Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer

Abstract

Insufficient tissue oxygenation, or hypoxia, contributes to tumor aggressiveness and has a profound impact on clinical outcomes in cancer patients. At decreased oxygen tensions, hypoxia-inducible factors (HIFs) 1 and 2 are stabilized and mediate a hypoxic response, primarily by acting as transcription factors. HIFs exert differential effects on tumor growth and affect important cancer hallmarks including cell proliferation, apoptosis, differentiation, vascularization/angiogenesis, genetic instability, tumor metabolism, tumor immune responses, and invasion and metastasis. As a consequence, HIFs mediate resistance to chemo- and radiotherapy and are associated with poor prognosis in cancer patients. Intriguingly, perivascular tumor cells can also express HIF-2α, thereby forming a "pseudohypoxic" phenotype that further contributes to tumor aggressiveness. Therefore, therapeutic targeting of HIFs in cancer has the potential to improve treatment efficacy. Different strategies to target hypoxic cancer cells and/or HIFs include hypoxia-activated prodrugs and inhibition of HIF dimerization, mRNA or protein expression, DNA binding capacity, and transcriptional activity. Here we review the functions of HIFs in the progression and treatment of malignant solid tumors. We also highlight how HIFs may be targeted to improve the management of patients with therapy-resistant and metastatic cancer.

Association Between Hypoxia-Inducible Factor-2α (HIF-2α) Expression and Colorectal Cancer and Its Prognostic Role: a Systematic Analysis

“…HIF-2α is a type of HIFs involved in body response to oxygen level [51]. The expression of HIF-2α in various cancers has been recorded and detected by many studies [10,52]. HIF-2α expression may have a longer overall survival in hepatocellular carcinoma by Yang et al [53].. Bangoura et al reported that HIF-2α expression was correlated with a shortened overall survival of hepatocellular carcinoma [54].…”

“…Tumor hypoxia is a pathological hallmark that may be correlated with metabolism, the activation of cell signaling, angiogenesis, differentiation, necrosis or cell apoptosis, tumor development and aggressiveness, etc [10][11][12].. Additionally, tumor hypoxia can have an adverse impact on the prognosis of some cancers (i.e., invasive breast cancer or cervical cancer) and the efficacy of chemo-and radiotherapy [13,14]. Hypoxia-inducible factor-2α (HIF-2α), also named the endothelial PAS domain protein 1 (EPAS1), a member of the hypoxia-inducible factors (HIFs), is an essential marker, which mediates the transcriptional response to hypoxia stress [15][16][17].…”

“…HIF-2α was not observed under normoxic conditions among multiple organs, while HIF-2α was markedly induced under hypoxia in various organs, including lung, kidney, liver, and intestine [18,19]. HIF-2α expression was detected in a variety of human tumors, and its expression may be correlated with the poor outcome of some tumors, such as gastric cancer, breast cancer, glioblastoma, neuroblastoma, head and neck squamous carcinoma, and nonsmall cell lung cancer [10,20]. Some studies have reported that HIF-2α expression can also be detected in CRC [21][22][23][24].…”

COX-2/PGE2 Axis Regulates HIF2α Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment

“…HIFs are transcription factors that control the expression of dozens of genes involved in angiogenic signalling, cell migration, energy metabolism, and other pathways (39).…”

A Molecular Mechanism To Switch the Aryl Hydrocarbon Receptor from a Transcription Factor to an E3 Ubiquitin Ligase

“…In contrast, the knockdown of the AhR in MDA-MB-468 cells, an estrogen-independent cell line, did not affect cell proliferation (27). Hypoxia-inducible transcription is important for tumor progression (28). Since hypoxia-inducible factors (HIFs) also use ARNT as a partner factor, the AhRR may affect HIF signaling.…”