Serum testosterone plays an important role in the metastatic ability of castration resistant prostate cancer.
OBJECTIVE
Prostate cells are dependent on androgens for growth and proliferation. Androgen deprivation therapy is the recommended treatment for advanced/metastatic prostate cancer. Under this therapy, prostate cancer will inevitably progress to castration resistant prostate cancer (CRPC). Despite putative castration resistance, testosterone might still play a crucial role in the progression of CRPC. The goal of this study was to determine the role of testosterone in the formation of metastases of CRPC in both in vitro and in vivo settings.


METHODS
In vitro, the effect of testosterone and the non-aromatizable androgen methyltrienolone on migration, invasion and proliferation of a castration-resistant prostate cancer rat cell line (Dunning R3327-MATLyLu) was assessed using a transwell assay and a sulforhodamine B assay and immunohistochemical detection of ki67. Androgen receptor status was determined using Western blot. In vivo, Copenhagen rats were divided in four groups (males, females, castrated males and females with testosterone suppletion) and inoculated with MATLyLu cells. Tumor size was assessed daily.


RESULTS
Testosterone increased cell migration and invasion in a concentration-dependent manner in vitro. Testosterone did not affect in vitro cell proliferation. No difference was shown between the effect of testosterone and methyltrienolone. In vivo, in groups with higher levels of circulating testosterone, more rats had (micro)metastases compared with groups with low levels of testosterone. No effect was observed on primary tumor size/growth.


CONCLUSIONS
Despite assumed castration resistance, progression of prostate cancer is still influenced by androgens. Therefore, continuous suppression of serum testosterone in patients who show disease progression during castration therapy is still warranted.
Department of Urology, VU University Medical Center, Room 4F027, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands.
Tim M
TM
van der Sluis
Irene V
IV
Bijnsdorp
John J L
JJ
Jacobs
Eric J H
EJ
Meuleman
Lawrence
L
Rozendaal
Albert A
AA
Geldof
R Jeroen A
RJ
van Moorselaar
André N
AN
Vis
D000728:Androgens / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D008297:Male; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology / Q000502:physiology*
D000728:Androgens; D011944:Receptors, Androgen; D013739:Testosterone