Hypoxia and Predicting Radiation Response

Hill, Richard P.; Bristow, Robert G.; Fyles, Anthony; Koritzinsky, Marianne; Milosevic, Michael; Wouters, Bradly G.

doi:10.1016/j.semradonc.2015.05.004

Cited by 78 publications

(68 citation statements)

References 137 publications

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“…A review of various endogenous hypoxia markers in cervix cancer including CA9 argued that they had limited prognostic value relative to direct measurements of hypoxic levels [61]. These results may reflect the fact that HIF-1α can be upregulated by a variety of factors and/or that hypoxia can play a variety of roles in the survival of tumour cells [62]. However, we and others have demonstrated that a sorted CA9 + population from ME180- or SiHa-derived xenografts constitute an hypoxic population [35, 36].…”

Section: Discussionmentioning

confidence: 99%

Cancer initiating-cells are enriched in the CA9 positive fraction of primary cervix cancer xenografts

et al. 2016

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Numerous studies have suggested that Cancer Initiating Cells (CIC) can be identified/enriched in cell populations obtained from solid tumors based on the expression of cell surface marker proteins. We used early passage primary cervix cancer xenografts to sort cells based on the expression of the intrinsic hypoxia marker Carbonic Anhydrase 9 (CA9) and tested their cancer initiation potential by limiting dilution assay. We demonstrated that CICs are significantly enriched in the CA9+ fraction in 5/6 models studied. Analyses of the expression of the stem cell markers Oct4, Notch1, Sca-1 & Bmi1 showed a trend toward an increase in the CA9+ populations, albeit not significant. We present evidence that enhanced autophagy does not play a role in the enhanced growth of the CA9+ cells. Our study suggests a direct in vivo functional link between hypoxic cells and CICs in primary cervix cancer xenografts.

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Section: Discussionmentioning

confidence: 99%

Cancer initiating-cells are enriched in the CA9 positive fraction of primary cervix cancer xenografts

et al. 2016

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“…23,26 Experimental studies demonstrate that hypoxia fosters resistance to RT through depleting free radicals and mitigating radiation-induced DNA damage. 27 Intratumoral hypoxia also mitigates chemotherapeutic efficacy, with abnormal vasculature impeding drug delivery, and decreased proliferation conferring resistance to agents that target rapidly dividing cells. 5,28 Here, we review the following six possible mechanisms of AAT resistance: i) enhanced invasion and migration, ii) shifts in cellular metabolism, iii) changes in autophagy regulation, iv) GBM stem cells (GSCs), v) GBM-EC transdifferentiation, and vi) vasoformative responses ( Figure 4).…”

Section: Bev-mediated Effects On Gbm Vasculature and Induction Of A Hmentioning

confidence: 99%

Hypoxia-Mediated Mechanisms Associated with Antiangiogenic Treatment Resistance in Glioblastomas

Mahase

Rattenni

Wesseling

et al. 2017

The American Journal of Pathology

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Glioblastomas (GBMs) are malignant tumors characterized by their vascularity and invasive capabilities. Antiangiogenic therapy (AAT) is a treatment option that targets GBM-associated vasculature to mitigate the growth of GBMs. However, AAT demonstrates transient effects because many patients eventually develop resistance to this treatment. Several recent studies attempt to explain the molecular and biochemical basis of resistance to AAT in GBM patients. Experimental investigations suggest that the induction of extensive intratumoral hypoxia plays a key role in GBM escape from AAT. In this review, we examine AAT resistance in GBMs, with an emphasis on six potential hypoxia-mediated mechanisms: enhanced invasion and migration, including increased expression of matrix metalloproteinases and activation of the c-MET tyrosine kinase pathway; shifts in cellular metabolism, including up-regulation of hypoxia inducible factor-1α's downstream processes and the Warburg effect; induction of autophagy; augmentation of GBM stem cell self-renewal; possible implications of GBM-endothelial cell transdifferentiation; and vasoformative responses, including vasculogenesis, alternative angiogenic pathways, and vascular mimicry. Juxtaposing recent studies on well-established resistance pathways with that of emerging mechanisms highlights the overall complexity of GBM treatment resistance while also providing direction for further investigation.

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“…Tumor oxygenation in situ is known to reach very low values, and repeated oxygen deprivation and reoxygenation promote tumor stem cell properties, metastasis, and negatively affect patient prognosis as adaptive responses to hypoxia severely decrease efficacy of both ionizing radiation and chemotherapy [2–7]. Hypoxia has also been shown to stimulate reprogramming and establishment of induced pluripotent stem cells [8–11].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia increases genome-wide bivalent epigenetic marking by specific gain of H3K27me3

Prickaerts

Adriaens

Beucken

et al. 2016

Epigenetics & Chromatin

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BackgroundTrimethylation at histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) controls gene activity during development and differentiation. Whether H3K4me3 and H3K27me3 changes dynamically in response to altered microenvironmental conditions, including low-oxygen conditions commonly present in solid tumors, is relatively unknown. Demethylation of H3K4me3 and H3K27me3 is mediated by oxygen and 2-oxoglutarate dioxygenases enzymes, suggesting that oxygen deprivation (hypoxia) may influence histone trimethylation. Using the MCF7 breast epithelial adenocarcinoma cell model, we have determined the relationship between epigenomic and transcriptomic reprogramming as a function of fluctuating oxygen tension.ResultsWe find that in MCF7, H3K4me3 and H3K27me3 marks rapidly increase at specific locations throughout the genome and are largely reversed upon reoxygenation. Whereas dynamic changes are relatively highest for H3K27me3 marking under hypoxic conditions, H3K4me3 occupation is identified as the defining epigenetic marker of transcriptional control. In agreement with the global increase of H3K27 trimethylation, we provide direct evidence that the histone H3K27me3 demethylase KDM6B/JMJD3 is inactivated by limited oxygen. In situ immunohistochemical analysis confirms a marked rise of histone trimethylation in hypoxic tumor areas. Acquisition of H3K27me3 at H3K4me3-marked loci results in a striking increase in “bivalent” epigenetic marking. Hypoxia-induced bivalency substantially overlaps with embryonal stem cell-associated genic bivalency and is retained at numerous loci upon reoxygenation. Transcriptional activity is selectively and progressively dampened at bivalently marked loci upon repeated exposure to hypoxia, indicating that this subset of genes uniquely maintains the potential for epigenetic regulation by KDM activity.ConclusionsThese data suggest that dynamic regulation of the epigenetic state within the tumor environment may have important consequences for tumor plasticity and biology.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0086-0) contains supplementary material, which is available to authorized users.

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Hypoxia and Predicting Radiation Response

Cited by 78 publications

References 137 publications

Cancer initiating-cells are enriched in the CA9 positive fraction of primary cervix cancer xenografts

Cancer initiating-cells are enriched in the CA9 positive fraction of primary cervix cancer xenografts

Hypoxia-Mediated Mechanisms Associated with Antiangiogenic Treatment Resistance in Glioblastomas

Hypoxia increases genome-wide bivalent epigenetic marking by specific gain of H3K27me3

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