Sex steroids in the tumor microenvironment and prostate cancer progression

Boibessot, Clovis; Toren, Paul

doi:10.1530/erc-17-0493

Cited by 24 publications

(16 citation statements)

References 179 publications

(163 reference statements)

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“…Another concern is the prostate tumor microenvironment which is immunosuppressive and impairs natural killer cell function [ 146 ]. Also, studies performed mainly in non-tumor models suggest that local sex steroids may influence immune cells in the prostate microenvironment [ 147 ]. Nonetheless, in view of the strong survival advantage provided by therapies with immune checkpoint inhibitors in different cancer types, the potential benefits of immunotherapy are also being evaluated in prostate cancer [ 42 , 148 ].…”

Section: Treatment Options and Potential Novel Therapiesmentioning

confidence: 99%

Recent Advances in Prostate Cancer Treatment and Drug Discovery

Nevedomskaya

Baumgart

Haendler

2018

IJMS

197

158

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Novel drugs, drug sequences and combinations have improved the outcome of prostate cancer in recent years. The latest approvals include abiraterone acetate, enzalutamide and apalutamide which target androgen receptor (AR) signaling, radium-223 dichloride for reduction of bone metastases, sipuleucel-T immunotherapy and taxane-based chemotherapy. Adding abiraterone acetate to androgen deprivation therapy (ADT) in order to achieve complete androgen blockade has proven highly beneficial for treatment of locally advanced prostate cancer and metastatic hormone-sensitive prostate cancer (mHSPC). Also, ADT together with docetaxel treatment showed significant benefit in mHSPC. Ongoing clinical trials for different subgroups of prostate cancer patients include the evaluation of the second-generation AR antagonists enzalutamide, apalutamide and darolutamide, of inhibitors of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, of inhibitors of DNA damage response, of targeted alpha therapy and of prostate-specific membrane antigen (PSMA) targeting approaches. Advanced clinical studies with immune checkpoint inhibitors have shown limited benefits in prostate cancer and more trials are needed to demonstrate efficacy. The identification of improved, personalized treatments will be much supported by the major progress recently made in the molecular characterization of early- and late-stage prostate cancer using “omics” technologies. This has already led to novel classifications of prostate tumors based on gene expression profiles and mutation status, and should greatly help in the choice of novel targeted therapies best tailored to the needs of patients.

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Section: Treatment Options and Potential Novel Therapiesmentioning

confidence: 99%

Recent Advances in Prostate Cancer Treatment and Drug Discovery

Nevedomskaya

Baumgart

Haendler

2018

IJMS

197

158

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“…© 2018 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from AD and estrogens higher than between testosterone and estrogens, suggesting more direct effects of estrogens may explain their prognostic value (2,8). Interestingly, we found E 1 and E 2 both reached statistical significance, whereas serum testosterone did not.…”

Section: Discussionmentioning

confidence: 47%

“…Our prior study in men receiving continuous ADT postradiotherapy for recurrent prostate cancer demonstrated that serum testosterone levels within the first year of ADT initiation predict the time to development of CRPC, which occurred about 5 to 7 years later (1). Multiple studies indicate the importance of sex steroids such as androgens in the development of castrationresistant prostate cancer (2). Their accessibility for measurement and their association with the biology of resistance thus make serum sex steroids ideal candidates as prognostic or predictive biomarkers.…”

Section: Introductionmentioning

confidence: 99%

Serum Sex Steroids as Prognostic Biomarkers in Patients Receiving Androgen Deprivation Therapy for Recurrent Prostate Cancer: A Post Hoc Analysis of the PR.7 Trial

Toren

Hoffman

Ding

et al. 2018

Clinical Cancer Research

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Phenotypic biomarkers are a high priority for patients receiving androgen deprivation therapy (ADT) for prostate cancer given the increasing number of treatment options. This study evaluates serum sex steroids as prognostic biomarkers in men receiving ADT for recurrent prostate cancer. Retrospective cohort study of Canadian patients in the PR.7 trial (accrual 1999-2005) who received continuous ADT for biochemical recurrence postradiotherapy. Patients were excluded with follow-up <2 years or who received estrogens or corticosteroids. Kaplan-Meier and multivariable Cox regression analyses adjusted for baseline prognostic factors assessed time to castration-resistant prostate cancer (CRPC), prostate cancer survival, and overall survival according to tertile of sex steroid measured by mass spectrometry. Post-ADT initiation, we measured samples in 219 patients as well as two subsequent annual samples in a subset of 101 patients. Testosterone levels correlated with androstenedione (AD) and DHT, while DHT, AD, androsterone (AST), dehydroepiandrosterone (DHEA), and androstenediol (A5diol) were highly correlated to each other and negatively associated with age. Higher tertiles of estrone (E) and estradiol (E) were significantly associated with sooner time to CRPC. In patients with longitudinal samples, increases in serum DHEA and AST were significantly associated with sooner time to CRPC. Limitations include the number of events for some groups. Our data suggest the patient hormonal milieu has long-term prognostic value in men receiving ADT for recurrent prostate cancer, including increased levels of E and E and rising DHEA and AST levels, which predict a shorter time to CRPC. .

