FMISO-PET-derived brain oxygen tension maps: application to glioblastoma and less aggressive gliomas

Chakhoyan, Ararat; Guillamo, Jean-Sébastien; Collet, S.; Kauffmann, F.; Delcroix, Nicolas; Lechapt‐Zalcman, Emmanuèle; Constans, Jean-Marc; Petit, Edwige; MacKenzie, Eric T.; Barré, Louisa; Bernaudin, Myriam; Touzani, Omar; Valable, Samuel

doi:10.1038/s41598-017-08646-y

Cited by 24 publications

(25 citation statements)

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“…Hypoxia, resulting from an inadequacy between oxygen supply and demand, is noticeably pronounced in various solid tumors such as glioblastoma (GB). While in the normal brain oxygen pressure ranges between 30 and 60 mmHg, it is suspected to be less than 10 mmHg in hypoxic brain tumors and can be less than 1 mmHg in some tumor areas [1, 2].…”

Section: Introductionmentioning

confidence: 99%

64Cu-ATSM/64Cu-Cl2 and their relationship to hypoxia in glioblastoma: a preclinical study

et al. 2019

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BackgroundDiacetyl-bis(N4-methylthiosemicarbazone), labeled with 64Cu (64Cu-ATSM) has been suggested as a promising tracer for imaging hypoxia. However, various controversial studies highlighted potential pitfalls that may disable its use as a selective hypoxic marker. They also highlighted that the results may be tumor location dependent. Here, we first analyzed uptake of Cu-ATSM and its less lipophilic counterpart Cu-Cl2 in the tumor over time in an orthotopic glioblastoma model. An in vitro study was also conducted to investigate the hypoxia-dependent copper uptake in tumor cells. We then further performed a comprehensive ex vivo study to compare 64Cu uptake to hypoxic markers, specific cellular reactions, and also transporter expression.MethodsμPET was performed 14 days (18F-FMISO), 15 days (64Cu-ATSM and 64Cu-Cl2), and 16 days (64Cu-ATSM and 64Cu-Cl2) after C6 cell inoculation. Thereafter, the brains were withdrawn for further autoradiography and immunohistochemistry. C6 cells were also grown in hypoxic workstation to analyze cellular uptake of Cu complexes in different oxygen levels.ResultsIn vivo results showed that Cu-ASTM and Cu-Cl2 accumulated in hypoxic areas of the tumors. Cu-ATSM also stained, to a lesser extent, non-hypoxic regions, such as regions of astrogliosis, with high expression of copper transporters and in particular DMT-1 and CTR1, and also characterized by the expression of elevated astrogliosis. In vitro results show that 64Cu-ATSM showed an increase in the uptake only in severe hypoxia at 0.5 and 0.2% of oxygen while for 64Cu-Cl2, the cell retention was significantly increased at 5% and 1% of oxygen with no significant rise at lower oxygen percentages.ConclusionIn the present study, we show that Cu-complexes undoubtedly accumulate in hypoxic areas of the tumors. This uptake may be the reflection of a direct dependency to a redox metabolism and also a reflection of hypoxic-induced overexpression of transporters. We also show that Cu-ATSM also stained non-hypoxic regions such as astrogliosis.

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Section: Introductionmentioning

confidence: 99%

64Cu-ATSM/64Cu-Cl2 and their relationship to hypoxia in glioblastoma: a preclinical study

et al. 2019

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“…Most of them are based on nitroimidazole compounds and demonstrate similar oxygen dependent binding kinetics as pimonidazole [ 53 ]. The tracer uptake is therefore directly related to hypoxia level ( Figure 4 C) [ 54 , 55 , 56 ]. Frequently used nitroimidazole tracers, 18 F-fluoromisonidazole ( 18 F-FMISO) and 18 F-fluoroazomycin-arabinoside ( 18 F-FAZA), show half maximum binding at about 0.1–0.3% O 2 (0.8-2.1 mmHg) in vitro [ 57 , 58 , 59 ].…”

