Progress toward overcoming hypoxia-induced resistance to solid tumor therapy

Abstract

Hypoxic tumors are associated with poor clinical outcome for multiple types of human cancer. This may be due, in part, to hypoxic cancer cells being resistant to anticancer therapy, including radiation therapy, chemotherapy, and targeted therapy. Hypoxia inducible factor 1, a major regulator of cellular response to hypoxia, regulates the expression of genes that are involved in multiple aspects of cancer biology, including cell survival, proliferation, metabolism, invasion, and angiogenesis. Here, we review multiple pathways regulated by hypoxia/hypoxia inducible factor 1 in cancer cells and discuss the latest advancements in overcoming hypoxia-mediated tumor resistance.

Keywords: HIF-1; apoptosis; cancer; chemoresistance; signaling.

Figure 1

Hypoxia/Hypoxia inducible factor 1 (HIF-1)-mediated mechanisms leading to anticancer therapy resistance. Notes: Under hypoxic conditions HIF-1 is stabilized, translocates to the nucleus, and activates expression of its target genes. Activity of many of these genes promotes resistance to anticancer therapy through regulation of metabolism, survival, drug efflux, signaling, and DNA repair.

Figure 2

Potential strategies to target hypoxic cancer cells in solid tumors. Notes: Multiple pathways may be targeted to reverse hypoxia-mediated anticancer therapy resistance. (1) Hypoxia inducible factor 1 (HIF-1) plays a critical role in cellular adaptation to hypoxic environment. Several agents can impair HIF-1 function by inhibiting its expression, translation, or transcriptional activity, or by promoting HIF-1 degradation. (2) Hypoxia-mediated angiogenesis plays an important role in tumorigenesis and could be targeted by anti-vascular endothelial growth factor (VEGF) therapy. (3) Multiple metabolic pathways are activated under hypoxia and the inhibition of these pathways targets hypoxic cells. (4) Activation of cancer signaling under hypoxia promotes proliferation, survival, and invasion. Targeting hypoxia/HIF-1-mediated signaling pathways has been shown to be efficient at decreasing tumorigenesis in vitro and in vivo. (5) Hypoxia and HIF-1 can remodel the extracellular matrix (ECM) in cancer cells that can also contribute to altered signaling by adhesion receptors such as integrins. The targeting ECM-regulating enzymes in hypoxic tumors may be used to reverse hypoxia-mediated resistance to cancer therapy. Abbreviations: Akt, protein kinase B; DCA, dichloroacetate; EGFR, epidermal growth factor receptor; FAS, fatty acid synthase; HIF-1α/β, hypoxia inducible factor 1 alpha/beta; HRE, hypoxia response element; LDHA, lactate dehydrogenase A; LOXL2, lysyl oxidase-like protein 2; PDK3, pyruvate dehydrogenase kinase 3; PI3K, phosphoinositide 3-kinase; RTK, receptor tyrosine kinase; VEGF-A, vascular endothelial growth factor-A.