Hypoxia-Inducible Factors in Cancer

Abstract

Low oxygen concentrations (hypoxia) are detrimental to most species on Earth; thus, cells have evolved with adaptations allowing them to withstand transient hypoxia. As with other survival pathways, cancer cells have co-opted these mechanisms to keep up with the metabolic demands of rapid growth and proliferation in harsh tumor microenvironments. The most well-studied oxygen response pathway involves hypoxia-inducible factors (HIF) and their regulation by the von Hippel-Lindau protein (pVHL) and the prolyl hydroxylases (PHD1-3). This study from Zhong and colleagues, published in Cancer Research in 1999, was the first to show increased HIF1α expression in several cancer types and in metastases, suggesting a role for HIFs in disease progression. Since publication, significant progress has been made in the understanding of tumor hypoxia responses and efforts to target this pathway as a therapeutic strategy for patients with cancer are underway.See related article by Zhong and colleagues, Cancer Res 1999;59:5830-5.

Figure 1.

As tumors grow beyond the diffusion limits of O₂, cancer cells stabilize HIFα, upregulating expression of HIF target genes, which include angiogenic factors like VEGF. Blood vessels formed during tumor angiogenesis are often tortuous and leaky, leading to poor tissue oxygen perfusion. Cancer cells must constitutively express HIF to survive in this perpetually hypoxic environment. These cells are primed for metastasis, as they are pre-selected to survive in harsh environments. Additionally, several genes known to be involved in invasion and metastasis are regulated by HIF.