Preconditioning of the Tumor Vasculature and Tumor Cells by Intermittent Hypoxia: Implications for Anticancer Therapies

Martinive, Philippe; Defresne, Florence; Bouzin, Caroline; Saliez, Julie; Lair, Florence; Grégoire, Vincent; Michiels, Carine; Dessy, Chantal; Feron, Olivier

doi:10.1158/0008-5472.can-06-2056

Cited by 175 publications

(187 citation statements)

References 36 publications

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“…Cycling hypoxia has been shown to render tumors more invasive in animal models (10,11). Moreover, cycling hypoxia positively modulates angiogenic processes and radioresistance in the vascular endothelium of tumors (9). We report here that both noninterrupted and cycling hypoxia pretreatment significantly increases cell resistance to ionizing radiation compared with normoxic controls in U87 cells or U87 glioma xenografts.…”

Section: Discussionmentioning

confidence: 70%

“…There is ample evidence to suggest that cycling hypoxia as well as chronic hypoxia play roles in many aspects of tumor development and growth (9)(10)(11). In vitro and in vivo studies have shown that cycling hypoxia can modulate tumor growth, angiogenesis, invasion and metastasis in several tumor models.…”

Section: Introductionmentioning

confidence: 99%

“…These complex effects may be regulated by hypoxia-inducible factor-1 (HIF-1). Although the detailed mechanism is complex and still unclear, recent studies have shown that cycling hypoxia can promote HIF-1 stabilization and increase HIF-1 transcriptional activity (9). HIF-1 has been referred to as a critical transcription factor that, in hypoxia, drives the induction or repression of a myriad of genes controlling multiple cell functions such as angiogenesis, metabolism, invasion, metastasis, apoptosis and therapy resistance (12,13).…”

Section: Introductionmentioning

confidence: 99%

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Cycling hypoxia increases U87 glioma cell radioresistance via ROS induced higher and long-term HIF-1 signal transduction activity

Hsieh¹,

Lee

Liang³

et al. 2010

Oncol Rep

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Abstract. Glioblastoma multiforme (GBM) tumors are the most common type of brain tumors and resistance to radiotherapy. This study aimed to investigate the differential effect and mechanism of tumor microenvironments, cycling hypoxia and non-interrupted hypoxia, on tumor cell radiosensitivity in the human U87 glioblastoma tumor model. We exposed U87 cells and mice bearing U87 glioma to experimentally imposed cycling or non-interrupted hypoxic stress in vitro and in vivo prior to treatment with ionizing irradiation. Clonogenic survival assay and tumor growth measurements were performed to determine tumor radiosensitivity. The differential regulation of non-interrupted vs. cycling hypoxia by hypoxia-inducible factor-1 (HIF-1) and the impact of HIF-1· on hypoxia-induced radioresistance were assessed by molecular assay and RNAiknockdown technology. Our results demonstrated that cycling hypoxia induced higher and longer term HIF-1 signal transduction activity via reactive oxygen species (ROS) in U87 cells compared with non-interrupted hypoxia. Cycling hypoxiainduced HIF-1· activation reflected ROS mediated HIF-1· synthesis and stabilization, whereas non-interrupted hypoxiainduced HIF-1· activation was due to decreased HIF-1· degradation resulting from decreased prolyl hydroxylation. With regard to tumor radiosensitivity, cycling hypoxia induced more tumor cell radioresistance and a decreased response to radiotherapy in U87 cells compared with non-interrupted hypoxia. HIF-1 knockdown during in vitro and in vivo hypoxic stresses combined with radiotherapy suppressed cycling and non-interrupted hypoxia-induced radioresistance while increasing overall tumor radiosensitivity. Our results suggest that cycling hypoxia induces more radioresistance than non-interrupted hypoxia in U87 gliomas, and ROS mediated HIF-1· activation is a crucial mechanism involved in hypoxia-induced differential radioresistant in U87 gliomas.

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Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cycling hypoxia increases U87 glioma cell radioresistance via ROS induced higher and long-term HIF-1 signal transduction activity

Hsieh¹,

Lee

Liang³

et al. 2010

Oncol Rep

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“…Repeated exposure of endothelial cells to hypoxia and reoxygenation can lead to much greater upregulation of HIF1α than can be achieved by chronic exposure to hypoxia. This effect may be regulated by increased phosphorylation of HIF1α 102,103 . Cycling hypoxia can also be expected to increase levels of free radicals, as a result of hypoxia-reoxygenation injury.…”

Section: Mechanisms Underlying Cycling Hypoxia and Implicationsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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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...

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“…Functional interference with HIF-1 α in various tumor cells has been shown to result in enhanced cell death upon treatment with chemotherapeutic agents (Ricker et al , 2004 ;Peng et al , 2006 ;Hao et al , 2008 ;Sermeus et al , 2008 ;Flamant et al , 2010 ). However, experimentally increasing HIF-1 α enhanced therapy resistance (Ji et al , 2006 ;Martinive et al , 2006 ). Of note, HIF-1 in germ cells of Ceanorhabditis elegans has recently been reported to antagonize p53-mediated apoptosis due to DNA damage (Sendoel et al , 2010 ).…”

Section: Targeting Hif To Improve Cancer Therapymentioning

confidence: 99%

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia

Wrann

Kaufmann²,

Wirthner³

et al. 2013

Biological Chemistry

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Abstract:The histone variant 2AX (H2AX) is phosphorylated at Serine 139 by the PI3K-like kinase family members ATM, ATR and DNA-PK. Genotoxic stress, such as tumor radioand chemotherapy, is considered to be the main inducer of phosphorylated H2AX ( γ H2AX), which forms distinct foci at sites of DNA damage where DNA repair factors accumulate. γ H2AX accumulation under severe hypoxic/anoxic (0.02 % oxygen) conditions has recently been reported to follow replication fork stalling in the absence of detectable DNA damage. In this study, we found HIF-dependent accumulation of γ H2AX in several cancer cell lines and mouse embryonic fibroblasts exposed to physiologically relevant chronic hypoxia (0.2 % oxygen), which did not induce detectable levels of DNA strand breaks. The hypoxic accumulation of γ H2AX was delayed by the RNAi-mediated knockdown of HIF-1 α or HIF-2 α and further decreased when both HIF-α s were absent. Conversely, basal phosphorylation of H2AX was increased in cells with constitutively stabilized HIF-2 α . These results suggest that both HIF-1 and HIF-2 are involved in γ H2AX accumulation by tumor hypoxia, which might increase a cancer cell ' s capacity to repair DNA damage, contributing to tumor therapy resistance.

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Preconditioning of the Tumor Vasculature and Tumor Cells by Intermittent Hypoxia: Implications for Anticancer Therapies

Cited by 175 publications

References 36 publications

Cycling hypoxia increases U87 glioma cell radioresistance via ROS induced higher and long-term HIF-1 signal transduction activity

Cycling hypoxia increases U87 glioma cell radioresistance via ROS induced higher and long-term HIF-1 signal transduction activity

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia

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