Modulation of cell death in the tumor microenvironment

Hypoxia tolerance in the development of cancer. Hypoxia is hypothesized to arise early in the process of tumor development. Deregulation of cell growth results in an excess demand for oxygen and leads to cellular hypoxia. In normal and minimally transformed cells, hypoxia leads to cell death through activation of apoptosis or through loss of ATP. To continue to proliferate, tumors need to induce angiogenesis. During tumor evolution, cells become resistant to hypoxia-induced cell death. We hypothesize that this hypoxia tolerance arises such that a persistent hypoxia-induced angiogenic signal can be produced. The continued presence of viable hypoxic cells allows the coordination between angiogenesis and tumor expansion. This hypothesis implies that heterogeneity in oxygenation is beneficial to overall tumor growth.