Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Abstract

Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.Virchow first described the abnormal structure of tumour vessels using contrast agents in human tumours as early as the mid 1800s 1 . A few decades later, Goldman was among the first to suggest that angiogenesis was associated with tumour growth 2 . A number of other investigators in the nineteenth and early twentieth centuries evaluated tumour angiogenesis, using techniques such as microangiography, vascular casting and window chamber models. Warren has reviewed this early work in great detail 3 . Folkman illuminated the crucial role of tumour angiogenesis by hypothesizing that tumour growth was dependent upon angiogenesis and that, if angiogenesis could be inhibited, it could maintain tumour deposits in a quiescent state 4 . These early works set the stage for the concept that tumours require angiogenesis to provide a nutrient supply. Although it is well-established that angiogenesis occurs in nearly all human solid tumours, it does not occur in an efficient manner, leading to spatial and temporal inadequacies in delivery of oxygen and other nutrients. These inefficiencies in nutrient delivery lead to a brutal cycle of unsatisfied demand by the tumour, which drives continued aberrant angiogenesis.The transcription factor hypoxia-inducible factor 1 (HIF1) plays an important part in tumour progression by upregulating genes that control angiogenesis, meta-stasis and resistance to oxidative stress. It also controls the switch to anaerobic metabolism, which can maintain cell NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript viability under hypoxic conditions. Further, HIF1 activity can promote treatment resistance by promoting endothelial and tumour cell survival after cytotoxic therapy. The mechanisms that control HIF1 activity are complex and are influenced by microenvironmental factors involving hypoxia, oxidative and nitrosative stress.In this Review we will discuss four important and interrelated aspects of tumour hypoxia. First, we will define the hypoxic response, discussing its relevance in influencing tumour cell survival, behaviour and angiogenesis. We will examine the physiological factors that contribute to hypoxia, emphasizing a perspective based on spatial and temporal dysfunction of tumour microcirculation. The question of whethe...

Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells

“…Hypoxia is a general stress in various solid tumors and limits tumor growth (Dewhirst et al, 2008). Increased tumor cell resistance to hypoxia may therefore contribute to tumor progression.…”

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

“…A transient activation of HIF-1 could also be observed in growing tumors in vivo by using an allografted murine tumor model (Lehmann et al, 2009). As a consequence of the low structural order of neoplastic tissues and given the enormous plasticity of the tumor-sustaining vasculature, spatial and temporal tumor oxygenation is highly variable (Dewhirst et al, 2008;Lehmann et al, 2009). Thus, acute temporal fluctuations in tumor oxygenation might preferentially induce HIF-1, whereas chronically hypoxic tumor areas would be marked by enhanced HIF-2 levels.…”

MPT0B098, a Novel Microtubule Inhibitor That Destabilizes the Hypoxia-Inducible Factor-1α mRNA through Decreasing Nuclear–Cytoplasmic Translocation of RNA-Binding Protein HuR

“…HIF-1a is also hydroxylated by asparaginyl hydroxylase at asparagine 803 and blocks its interaction with the transcriptional coactivators CBP and p300 (5). Both prolyl and asparaginyl hydroxylation are inhibited under the hypoxic condition, which allows HIF1a to accumulate and subsequently leads to the transactivation of hundreds of downstream target genes involved in cell metabolism, survival, angiogenesis, and metastasis (6). Because of its central role in tumor progression and therapy resistance, HIF-1a might be considered an attractive target for cancer chemotherapy.…”