Hypoxia and senescence: the impact of oxygenation on tumor suppression

Abstract

Cellular senescence has emerged as a biological response to two major pathophysiological states of our being: cancer and aging. In the course of the transformation of a normal cell to a cancerous cell, senescence is frequently induced to suppress tumor development. In aged individuals, senescence is found in cells that have exhausted their replication potential. The similarity in these responses suggests that understanding how senescence is mediated can provide insight into both cancer and aging. One environmental factor that is implicated in both of these states is tissue hypoxia, which increases with aging and can inhibit senescence. Hypoxia is particularly important in normal physiology to maintain the stem cell niche; but at the same time, hypoxic inhibition of an essential tumor suppressor response can theoretically contribute to cancer initiation.

Figure 1

Levels of normal oxygen content in various organs throughout the body.

Figure 2

Hypoxia modulates senescence in a variety of ways. A. Excess oxygen feeds the mitochondria and produces reactive oxygen species (ROS) that can promote senescence. Reduced oxygen can reduce damaging ROS. B. Hypoxia leads to the stabilization of HIF, which impacts many pathways that can affect senescence. Binding to Myc can induce p21 expression and inhibit CDC25C, thereby promoting cell cycle arrest. HIF transcriptionally controls a number of genes in the senescence associated secretory phenotype (SASP) that can promote senescence in an autocrine or paracrine fashion. In contrast, HIF also promotes glycolysis and reduces oxidative phosphorylation through transcriptional regulation of glycolytic enzymes. HIF can induce expression of the telomerase active subunit (TERT) and negatively regulate p53 at several levels. These latter effects are all inhibitory to senescence.

Figure 3

Oxygen gradients regulate senescence such that within the physiological range of oxygen, a similar oncogenic stimulus may or may not induce senescence. As these gradients are different in different tissues, oxygen levels may contribute to tissue selectivity of oncogenesis.