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“…This highlights the need to find novel approaches for the treatment of PCa.Estrogens and the most active form estradiol (E 2 ) are naturally produced from androgens through steroidogenesis and have been linked to PCa evolution, as reviewed recently by Dobbs et al 8 . Indeed, it has been demonstrated in murine models and in human patients that increased levels of estrogens were positively correlated with the aggressiveness of PCa 9-15 , and that estrogen synthesis increases in cancer cells during disease progression [16][17][18][19][20] . This modulation of cancer evolution is thought to be caused by the activity of the estrogen receptors ERα and ERβ, two transcription factors that are both essential for the normal development of the prostate 21-23 .…”

mentioning

confidence: 99%

A Systematic Study of the Impact of Estrogens and Selective Estrogen Receptor Modulators on Prostate Cancer Cell Proliferation

Lafront

Germain

Weidmann

et al. 2020

Sci Rep

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the estrogen signaling pathway has been reported to modulate prostate cancer (pca) progression through the activity of estrogen receptors α and β (eRα and eRβ). Given that selective estrogen receptor modulators (SERMs) are used to treat breast cancer, ERs have been proposed as attractive therapeutic targets in PCa. However, many inconsistencies regarding the expression of ERs and the efficacy of SERMs for PCa treatment exist, notably due to the use of ERβ antibodies lacking specificity and treatments with high SERM concentrations leading to off-target effects. To end this confusion, our objective was to study the impact of estrogenic and anti-estrogenic ligands in well-studied in vitro PCa models with appropriate controls, dosages, and ER subtype-specific antibodies. When using physiologically relevant concentrations of nine estrogenic/anti-estrogenic compounds, including five SERMs, we observed no significant modulation of PCa cell proliferation. Using RNA-seq and validated antibodies, we demonstrate that these PCa models do not express ERs. In contrast, RNA-seq from PCa samples from patients have detectable expression of ERα. Overall, our study reveals that commonly used pca models are inappropriate to study eRs and indicate that usage of alternative models is essential to properly assess the roles of the estrogen signaling pathway in pca.In the context of prostate cancer (PCa), the androgen receptor (AR) has many oncogenic functions such as increasing the proliferation and survival of cancer cells 1 . Furthermore, it is also now known that AR is an important regulator of metabolic pathways that sustain aberrant proliferation of PCa cells 2-6 . Accordingly, current hormonal treatments target this receptor with the objective of inhibiting its functions, with anti-androgens or androgen deprivation therapies 1,7 . However, despite a positive response to these treatments initially, progression of the disease to castration-resistant PCa (CRPC) is mostly inevitable 1,7 . This highlights the need to find novel approaches for the treatment of PCa.Estrogens and the most active form estradiol (E 2 ) are naturally produced from androgens through steroidogenesis and have been linked to PCa evolution, as reviewed recently by Dobbs et al. 8 . Indeed, it has been demonstrated in murine models and in human patients that increased levels of estrogens were positively correlated with the aggressiveness of PCa 9-15 , and that estrogen synthesis increases in cancer cells during disease progression [16][17][18][19][20] . This modulation of cancer evolution is thought to be caused by the activity of the estrogen receptors ERα and ERβ, two transcription factors that are both essential for the normal development of the prostate 21-23 . The actual model supports that ERα has oncogenic functions, as seen in murine models where its activation leads to an increased proliferation of cancer cells 24-26 ; on the other hand, ERβ is thought to act as a tumor suppressor since its loss promotes prostate hyperplasia and the development of the dise...

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Sex steroids in the tumor microenvironment and prostate cancer progression

Cited by 24 publications

References 179 publications

Recent Advances in Prostate Cancer Treatment and Drug Discovery

Recent Advances in Prostate Cancer Treatment and Drug Discovery

Serum Sex Steroids as Prognostic Biomarkers in Patients Receiving Androgen Deprivation Therapy for Recurrent Prostate Cancer: A Post Hoc Analysis of the PR.7 Trial

A Systematic Study of the Impact of Estrogens and Selective Estrogen Receptor Modulators on Prostate Cancer Cell Proliferation

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