Hypoxia in Cancer and Fibrosis: Part of the Problem and Part of the Solution

Abstract

Adaptive responses to hypoxia are involved in the progression of lung cancer and pulmonary fibrosis. However, it has not been pointed out that hypoxia may be the link between these diseases. As tumors or scars expand, a lack of oxygen results in the activation of the hypoxia response, promoting cell survival even during chronic conditions. The role of hypoxia-inducible factors (HIFs) as master regulators of this adaptation is crucial in both lung cancer and idiopathic pulmonary fibrosis, which have shown the active transcriptional signature of this pathway. Emerging evidence suggests that interconnected feedback loops such as metabolic changes, fibroblast differentiation or extracellular matrix remodeling contribute to HIF overactivation, making it an irreversible phenomenon. This review will focus on the role of HIF signaling and its possible overlapping in order to identify new opportunities in therapy and regeneration.

Keywords: hypoxia-inducible factors; idiopathic pulmonary fibrosis; lung cancer; regeneration.

Figure 1

Hypoxia adaptation by HIF system. Hydroxylation reactions in proline residues of alpha subunits (HIF-1α, HIF-2α and HIF-3α) depend on available oxygen (normoxia); these reactions cause its degradation by interaction with Von Hippel Lindau protein (VHL). The decrease in oxygen concentration inhibits HIF-α hydroxylation and induces its accumulation in the cytoplasm and subsequent translocation to the nucleus, where it heterodimerizes with the HIF-1β (hypoxia). This heterodimer is able to bind to hypoxia response elements (HRE) found in promoters of diverse genes. Structure and functional domains of hypoxia-inducible factors (below).

Figure 2

Hypoxia drives the progression in cancer and fibrosis. Hypoxia is an important part in the integration of the microenvironment signals; both tumors and fibroblast foci induce an activation of hypoxia and this in turn activates different mechanisms involved in its progression.

Figure 3

Persistent hypoxia activation. In cancer and fibrosis, hypoxia is a key participant in several processes that have feedback loops, especially when these processes have dysfunctions that promote hypoxia perpetuation (in black).