Hypoxia is a physiological characteristic of a wide range of diseases from cancer to infection. Cellular hypoxia is sensed by oxygen-sensitive hydrolase enzymes, which control the protein stability of hypoxia-inducible factor alpha 1 (HIF-1α) transcription factors (Santos et al. 2017). HIF-1α stabilization is a biological process in response to low oxygen. This biological response does not differentiate between healthy cells and non-healthy cells, virus infected cells versus non-infected cells, etc. When oxygen supply is low, HIF stabilization plays a prominent causative role in cancer progression and development as well as protecting solid state tumors from chemotherapy and radiation resulting in treatment resistant cancers (Cummins et al. 2015).
Hypoxia and Cancer
Solid tumors contain hypoxic regions due to their high rates of cell proliferation and formation of aberrant blood vessels (Dewhirst et al. 2008)). Intratumoral hypoxia is associated with increased risk of invasion, metastasis, and patient mortality (Semenza et al. 2003). Cancer cells respond to hypoxia by stabilizing HIF-1 and HIF-2. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that mediate major adaptive responses to hypoxia (Semenza 2003).
Increased HIF-1α or HIF-2α levels are found in human lung, colon, breast, and prostate carcinomas, and are associated with disease progression and increased patient mortality (Semenza 2003). A large body of experimental data indicates that disruption of HIF-1 signaling inhibits tumor growth (Melilo et al. 2007; Lee et al. 2009).
Specifically, hypoxia (low O2 condition) is considered an early event in carcinogenesis associated with an aggressive phenotype. In fact, clinically, hypoxia and hypoxia-related biomarkers are associated with treatment failure and disease progression. Hypoxia-inducible factor 1 (HIF-1) is the key factor that is activated under hypoxia, and mediates the response of cells to hypoxic conditions through regulating the expression of genes associated with angiogenesis, epithelial-to-mesenchymal transition (EMT), metastasis, survival, proliferation, metabolism, stemness, hormone-refractory progression, and therapeutic resistance.
By targeting the genes HIF-1 and HIF-2, cancer treatments are directed to the source of cancer progression and development and have the potential to treat all solid state cancers without significant side effects.