Tumor Hypoxia: Impact on Radiation Therapy and Molecular Pathways

Abstract

Tumor hypoxia is a common feature of the microenvironment in solid tumors, primarily due to an inadequate, and heterogeneous vascular network. It is associated with resistance to radiotherapy and results in a poorer clinical outcome. The presence of hypoxia in tumors can be identified by various invasive and non-invasive techniques, and there are a number of approaches by which hypoxia can be modified to improve outcome. However, despite these factors and the ongoing extensive pre-clinical studies, the clinical focus on hypoxia is still to a large extent lacking. Hypoxia is a major cellular stress factor and affects a wide range of molecular pathways, and further understanding of the molecular processes involved may lead to greater clinical applicability of hypoxic modifiers. This review is a discussion of the characteristics of tumor hypoxia, hypoxia-related molecular pathways, and the role of hypoxia in treatment resistance. Understanding the molecular aspects of hypoxia will improve our ability to clinically monitor hypoxia and to predict and modify the therapeutic response.

Keywords: gene regulation; hypoxia; hypoxia classifyer; intracellular signaling; radiation response.

Figure 1

Schematic illustration of the vascular networks in tumors and associated normal tissues. Compared to the well-organized blood supply of normal tissues, in tumors the system is primitive and chaotic. The tumor vascular supply shows abnormal vascular density, contour irregularities, enlarged vessels, vessels with blind ends, and transiently blocked vessels. In addition, there is a loss of hierarchy, a lack of regulatory control mechanisms, and the vessel walls can be structurally defective causing increased vascular permeability. These factors result in the development of diffusion limited chronic hypoxia and perfusion limited acute hypoxia.

Figure 2

Schematic illustration of cellular pathways affected by hypoxia. Hypoxia affects regulation of hypoxia-inducible factors and induction of HIF target. HIF is a heterodimer consisting of an alpha (α) subunit (HIF-1α, HIF-2α or HIF-3α) and a HIF-1β subunit. Under normoxic conditions, HIF-α is rapidly degraded due to hydroxylation by prolyl hydroxylase domain (PHD) protein. The proline-hydroxylated HIF-α interacts with the von Hippel-Lindau protein (VHL), which targets HIF-α for ubiquitination and degradation via the proteasome. Under hypoxia, HIF-α is stable, and forms the active transcription complex with HIF-1β. After translocation to the nucleus the HIF heterodimer binds at the hypoxia response element (HRE) of target genes thereby initiating the transcription of the HIF target genes. At severe hypoxia, the cellular response also affects the DNA Damage Response (DDR), which leads to DNA replication arrest. Exposure to very low oxygen concentrations also leads to an reduction in mRNA translation initiation and overall protein synthesis, through an activation of the Untranslated Protein Response (UPR).