Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response

Ylitalo, Erik Bovinder; Thysell, Elin; Jernberg, Emma; Lundholm, Marie; Crnalic, Sead; Egevad, Lars; Stattin, Pär; Widmark, Anders; Bergh, Anders; Wikström, Pernilla

doi:10.1016/j.eururo.2016.07.033

Cited by 88 publications

(121 citation statements)

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“…The patient series has been previously described [10, 11] and clinical characteristics are summarized in Supplementary Table 1. Expression of IGF-1R was assessed by immunohistochemistry in 61 biopsies (patients) of which 42 had been previously profiled by whole-genome expression analysis [11] and data was available for functional enrichment analysis, see below. The study was approved by the local ethical review board of Umeå University.…”

Section: Methodsmentioning

confidence: 99%

“…Multivariate modelling by means of orthogonal projections to latent structures (OPLS) was used to extract systematic variation in whole-genome expression data from human PCa bone metastasis samples previously analysed [11], in relation to corresponding IGF-1R IHC score in each sample. OPLS-DA was performed in SIMCA version 14.0 (MKS Umetrics AB, Umeå, Sweden) on mean centred and unit variance scaled gene expression data and validated by cross-validation.…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of the insulin-like growth factor-1 receptor potentiates acute effects of castration in a rat model for prostate cancer growth in bone

Nordstrand

Bergström

Thysell

et al. 2017

Clin Exp Metastasis

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Prostate cancer (PCa) patients with bone metastases are primarily treated with androgen deprivation therapy (ADT). Less pronounced ADT effects are seen in metastases than in primary tumors. To test if acute effects of ADT was enhanced by concurrent inhibition of pro-survival insulin-like growth factor 1 (IGF-1), rats were inoculated with Dunning R3327-G tumor cells into the tibial bone marrow cavity and established tumors were treated with castration in combination with IGF-1 receptor (IGF-1R) inhibitor NVP-AEW541, or by each treatment alone. Dunning R3327-G cells were stimulated by androgens and IGF-1 in vitro. In rat tibia, Dunning R3327-G cells induced bone remodeling, identified through increased immunoreactivity of osteoblast and osteoclast markers. Tumor cells occasionally grew outside the tibia, and proliferation and apoptotic rates a few days after treatment were evaluated by scoring BrdU- and caspase-3-positive tumor cells inside and outside the bone marrow cavity, separately. Apoptosis was significantly induced outside, but unaffected inside, the tibial bone by either castration or NVP-AEW541, and the maximum increase (2.7-fold) was obtained by the combined treatment. Proliferation was significantly reduced by NVP-AEW541, independently of growth site, although the maximum decrease (24%) was observed when NVP-AEW541 was combined with castration. Tumor cell IGF-1R immunoreactivity was evaluated in clinical PCa bone metastases (n = 61), and positive staining was observed in most cases (74%). In conclusion, IGF-1R inhibition may be evaluated in combination with ADT in patients with metastatic PCa, or in combination with therapies for the subsequent development of castration-resistant disease, although diverse responses could be anticipated depending on metastasis site.Electronic supplementary materialThe online version of this article (doi:10.1007/s10585-017-9848-8) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Inhibition of the insulin-like growth factor-1 receptor potentiates acute effects of castration in a rat model for prostate cancer growth in bone

Nordstrand

Bergström

Thysell

et al. 2017

Clin Exp Metastasis

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“…Indeed, even at the metastatic level, androgensand more precisely the androgen receptor (AR)-are well known to stimulate proliferation (Bolla et al 2009;Ylitalo et al 2017). However, androgen deprivation therapy (ADT) does not cure PCa, as the disease eventually evolves to castration-resistant PCa (CRPC).…”

mentioning

confidence: 99%

“…However, androgen deprivation therapy (ADT) does not cure PCa, as the disease eventually evolves to castration-resistant PCa (CRPC). At this stage, several molecular mechanisms have been discovered, most of them leading to AR hyperactivation, including AR genomic amplification and mutation (Montgomery et al 2008;Robinson et al 2015;Watson et al 2015;Schweizer and Yu 2017;Ylitalo et al 2017). Consequently, further knowledge of downstream effectors of the AR is necessary to dissect the molecular mechanisms governing PCa progression and develop novel therapeutic approaches.…”

