HIF-1α, pimonidazole, and iododeoxyuridine to estimate hypoxia and perfusion in human head-and-neck tumors

Janssen, Hilde; Haustermans, Karin; Sprong, Debbie; Blommestijn, G.J.F.; Hofland, Ingrid; Hoebers, Frank; Blijweert, Elke; Raleigh, James A.; Semenza, Gregg L.; Varia, Mahesh A.; Balm, Alfons J. M.; Velthuysen, Marie‐Louise F. van; Delaere, Pierre; Sciot, Raf; Begg, Adrian C.

doi:10.1016/s0360-3016(02)03935-4

Cited by 112 publications

(84 citation statements)

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“…In cervical cancer it has been shown that there is good correlation between the expression of HIF1 targets and the hypoxia marker drug, pimonidazole 50 , but in other reports there has been poor correlation between HIF1 or its regulated cytokine VEGF 51 and localization of hypoxia marker drugs 52,53 . Given the complexities involved in regulating HIF1α, as outlined above, it comes as no surprise that there is generally a lack of correlation between hypoxia and HIF1 levels in tumours.…”

Section: Free Radical Regulation Of Hif1 Under Hypoxic Conditionsmentioning

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: Free Radical Regulation Of Hif1 Under Hypoxic Conditionsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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“…A recurring theme in the study of endogenous hypoxia markers -whether it be HIF-1a, CAIX, Glut-1 or involucrin -is heterogeneity of expression (Olive et al, 2001;Wiesener et al, 2001;Haugland et al, 2002;Janssen et al, 2002;Kaanders et al, 2002;Airley et al, 2003). The basis for heterogeneity in the case of involucrin appears to be related to cell differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…The basis for heterogeneity in the case of involucrin appears to be related to cell differentiation. In the case of HIF-1a, functional inactivation of the von Hippel Lindau factor might be the most important factor (Wiesener et al, 2001;Haugland et al, 2002;Janssen et al, 2002;Turner et al, 2002). Endogenous ORPs appear to be useful as hypoxia markers in normal tissues (e.g.…”

Section: Discussionmentioning

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).…”

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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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“…To date, various methods are available to measure tumour oxygenation, including polarographic oxygen sensors (Vaupel et al, 1991), luminescence-based optical sensors (Bussink et al, 2000) and antibody-based detection of exogenous (Haustermans et al, 2000;Raleigh et al, 2001;Koch, 2002) and endogenous markers of hypoxia (Wykoff et al, 2000;Janssen et al, 2002;Airley et al, 2003). At this time, only the polarographic oxygen-sensor and the exogenous hypoxia marker pimonidazole (PIMO) can be considered as 'standard'.…”

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confidence: 99%

Evaluation of hypoxia in an experimental rat tumour model by [18F]Fluoromisonidazole PET and immunohistochemistry

et al. 2004

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This study aimed to evaluate tumour hypoxia by comparing [ 18 F]Fluoromisonidazole uptake measured using positron emission tomography ([ 18 F]FMISO-PET) with immunohistochemical (IHC) staining techniques. Syngeneic rhabdomyosarcoma (R1) tumour pieces were transplanted subcutaneously in the flanks of WAG/Rij rats. Tumours were analysed at volumes between 0.9 and 7.3 cm 3 . Hypoxic volumes were defined using a 3D region of interest on 2 h postinjection [ 18 F]FMISO-PET images, applying different thresholds (1.2 -3.0). Monoclonal antibodies to pimonidazole (PIMO) and carbonic anhydrase IX (CA IX), exogenous and endogenous markers of hypoxia, respectively, were used for IHC staining. Marker-positive fractions were microscopically measured for each tumour, and hypoxic volumes were calculated. A heterogeneous distribution of hypoxia was observed both with histology and

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HIF-1α, pimonidazole, and iododeoxyuridine to estimate hypoxia and perfusion in human head-and-neck tumors

Cited by 112 publications

References 40 publications

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

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

Evaluation of hypoxia in an experimental rat tumour model by [18F]Fluoromisonidazole PET and immunohistochemistry

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