Evidence that hypoxia markers detect oxygen gradients in liver: pimonidazole and retrograde perfusion of rat liver

Arteel, Gavin E.; Thurman, Ronald G.; Yates, J. M.; Raleigh, James A.

doi:10.1038/bjc.1995.429

Cited by 267 publications

(220 citation statements)

References 33 publications

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“…Hypoxia has diverse roles in the function of these normal tissues. Hepatocytes surrounding the central vein have been shown to be hypoxic 19,20 , and their location coincides with overexpression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF, also known as FGF2) 21 . In an unperturbed state, there is no angiogenesis, so the cytokines are probably bound to proteoglycans, which maintain them in an inactive state 22,23 .…”

Section: Regulation Of Hif1 By Hypoxiamentioning

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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Section: Regulation Of Hif1 By Hypoxiamentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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“…We injected wild-type C57BL/6 mice with pimonidazole (Hypoxyprobe-1), a marker substance suitable to detect local oxygen gradients below 10 mm Hg (Arteel et al, 1995;Gross et al, 1995). This threshold is within the physiologic range of brain tissue oxygen levels (Ndubuizu and LaManna, 2007).…”

Section: Hba Expression Correlates To Tissue Oxygen Levels In the Moumentioning

confidence: 99%

Expression of Hemoglobin in Rodent Neurons

Schelshorn

Schneider²,

Kuschinsky

et al. 2008

J Cereb Blood Flow Metab

132

119

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Hemoglobin is the major protein in red blood cells and transports oxygen from the lungs to oxygen-demanding tissues, like the brain. Mechanisms that facilitate the uptake of oxygen in the vertebrate brain are unknown. In invertebrates, neuronal hemoglobin serves as intracellular storage molecule for oxygen. Here, we show by immunohistochemistry that hemoglobin is specifically expressed in neurons of the cortex, hippocampus, and cerebellum of the rodent brain, but not in astrocytes and oligodendrocytes. The neuronal hemoglobin distribution is distinct from the neuroglobin expression pattern on both cellular and subcellular levels. Probing for low oxygen levels in the tissue, we provide evidence that hemoglobin a-positive cells in direct neighborhood with hemoglobin a-negative cells display a better oxygenation than their neighbors and can be sharply distinguished from those. Neuronal hemoglobin expression is upregulated by injection or transgenic overexpression of erythropoietin and is accompanied by enhanced brain oxygenation under physiologic and hypoxic conditions. Thus we provide a novel mechanism for the neuroprotective actions of erythropoietin under ischemic-hypoxic conditions. We propose that neuronal hemoglobin expression is connected to facilitated oxygen uptake in neurons, and hemoglobin might serve as oxygen capacitator molecule.

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“…The hypoxia marker, pimonidazole hydrochloride (Hypoxyprobet-1; Chemicon International Inc., Temecula, CA, USA), was used as previously described (Arteel et al, 1995;Kennedy et al, 1997;Varia et al, 1998;Raleigh et al, 1999Raleigh et al, , 2000 …”

Section: Chemicalsmentioning

confidence: 99%

“…Local control is believed to depend on local radiation response while distant spread is thought to depend, at least in part, on the induction of oxygen-regulated proteins. In order to test this, pimonidazole, an extrinsic marker for tissue hypoxia (Arteel et al, 1995;Kennedy et al, 1997;Varia et al, 1998;Raleigh et al, 1999), with prognostic value (Kaanders et al, 2002) was used to examine whether ORPs such as VEGF (Raleigh et al, 1998a), metallothionein (Raleigh et al, 2000), HIF-1a (Janssen et al, 2002), Glut-1 (Airley et al, 2003) and CAIX (Olive et al, 2001) were, in fact, associated with cellular hypoxia in human tumours. Unexpectedly, VEGF and metallothionein (MT) were not expressed in the majority of hypoxic cells in squamous cell carcinomas (Raleigh et al, 1998a(Raleigh et al, , 2000 even though these ORPs were induced by hypoxia in experimental systems (Shweiki et al, 1992;Raleigh et al, 1998b;Murphy et al, 1999).…”

mentioning

confidence: 99%

“…Many oxygen-regulated processes are half maximally induced at oxygen partial pressures (K m ¼ 6 -20 mmHg) (Leith and Michelson, 1995;Jiang et al, 1996;Chiarotto and Hill, 1999;Wykoff et al, 2000) that would strongly inhibit the binding of nitroimidazole hypoxia markers such as pimonidazole, EF5 and misonidazole (K m ¼ 0.8 -2.0 mmHg) (Franko et al, 1987;Arteel et al, 1995;Gross et al, 1995;Koch et al, 1995). This could account for the immunostaining patterns for Glut-1 and CAIX.…”

mentioning

confidence: 99%

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Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas

Azuma

et al. 2004

Br J Cancer

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The majority of hypoxic cells in squamous cell carcinomas of the head and neck and cervix express involucrin, a molecular marker for differentiation. This raises the question of whether involucrin is an oxygen-regulated protein and, if so, whether it could serve as an endogenous marker for tumour hypoxia. Consistent with oxygen regulation, involucrin protein was found to increase with increasing hypoxia in confluent cultures of moderately differentiated human SCC9 cells. Cells harvested at the point of confluence and exposed to graded concentrations of oxygen revealed a K m of approximately 15 mmHg for involucrin induction. This is similar to K m s for HIF1a, CAIX and VEGF. Involucrin induction showed a steep dependence on pO 2 with a transition from minimum to maximum expression occurring over less than an order of magnitude change in pO 2 . In contrast to SCC9 cells, involucrin was not induced by hypoxia in poorly differentiated SCC4 cells. It is concluded that involucrin is an oxygen-regulated protein, but that differentiation modulates its transcription status with respect to hypoxia induction.

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Evidence that hypoxia markers detect oxygen gradients in liver: pimonidazole and retrograde perfusion of rat liver

Cited by 267 publications

References 33 publications

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Expression of Hemoglobin in Rodent Neurons

Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas

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