Section: Quantification Of Hypoxia Levelsmentioning

confidence: 99%

Tumor Hypoxia as a Barrier in Cancer Therapy: Why Levels Matter

Hompland

Fjeldbo

Lyng

2021

Cancers

107

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Hypoxia arises in tumor regions with insufficient oxygen supply and is a major barrier in cancer treatment. The distribution of hypoxia levels is highly heterogeneous, ranging from mild, almost non-hypoxic, to severe and anoxic levels. The individual hypoxia levels induce a variety of biological responses that impair the treatment effect. A stronger focus on hypoxia levels rather than the absence or presence of hypoxia in our investigations will help development of improved strategies to treat patients with hypoxic tumors. Current knowledge on how hypoxia levels are sensed by cancer cells and mediate cellular responses that promote treatment resistance is comprehensive. Recently, it has become evident that hypoxia also has an important, more unexplored role in the interaction between cancer cells, stroma and immune cells, influencing the composition and structure of the tumor microenvironment. Establishment of how such processes depend on the hypoxia level requires more advanced tumor models and methodology. In this review, we describe promising model systems and tools for investigations of hypoxia levels in tumors. We further present current knowledge and emerging research on cellular responses to individual levels, and discuss their impact in novel therapeutic approaches to overcome the hypoxia barrier.

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“…However, these methods are much more complex than DPBC and require specific algorithms and software for numerical processing steps (67). Some methods are proposed (68) but remain subject to discussion (69). Some authors consider a linear transformation of the image intensity into a prescribed dose (65, 67), whereas others assume a “dose redistribution” between hypoxic and normoxic pixels resulting in the same average dose as a conventional RT plan (58, 62, 70).…”

Section: Hypoxia From the Radiation Oncologist's Point Of Viewmentioning

confidence: 99%

“…For head and neck tumors, Toma-Dasu et al used a nonlinearity approach, which considers that the relationship between [ 18 F]-FMISO uptake and ptO 2 follows a hyperbolic function (65). This equation was adapted for brain tumors and fine-tuned patient by patient using two healthy regions of interest for calibration of the model (68). This approach enables the computation of ptO 2 maps.…”

Section: Hypoxia From the Radiation Oncologist's Point Of Viewmentioning

confidence: 99%

Hypoxia Imaging and Adaptive Radiotherapy: A State-of-the-Art Approach in the Management of Glioma

et al. 2019

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Severe hypoxia [oxygen partial pressure (pO 2 ) below 5–10 mmHg] is more frequent in glioblastoma multiforme (GBM) compared to lower-grade gliomas. Seminal studies in the 1950s demonstrated that hypoxia was associated with increased resistance to low–linear energy transfer (LET) ionizing radiation. In experimental conditions, the total radiation dose has to be multiplied by a factor of 3 to achieve the same cell lethality in anoxic situations. The presence of hypoxia in human tumors is assumed to contribute to treatment failures after radiotherapy (RT) in cancer patients. Therefore, a logical way to overcome hypoxia-induced radioresistance would be to deliver substantially higher doses of RT in hypoxic volumes delineated on pre-treatment imaging as biological target volumes (BTVs). Such an approach faces various fundamental, technical, and clinical challenges. The present review addresses several technical points related to the delineation of hypoxic zones, which include: spatial accuracy, quantitative vs. relative threshold, variations of hypoxia levels during RT, and availability of hypoxia tracers. The feasibility of hypoxia imaging as an assessment tool for early tumor response to RT and for predicting long-term outcomes is discussed. Hypoxia imaging for RT dose painting is likewise examined. As for the radiation oncologist's point of view, hypoxia maps should be converted into dose-distribution objectives for RT planning. Taking into account the physics and the radiobiology of various irradiation beams, preliminary in silico studies are required to investigate the feasibility of dose escalation in terms of normal tissue tolerance before clinical trials are undertaken.

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FMISO-PET-derived brain oxygen tension maps: application to glioblastoma and less aggressive gliomas

Cited by 24 publications

References 25 publications

64Cu-ATSM/64Cu-Cl2 and their relationship to hypoxia in glioblastoma: a preclinical study

64Cu-ATSM/64Cu-Cl2 and their relationship to hypoxia in glioblastoma: a preclinical study

Tumor Hypoxia as a Barrier in Cancer Therapy: Why Levels Matter

Hypoxia Imaging and Adaptive Radiotherapy: A State-of-the-Art Approach in the Management of Glioma

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