mentioning

confidence: 99%

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

et al. 2017

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Androgen receptor (AR) signaling reprograms cellular metabolism to support prostate cancer (PCa) growth and survival. Another key regulator of cellular metabolism is mTOR, a kinase found in diverse protein complexes and cellular localizations, including the nucleus. However, whether nuclear mTOR plays a role in PCa progression and participates in direct transcriptional cross-talk with the AR is unknown. Here, via the intersection of gene expression, genomic, and metabolic studies, we reveal the existence of a nuclear mTOR-AR transcriptional axis integral to the metabolic rewiring of PCa cells. Androgens reprogram mTOR-chromatin associations in an AR-dependent manner in which activation of mTOR-dependent metabolic gene networks is essential for androgeninduced aerobic glycolysis and mitochondrial respiration. In models of castration-resistant PCa cells, mTOR was capable of transcriptionally regulating metabolic gene programs in the absence of androgens, highlighting a potential novel castration resistance mechanism to sustain cell metabolism even without a functional AR. Remarkably, we demonstrate that increased mTOR nuclear localization is indicative of poor prognosis in patients, with the highest levels detected in castration-resistant PCa tumors and metastases. Identification of a functional mTOR targeted multigene signature robustly discriminates between normal prostate tissues, primary tumors, and hormone refractory metastatic samples but is also predictive of cancer recurrence. This study thus underscores a paradigm shift from AR to nuclear mTOR as being the master transcriptional regulator of metabolism in PCa.

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“…In general, testosterone is considered as an anti-inflammatory while estrogens are more proinflammatory, but several studies show shared effects on immune cells between hormones (indicated in red). References not cited in text: androgens on T helper cells (Sutherland et al 2005, Hepworth et al 2010, Fijak et al 2011, Andersson et al 2015, Wang et al 2017b) and on DCs (Koh et al 2009, Corrales et al 2012; estrogens on T helper cells (Correale et al 1998, Maret et al 2003, Lélu et al 2011, Morse & McNeel 2012, Chen et al 2015 and on DCs (Zhang et al 2004 linked to patient outcomes (Ylitalo et al 2016, Strömvall et al 2017, emphasizing the importance of understanding this biology. The receptor and non-receptor-mediated effects of steroids on innate immune cells have been widely studied in experimental animal models as well as in clinical studies of many diseases (Trigunaite et al 2015, Roved et al 2017.…”

Section: Sex Steroids and The Immune Tumor Microenvironment Effect Ofmentioning

confidence: 99%

Sex steroids in the tumor microenvironment and prostate cancer progression

Boibessot¹,

Toren²

2018

Endocrine-Related Cancer

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Prostate cancer is uniquely dependent on androgens. Despite years of research on the relationship between androgens and prostate cancer, many questions remain as to the biological effects of androgens and other sex steroids during prostate cancer progression. This article reviews the clinical and basic research on the influence of sex steroids such as androgens, estrogens and progesterone within the prostate tumor microenvironment on the progression of prostate cancer. We review clinical studies to date evaluating serum sex steroids as prognostic biomarkers and discuss their respective biological effects within the prostate tumor microenvironment. We also review the link between genomic alterations and sex steroid levels within prostate tumors. Finally, we highlight the links between sex steroid levels and the function of the immune system within the tumor microenvironment. As the context of treatment of lethal prostate cancer evolves over time, an understanding of this underlying biology remains central to developing optimal treatment approaches.

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Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response

Abstract: We studied heterogeneities at a molecular level in bone metastasis samples obtained from men with castration-resistant prostate cancer. We found differences of possible importance for therapy selection in individual patients.

Cited by 88 publications

References 36 publications

Inhibition of the insulin-like growth factor-1 receptor potentiates acute effects of castration in a rat model for prostate cancer growth in bone

Inhibition of the insulin-like growth factor-1 receptor potentiates acute effects of castration in a rat model for prostate cancer growth in bone

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

Sex steroids in the tumor microenvironment and prostate cancer progression

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