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.

Tumors Resistant to Checkpoint Inhibitors Can Become Sensitive after Treatment with Vascular Disrupting Agents

“…Hypoxia also seems to play a role in influencing anti-cancer immune responses [27,28]. In response to hypoxia, cells experience a number of molecular changes that are mediated by intracellular signaling pathways under the control of hypoxia inducible factors (HIFs) [44][45][46]. Via several of these HIF-dependent mechanisms, hypoxia can cause tumor resistance to immune attack [46][47][48][49].…”

“…In response to hypoxia, cells experience a number of molecular changes that are mediated by intracellular signaling pathways under the control of hypoxia inducible factors (HIFs) [44][45][46]. Via several of these HIF-dependent mechanisms, hypoxia can cause tumor resistance to immune attack [46][47][48][49]. It can promote an immunosuppressive microenvironment by recruiting protumor immune cells such as Tregs, tumor-associated macrophages, neutrophils, and myeloid-derived suppressor cells [44,45].…”

Hypoxia-induced therapy resistance: Available hypoxia-targeting strategies and current advances in head and neck cancer

“…It is a well-known fact that many solid tumors feature an abnormal vasculature, characterized by poorly organized, leaky and irregular vessels [1] . The main cause of this chaotic web is the pro-angiogenic switch the tumor permanently turns on by releasing factors such as tumour growth factor-β (TGF-β), platelet-derived growth factor-β (PDGF-β) and vascular endothelial growth factor (VEGF) [2] .…”

“…The classic hypoxia signalling pathway is triggered by the activation of hypoxia-inducible factors (HIFs) composed of two subunits: an alpha (HIF-1α, HIF-2α, or HIF-3α) and a beta (HIF-1β) [ 1 , 8 , 9 ]. In the presence of oxygen, two proline residues of the HIF-α subunit are subject to hydroxylation by prolyl hydroxylase domain proteins (PHDs), which allows the interaction between HIF-α and the von Hippel-Lindau protein (pVHL) [10] .…”

“…1 ) [14] . More than 100 genes are regulated by HIF, influencing a large range of cellular functions such as angiogenesis, metabolism, cell proliferation, immunity, invasion/metastasis and apoptosis [ 1 , 7 , 15 ].

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