits expression of the subunit D of the succinate dehydrogenase complex (SDHD) and simultaneously induces cell cycle arrest by inhibition of E2F3. Thus, the tumor cell switches to the evasive metastatic phenotype for which adaptation to hypoxia by their potential of executing anaerobic glycolysis is a pre-requisite.