Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

Ragnum, Harald Bull; Røe, Kathrine; Holm, Ruth; Vlatkovic, Ljiljana; Nesland, Jahn M.; Aarnes, Eva‐Katrine; Ree, Anne Hansen; Flatmark, Kjersti; Seierstad, Therese; Lilleby, Wolfgang; Lyng, Heidi

doi:10.1016/j.ijrobp.2013.07.023

Cited by 22 publications

(21 citation statements)

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“…Still, a significant proportion of patients relapses, and a hypoxia biomarker could be useful for planning radiotherapy initiation and a possible need for concurrent hypoxia targeted therapy. In a xenograft model system, we demonstrated ADT-driven down-regulation of HIF1 target genes without changes in the hypoxic fraction 356 . The down-regulation was probably a consequence of androgen withdrawal per se, since AR activation by androgens can contribute to HIF1 activation in a reversible manner 357,358 .…”

Section: Assessment Of Tumour Hypoxia Using Hypoxic Metagenesmentioning

confidence: 87%

Targeting tumour hypoxia to prevent cancer metastasis. From biology, biosensing and technology to drug development: the METOXIA consortium

Pettersen

Ebbesen

Gieling

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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The hypoxic areas of solid cancers represent a negative prognostic factor irrespective of which treatment modality is chosen for the patient. Still, after almost 80 years of focus on the problems created by hypoxia in solid tumours, we still largely lack methods to deal efficiently with these treatment-resistant cells. The consequences of this lack may be serious for many patients: Not only is there a negative correlation between the hypoxic fraction in tumours and the outcome of radiotherapy as well as many types of chemotherapy, a correlation has been shown between the hypoxic fraction in tumours and cancer metastasis. Thus, on a fundamental basis the great variety of problems related to hypoxia in cancer treatment has to do with the broad range of functions oxygen (and lack of oxygen) have in cells and tissues. Therefore, activation-deactivation of oxygen-regulated cascades related to metabolism or external signalling are important areas for the identification of mechanisms as potential targets for hypoxia-specific treatment. Also the chemistry related to reactive oxygen radicals (ROS) and the biological handling of ROS are part of the problem complex. The problem is further complicated by the great variety in oxygen concentrations found in tissues. For tumour hypoxia to be used as a marker for individualisation of treatment there is a need for non-invasive methods to measure oxygen routinely in patient tumours. A large-scale collaborative EU-financed project 2009-2014 denoted METOXIA has studied all the mentioned aspects of hypoxia with the aim of selecting potential targets for new hypoxia-specific therapy and develop the first stage of tests for this therapy. A new non-invasive PET-imaging method based on the 2-nitroimidazole [(18)F]-HX4 was found to be promising in a clinical trial on NSCLC patients. New preclinical models for testing of the metastatic potential of cells were developed, both in vitro (2D as well as 3D models) and in mice (orthotopic grafting). Low density quantitative real-time polymerase chain reaction (qPCR)-based assays were developed measuring multiple hypoxia-responsive markers in parallel to identify tumour hypoxia-related patterns of gene expression. As possible targets for new therapy two main regulatory cascades were prioritised: The hypoxia-inducible-factor (HIF)-regulated cascades operating at moderate to weak hypoxia (<1% O(2)), and the unfolded protein response (UPR) activated by endoplasmatic reticulum (ER) stress and operating at more severe hypoxia (<0.2%). The prioritised targets were the HIF-regulated proteins carbonic anhydrase IX (CAIX), the lactate transporter MCT4 and the PERK/eIF2α/ATF4-arm of the UPR. The METOXIA project has developed patented compounds targeting CAIX with a preclinical documented effect. Since hypoxia-specific treatments alone are not curative they will have to be combined with traditional anti-cancer therapy to eradicate the aerobic cancer cell population as well.

