Hypoxia-inducible factors: A target of cancer treatment

Abstract

Hypoxia, a characteristic of the tumor microenvironment caused by abnormal blood vessels and rapid cellular growth, enhances tumor aggressiveness and leads to resistance against conventional therapies. Unlike normal cells, hypoxic tumor cells activate adaptive survival mechanisms, prominently mediated by hypoxia-inducible factors (HIFs). HIF-1α is the most studied member of the HIF family, and the stability of its alpha subunit (HIF-1α) is a crucial determinant of the overall activity of the HIF-1α complex. HIF-1α stabilization under low oxygen occurs via oxygen-dependent and oxygen-independent pathways: in the oxygen-dependent pathway, HIf-1α is normally degraded by the von Hippel–Lindau protein (pVHL) when oxygen is present. Under hypoxia, hydroxylation is inhibited, allowing HIF-1α to accumulate. In the oxygen-independent pathway, growth factor signals activate cascades like PI3K/Akt/mTOR and MAPK/ERK, stabilizing HIF-1α regardless of oxygen levels. Stabilized HIF-1α translocates to the nucleus, promoting transcription of proangiogenic genes such as vascular endothelial growth factor (VEGF), thereby facilitating angiogenesis, tumor invasion, and progression. Dysregulation of these signaling pathways underpins the pathogenesis of many cancers, making HIF and its associated cascades critical targets for innovative cancer therapies. This review focuses on the pivotal role of HIF in tumor angiogenesis and emphasizes the therapeutic potential of targeting HIF signaling in cancer treatment.