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  • Knuuttila, M. (author)

Castration Induces Up-Regulation of Intratumoral Androgen Biosynthesis and Androgen Receptor Expression in an Orthotopic VCaP Human Prostate Cancer Xenograft Model

  • Article/chapterEnglish2014

Publisher, publication year, extent ...

  • Elsevier BV,2014

Numbers

  • LIBRIS-ID:oai:gup.ub.gu.se/201905
  • https://gup.ub.gu.se/publication/201905URI
  • https://doi.org/10.1016/j.ajpath.2014.04.010DOI

Supplementary language notes

  • Language:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Androgens are key factors involved in the development and progression of prostate cancer (PCa), and PCa growth can be suppressed by androgen deprivation therapy. In a considerable proportion of men receiving androgen deprivation therapy, however, PCa progresses to castration-resistant PCa (CRPC), making the development of efficient therapies challenging. We used an orthotopic VCaP human PCa xenograft model to study cellular and molecular changes in tumors after androgen deprivation therapy (castration). Tumor growth was monitored through weekly serum prostate-specific antigen measurements, and mice with recurrent tumors after castration were randomized to treatment groups. Serum prostate-specific antigen concentrations showed significant correlation with tumor volume. Castration-resistant tumors retained concentrations of intratumoral androgen (androstenedione, testosterone, and 5 alpha-dihydrotestosterone) at Levels similar to tumors growing in intact hosts. Accordingly, castration induced up-regulation of enzymes involved in androgen synthesis (CYP17A1, AKR1C3, and HSD17B6), as well as expression of full-length androgen receptor (AR) and AR splice variants (AR-V1 and AR-V7). Furthermore, AR target gene expression was maintained in castration-resistant xenografts. The AR antagonists enzalutamide (MDV3100) and ARN-509 suppressed PSA production of castration-resistant tumors, confirming the androgen dependency of these tumors. Taken together, the findings demonstrate that our VCaP xenograft model exhibits the key characteristics of clinical CRPC and thus provides a valuable tool for identifying druggable targets and for testing therapeutic strategies targeting AR signaling in CRPC.

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Added entries (persons, corporate bodies, meetings, titles ...)

  • Yatkin, E. (author)
  • Kallio, J. (author)
  • Savolainen, S. (author)
  • Laajala, T. D. (author)
  • Aittokallio, T. (author)
  • Oksala, R. (author)
  • Hakkinen, M. (author)
  • Keski-Rahkonen, P. (author)
  • Auriola, S. (author)
  • Poutanen, MattiGothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition(Swepub:gu)xpouma (author)
  • Mäkelä, SariGothenburg University,Göteborgs universitet,Institutionen för medicin,Institute of Medicine (author)
  • Göteborgs universitetInstitutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition (creator_code:org_t)

Related titles

  • In:American Journal of Pathology: Elsevier BV184:8, s. 2163-21730002-9440

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