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Section: Assessment Of Tumour Hypoxia Using Hypoxic Metagenesmentioning

confidence: 87%

Targeting tumour hypoxia to prevent cancer metastasis. From biology, biosensing and technology to drug development: the METOXIA consortium

Pettersen

Ebbesen

Gieling

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

Self Cite

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“…The clinical importance of HIF-1α expression in prostate cancer has been demonstrated and HIF-1α has been examined as a potential prognostic marker, being elevated in high grade PIN and not BPH [54]. Response to androgen deprivation therapy in mice with CWR22RV1 xenografts, suggests that AR may regulate HIF-1α levels, as expression of both AR and HIF-1α target genes were affected even outside of hypoxic tumor areas [55]. …”

Section: Transcription Factors That Regulate Androgen Induction Ofmentioning

confidence: 99%

The Androgen Receptor and VEGF: Mechanisms of Androgen-Regulated Angiogenesis in Prostate Cancer

Eisermann

Fraizer

2017

Cancers

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Prostate cancer progression is controlled by the androgen receptor and new blood vessel formation, or angiogenesis, which promotes metastatic prostate cancer growth. Angiogenesis is induced by elevated expression of vascular endothelial growth factor (VEGF). VEGF is regulated by many factors in the tumor microenvironment including lowered oxygen levels and elevated androgens. Here we review evidence delineating hormone mediated mechanisms of VEGF regulation, including novel interactions between the androgen receptor (AR), epigenetic and zinc-finger transcription factors, AR variants and the hypoxia factor, HIF-1. The relevance of describing the impact of both hormones and hypoxia on VEGF expression and angiogenesis is revealed in recent reports of clinical therapies targeting both VEGF and AR signaling pathways. A better understanding of the complexities of VEGF expression could lead to improved targeting and increased survival time for a subset of patients with metastatic castration-resistant prostate cancer.

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“…In those same patients, it has been reported that the administration of neo‐adjuvant AD results in an increase in tumor oxygenation in the prostate. Such a change would tend to enhance radiation response . This androgen suppression induced increase in prostate cancer oxygenation has been confirmed in another report by measuring hypoxia inducible factor‐1α (HIF‐1α) expression before and after ADT.…”

Section: Discussionmentioning

confidence: 60%

Androgen withdrawal fails to induce detectable tissue hypoxia in the rat prostate

et al. 2014

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BACKGROUND It has been reported that significant hypoxia may occur in the rat prostate following androgen deprivation (AD). It is well known that hypoxia substantially reduces radiation sensitivity of cells both in vitro and in vivo. Given that contemporary management of men with intermediate and high-risk prostate cancer includes the use of neoadjuvant androgen suppression and radiation, AD-induced hypoxia in the prostate could result in suboptimal therapeutic results. Given this concern, we fully investigate possible AD-induced hypoxia in the ventral prostate (VP) of adult rats by two independent methods. METHODS Tissue pO2 levels in the VP of adult Spraque-Dawley rats were evaluated prior to and at various time points following castration by two independent techniques. First, an Oxylab tissue oxygen monitor with a 240 μm probe was used for quantitative monitoring of global VP oxygenation. Second, fluorescence immunohistochemistry using the hypoxia marker EF5, known to be metabolically activated by hypoxic cells, was used to evaluate cell-to-cell variation in hypoxia at various days post-castration. RESULTS Neither the oxygen probe nor EF5 method demonstrate any substantive change in pO2 levels in the rat VP at any time point post-castration. CONCLUSIONS We find no evidence that the rat VP becomes hypoxic at any point following castration using an animal model that closely mimics the human prostate. These data are in contrast to previous reports suggesting prostatic hypoxia occurs following AD and provide assurance that our present therapeutic strategy of neoadjuvant AD followed by radiation is not compromised by AD-induced tissue hypoxia.

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Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

Cited by 22 publications

References 30 publications

Targeting tumour hypoxia to prevent cancer metastasis. From biology, biosensing and technology to drug development: the METOXIA consortium

Targeting tumour hypoxia to prevent cancer metastasis. From biology, biosensing and technology to drug development: the METOXIA consortium

The Androgen Receptor and VEGF: Mechanisms of Androgen-Regulated Angiogenesis in Prostate Cancer

Androgen withdrawal fails to induce detectable tissue hypoxia in the rat prostate

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