Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth.

@article{Montgomery2008MaintenanceOI,
  title={Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth.},
  author={Robert B. Montgomery and Elahe A. Mostaghel and Robert L. Vessella and David L. Hess and Thomas F. Kalhorn and Celestia S. Higano and Lawrence D. True and Peter S. Nelson},
  journal={Cancer research},
  year={2008},
  volume={68 11},
  pages={
          4447-54
        }
}
Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription-PCR, we evaluated androgen levels and… 

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References

SHOWING 1-10 OF 58 REFERENCES
The Androgen Axis in Recurrent Prostate Cancer
TLDR
Novel therapies for recurrent prostate cancer should target androgen receptor directly and prevent the formation of androgens within prostate cancer tissue at levels sufficient to activate androgenceptor.
Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer.
TLDR
Optimal clinical efficacy will require testing of novel approaches targeting complete suppression of systemic and intracrine contributions to the prostatic androgen microenvironment.
Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer.
TLDR
Enhanced intracellular conversion of adrenal androgens to testosterone and dihydrotestosterone is a mechanism by which prostate cancer cells adapt to androgen deprivation and suggest new therapeutic targets.
Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer.
TLDR
It is demonstrated that AR is highly expressed in androgen-independent prostate cancer, suggesting that the AR signaling pathway is important in the progression of prostate cancer during endocrine treatment.
Androgen receptor gene amplification and protein expression in recurrent prostate cancer.
TLDR
AR amplification in recurrent prostate cancer results in higher levels of AR protein expression but does not affect survival, and no differences were found when comparing clinical characteristics between these groups.
Androgen-Independent Prostate Cancer Is a Heterogeneous Group of Diseases
TLDR
Metastatic hormone-refractory prostate cancer has a heterogeneous morphology, immunophenotype, and genotype, demonstrating that “metastatic disease” is a group of diseases even within the same patient.
Androgens, Adrenal Androgen Precursors, and Their Metabolism in Untreated Primary Tumors and Lymph Node Metastases of Human Prostatic Cancer
TLDR
Primary tumors and metastases of prostatic cancers not treated by endocrine manipulations retain their androgen receptor system and possess the same capacity to metabolize adrenal androgen precursors along the pathway to DHT as benign prostatic tissue.
Characterization of a novel androgen-sensitive, prostate-specific antigen-producing prostatic carcinoma xenograft: LuCaP 23.
  • W. Ellis, R. Vessella, P. Lange
  • Medicine, Biology
    Clinical cancer research : an official journal of the American Association for Cancer Research
  • 1996
TLDR
A new series of prostate cancer xenografts propagated in athymic mice, designated LuCaP 23, developed from prostate metastases harvested at autopsy shortly after death exhibits many phenotypic characteristics of clinical prostatic carcinoma, including androgen sensitivity.
Steroid 5α-Reductase Isozymes I and II in Recurrent Prostate Cancer
TLDR
It was shown that recurrent prostate cancer tissue has testosterone levels similar to androgen-stimulated benign prostate, whereas dihydrotestosterone levels were reduced 82% to 1.45 nmol/L, sufficient for androgen receptor activation, suggesting loss of 5α-reducing capability.
Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen.
TLDR
The results suggest that AR is transcriptionally active in recurrent CaP and can increase cell proliferation at the low circulating levels of androgen reported in castrated men.
...
...