Biological consequences of tumor hypoxia.

Growing evidence from experimental and clinical studies points to the fundamental, pathophysiologic role of hypoxia in solid tumors. Intratumoral hypoxia is a consequence of a structurally and functionally disturbed microcirculation, with deterioration of the diffusion geometry and of tumor-associated anemia. Hypoxia-induced changes of the proteome in the neoplastic and stroma cells may lead to neoplastic growth impairment through molecular mechanisms, resulting in cellular quiescence, differentiation, and apoptosis. Alternatively, hypoxia-induced proteome changes activating nonspecific stress response, anaerobic metabolism, angiogenesis, tissue remodeling, and change of cell contacts may promote tumor propagation by enabling neoplastic cells to overcome the nutritive deprivation through adaptation or escape from the "hostile" environment. Whether the phenotypic result of hypoxia-induced proteome change is impairment, stasis, or promotion of neoplastic growth is thought to be determined by the genome of the tumor cells and additional microenvironmental factors. Tumor cells with genomic alterations (such as loss of apoptotic potential) allowing their survival under hypoxia will aggravate tumor hypoxia. Sustained hypoxia increases genomic instability, genomic heterogeneity, and the selection pressure of the microenvironment. New variants even better adapted to survive and proliferate under reduced pO2 will be selected through clonal expansion. These variants will further drive the vicious circle of malignant progression which is clinically characterized by an increasing probability of local, perifocal, regional, and distant spread.